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Molecular oxygen in living cells is distributed and consumed inhomogeneously, depending on the activity of each organelle. Therefore, tractable methods that can be used to monitor the oxygen status in each organelle are needed to understand cellular function. Here we report the design of a new oxygen-sensing probe for use in the cell nucleus. We prepared "Ru-Hoechsts", each consisting of a phosphorescent ruthenium complex linked to a Hoechst 33258 moiety, and characterized their properties as oxygen sensors. The Hoechst unit shows strong DNA-binding properties in the nucleus, and the ruthenium complex shows oxygen-dependent phosphorescence. Thus, Ru-Hoechsts accumulated in the cell nucleus and showed oxygen-dependent signals that could be monitored. Of the Ru-Hoechsts prepared in this study, Ru-Hoechst b, in which the ruthenium complex and the Hoechst unit were linked through a hexyl chain, showed the most suitable properties for monitoring the oxygen status. Ru-Hoechsts are probes with high potential for visualizing oxygen fluctuations in the nucleus.

Magnetic resonance imaging (MRI) has become a prominent non- or low-invasive imaging technique, providing high-resolution, three-dimensional images as well as physiological information about tissues. Low-molecular-weight Gd-MRI contrast agents (CAs), such as Gd-DTPA (DTPA: diethylenetriaminepentaacetic acid), are commonly used in the clinical diagnosis, while macromolecular Gd-MRI CAs have several advantages over low-molecular-weight Gd-MRI CAs, which help minimize the dose of CAs and the risk of side effects. Accordingly, we developed chiral dendrimer Gd-MRI CAs, which showed high r1 values. The association constant values (Ka ) of S-isomeric dendrimer CAs to bovine serum albumin (BSA) were higher than those of R-isomeric dendrimer CAs. Besides, based on a totally new concept, we developed 13 C/15 N-enriched multiple-resonance NMR/MRI probes, which realized highly selective observation of the probes and analysis of metabolic reactions of interest. This account summarizes our recent study on developing both chiral dendrimer Gd-MRI CAs, and self-traceable 13 C/15 N-enriched phosphorylcholine polymer probes for early detection of tumors.

The synthesis of new functional organic molecules that cannot be obtained by a simple combination of conventional synthetic methods is a challenging subject in organic, organometallic, and industrial chemistry as well as in atom-efficient and environmental organic synthesis. Among the various possibilities that have been considered, the catalytic cleavage and reconstruction of the C–C bond has opened the door to a new branch of synthetic organic chemistry. This microreview summarizes progress on the ruthenium- and rhodium-catalyzed strain-driven cleavage of the C–C bond, the methods of which were mostly developed by the author. The direct oxidative addition of 2,5-norbornadienes, cyclopropenones, cyclobutenones, and cyclobutenediones, and to catalytically active metal species followed by the construction of the C–C bond has been used for the preparation of new organic molecules.

In an attempt to monitor μm-level trace constituents, we applied here (1)H-{(13)C-(15)N} triple-resonance nuclear magnetic resonance (NMR) to (13)C/(15)N-enriched l-Dopa as the inevitable precursor of the neurotransmitter dopamine in the brain. The perfect selectivity (to render endogenous components silent) and μm-level sensitivity (700 MHz spectrometer equipped with a cryogenic probe) of triple-resonance allowed the unambiguous and quantitative metabolic and pharmacokinetic analyses of administered l-Dopa/dopamine in the brain and liver of mice. The level of dopamine generated in the brain (within the range 7-76 μm, which covers the typical stimulated level of ∼30 μm) could be clearly monitored ex vivo, but was slightly short of the detection limit of a 7 T MR machine for small animals. This work suggests that μm-level trace constituents are potential targets of ex vivo monitoring as long as they contain N atom(s) and their appropriate (13)C/(15)N-enrichment is synthetically accessible.

The synthesis of new functional organic molecules that cannot be obtained by a simple combination of conventional synthetic methods is a challenging subject in organic, organometallic, and industrial chemistry as well as in atom-efficient and environmental organic synthesis. Among the various possibilities that have been considered, the catalytic cleavage and reconstruction of the C–C bond has opened the door to a new branch of synthetic organic chemistry. This microreview summarizes progress on the ruthenium- and rhodium-catalyzed strain-driven cleavage of the C–C bond, the methods of which were mostly developed by the author. The direct oxidative addition of 2,5-norbornadienes, cyclopropenones, cyclobutenones, and cyclobutenediones, and to catalytically active metal species followed by the construction of the C–C bond has been used for the preparation of new organic molecules.

The chemistry of a novel zerovalent Ru complex, Ru(η6-cot)(η2-dmfm)2 (1) (cot=1,3,5-cyclooctatriene; dmfm=dimethyl fumarate), is reviewed with a focus on its reactivity toward phosphines, amines, and H2O, as well as arenes and p-quinones. A variety of novel zerovalent Ru complexes were synthesized from Ru(η6-cot)(η2-dmfm)2 (1), and it was shown that the complexes preferably bear both electron-donating and -accepting ligands simultaneously to exhibit thermodynamic stability. The first isolable zerovalent Ru aqua complexes were successfully prepared, and in these complexes, the generation of a chiral center on the O atom of the coordinated H2O was disclosed. In addition, the characteristic catalytic activity of 1 in organic synthesis was considered by reviewing recently developed novel reactions: (i) dimerization of 2,5-norbornadiene to pentacyclo[6.6.0.02,6.03,13.010,14]tetradeca-4,11-diene (PCTD), (ii) intramolecular hydroamination of aminoalkynes to cyclic imines, (iii) formal [4+2] cycloaddition of alkynes with dmfm to trans-4-cyclohexene-1,2-dicarboxylates, and (iv) co-dimerization of dihydrofurans with α,β-unsaturated esters to 2-alkylidenetetrahydrofurans. The products obtained here are expected to be used as novel functional organic monomers. © 2006 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 6: 107–116; 2006: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20076

This paper proposes an evolutionary approach for discovering difference in the usage of words to facilitate collaboration among people. In general, different people seem to have different ways of conception and thus can have different concepts even on the same thing. When people try to communicate their concepts with words, such difference in the meaning and usage can lead to misunderstanding in communication, which can hinder their collaboration. In our approach each granule of knowledge in classification from users is structured into a decision tree so that difference in the usage of words can be discovered as difference in the structure of decision trees. By treating each granule of classification knowledge (i.e., decision tree) as an individual in Genetic Algorithm (GA), evolution is carried out with respect to both classification efficiency of each individual and diversity as a population so that the granule for classification is gradually evolved with diverse structure. Experiments were carried out on motor diagnosis cases with artificially encoded difference in the usage of words and the result shows the effectiveness of the proposed evolutionary approach.

The novel title catalyst system enables a simple, selective, and practical synthesis of indoles from aminoalcohols.

Low-valent ruthenium complexes often show intriguing and characteristic catalytic activity for novel organic transformations with high atom efficiency. The design and synthesis of novel low-valent ...

Indole derivatives were readily prepared from the reductive N-heterocyclization of o-nitrostyrene derivatives in the presence of a catalytic amount of PdCl2(PPh3)2–SnCl2 under carbon monoxide pressure (20 kg/cm2) at 100 °C for 16 h. With o-nitrostilbene, 2-phenylindole was obtained in 75% yield.

Allylamines react with acrylic compounds in the presence of Ru(cod)(cot) catalyst to give cyclobutane-β-amino acid derivatives in high yield (up to 85%); cod = cycloocta-1,5-diene, cot = cycloocta-1,3,5-triene.

Ru(cod)(cot) catalyzes highly selective codimerization of 1,3-dienes with acrylic compounds and first linear coupling reaction of allylic carbonates with the acrylic amide to give 3,5-dienoic acid derivatives; cod = cycloocta-1,5-diene, cot = cycloocta-1,3,5-triene.

Allylic carbonates except for allyl methyl carbonate reacted with carbonucleophiles such as ethyl acetoacetate in the presence of a catalytic amount of Ru(cod)(cot) [cod = cycloocta-1,5-diene, cot = cycloocta-1,3,5-triene] in N -methylpiperidine at 80°C to give the corresponding monoallylated carbonucleophiles in high yields with high regioselectivity. The regioselectivity was quite different from that in the palladium-catalyzed reactions. The allylation of carbonucleophiles using allyl methyl carbonate selectively gave the diallylated carbonucleophiles in high yields.

Ruthenium complex-catalyzed N-heterocyclization of 2-aminopyridines with vicinal-diols offers a novel synthetic method for various imidazo[1,2-a]pyridines. For example, the reaction of 2-amino-4-methylpyridine with 1,2-cyclohexanediol in the presence of a catalytic amount of RuCl2(PPh3)3 under reflux in diglyme for 24 h afforded 2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazole in 74% yield.

Co2(CO)8-catalyzed ring-opening carbonylation of oxiranes and oxetane smoothly proceeds with high regioselectivity under 1 atm of carbon monoxide at room temperature to give the corresponding β- and γ-siloxy amides in high yields, respectively. [(R3Si)2NR1R2]+[Co(CO)4]− is thought to be an active catalyst species and directs the high regioselectivity of the carbonylation.

The dichlorobis(triphenylphosphine)palladium (PdCl 2 (PPh 3 ) 1 )-tin(II) chloride (SnCl 2 ) system shows high catalytic activity for the reductive N-heterocyclization of various 2-nitrostyrene and N-(2-nitrobenzylidene)amine derivatives when employed at 100 o C for 16 h under 20 kg cm -2 of initial carbon monoxide pressure, to give the corresponding indole and 2H-indazole derivatives in good yield. For example, 2-phenylindole was obtained in 75% yield from the reductive N-heterocyclization of 2-nitrostilbene

Ru{sub 3}(CO){sub 12}/1,10-phenanthroline catalyzes the carbonylation of allylic alkyl carbonates to give esters. The authors studied this reaction with various substrates at different CO pressures.

A combination of the palladium complex PdCl2(PPh3)2 with MoCl5 shows a high catalytic activity for the intermolecular reductive N-heterocyclization of 2-nitrobenzaldehyde or 2-nitrophenyl ketones with formamide to give the corresponding quinazoline derivatives in moderate yields. For example, in the reaction of 2-nitrobenzaldehyde with formamide, quinazoline was obtained in 46% yield. We assume that the present reaction proceeds via an active nitrene intermediate which would be generated by selective deoxygenation of nitro group by carbon monoxide.

The following ruthenium-catalyzed novel transformations of alkyl formates have been developed: (1) selective decarbonylation of alkyl formates to the corresponding alcohols; (2) alkylation of arenes and alkenes using alkyl formates as an alkylating reagent via decarboxylation. Also the ruthenium-catalyzed addition of alcohols to alkenes has been developed as an appendant reaction, providing an effective method for the protection of alcohols.

Heteroaromatic amines were N-alkylated with primary alcohols at 150−200 °C in the presence of a catalytic amount of various ruthenium complexes to give the corresponding monoalkylated and dialkylated amines in good to high yields. For example, 2-aminopyridine reacted with an excess of ethanol at 180 °C for 20 h in the presence of dichlorotris(triphenylphosphine)ruthenium [RuCl2(PPh3)3] to give 2-(ethylamino)pyridine (1) and 2-(diethylamino)pyridine (2) in 9% and 70% yields, respectively. On the other hand, when (η4-1,5-cyclooctadiene)(η6-1,3,5-cyclooctatriene)ruthenium [Ru(cod)(cot)] was used as a catalyst, even in the presence of excess ethanol, 1 was obtained in 85% yield with high selectivity. The addition of tertiary phosphines and phosphites to Ru(cod)(cot) increased the yield of the dialkylated amine.

Various N,N‘-disubstituted and trisubstituted ureas were obtained in high yields by the ruthenium-complex-catalyzed dehydrogenation of N-substituted formamides and amines under reflux in mesitylene for 12 h under an argon atmosphere. From formanilide (1a) and aniline (2a), N,N ‘-diphenylurea (3a) was obtained in 92% yield. During this reaction, a stoichiometric amount of gaseous hydrogen was spontaneously evolved; thus, the addition of a hydrogen acceptor was not required. Formamide itself, i.e., HCONH2 (4), can also be used as a versatile carbonyl source. From HCONH2 (4) and primary amines, the corresponding N,N‘-disubstituted ureas were obtained in high yields together with the evolution of hydrogen and ammonia. To identify a catalytically active species, the stoichiometric reaction of RuCl2(PPh3)3 with formanilide (1a) was carried out in CH2Cl2 at room temperature to give a novel oxygen-atom-bridged dinuclear ruthenium complex, Ru2(μ-Cl)2Cl2(μ-PhNHCHO-O,O)(PPh3)4 (5), in 87% yield. Complex 5 showed a h...

Unsymmetrically substituted hydroquinones were obtained in high yields by the novel ruthenium-catalyzed cross-carbonylation of alkynes and 2-norbornenes. For example, treatment of 4-octyne and 2-norbornene with 2 mol % Ru3(CO)12 in N-methylpiperidine under 60 atm of carbon monoxide at 140 °C for 20 h gave the corresponding hydroquinone, 4,5-dipropyltricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-3,6-diol, in 85% yield. The reaction apparently involves a maleoylruthenium intermediate which is generated by the reaction of an alkyne and two molecules of carbon monoxide on the ruthenium.

A novel ruthenium catalyst system of [PPN][Ru3H(CO)11]/PCy3 [PPN = bis(triphenylphosphine)iminium, Cy = cyclohexyl] for the direct hydroamidation and hydroesterification of alkenes with formamides and alkyl formates has been developed. These addition reactions proceeded smoothly under an argon atmosphere, and carbon monoxide is not needed to suppress decarbonylation of formyl compounds or to maintain the catalytic activity.

Low-valent ruthenium complexes with a p-acidic ligand, such as Ru(h 6 -cot)(dmfm)2 [cot 1,3,5-cyclooctatriene, dmfm dimethyl fumarate] and Ru3(CO)12, showed high catalytic activity for the intramolecular hydroamination of aminoalkynes. The reaction is highly regioselective, in which a nitrogen atom is selectively attached to an internal carbon of alkynes to give five-, six-, and seven-membered nitrogen heterocycles as well as indoles in good to high yields. © 2001 Elsevier Science B.V. All rights reserved.

The development of efficient methods for the selective formation and cleavage of C-C bonds leading to construction of new carbon skeletons catalyzed by transition-metal complexes is a central and challenging subject of modern organic synthesis. Among the various transition-metal complexes, we have recently focused our attention on novel catalytic activity of low valent ruthenium complexes, since ruthenium complexes often show interesting catalytic activity and product selectivity, which are quite different from those with palladium and other transition-metal complexes. Here, we report our recent results of novel catalytic performance of ruthenium complexes for organic synthesis, which include (1) ruthenium-catalyzed novel C-C bond formation using an ambiphilic reactivity of π-allylruthenium complexes as well as the selective cleavage of C-C bonds via β-allyl elimination, (2) ruthenium-catalyzed novel methods for preparation of cyclopentenones via ruthenacycle intermediates, and (3) ruthenium-catalyzed novel transformation of sulfur-containing compounds, which enables simple, selective and general syntheses of vicinal-dithioethers and allylic sulfides.

Novel alkenylene-bridged oligosilsesquioxanes composed of half-caged structures with 16- or 17-membered rings as well as a titanium-containing molecule with a twisted 21-membered macrocycle have been synthesized by ruthenium or rhodium-catalyzed ring-closing reactions of silsesquioxanes with bis(allyldimethylsilyl) groups.

[RuCl2(CO)3]2/dppp is shown to be a highly effective catalyst system for the first intramolecular oxidative amination of a variety of aminoalkenes when it is used concomitantly with K2CO3 and allyl acetate in N-methylpiperidine, to give the corresponding cyclic imines and indoles in excellent yields. For example, the reaction of 2,2-diphenyl-4-pentenyl-1-amine performed in the presence of 2 mol % of [RuCl2(CO)3]2, 4 mol % of dppp, K2CO3, and allyl acetate in N-methylpiperidine at 140 °C for 8 h gives 4,4-diphenyl-2-methyl-1-pyrroline in quantitative (>99%) yield.

Novel catalytic reactions via ruthena- or rhodacyclic intermediates developed by our research group are reviewed. We initiate our study from (1) ruthenium-catalyzed [2 + 2] cycloaddition of alkynes with alkenes, followed by developing (2) intramolecular Pauson-Khand-type reaction of 1, 6-enynes, (3) hydroquinone synthesis, (4) codimerization of styrenes with ethylene . Another approach to construct novel functional monomers, such as cyclopentenones, pyranopyrandiones, and phenols, involves cleavage of carbon-carbon bonds in cyclobutenediones, cyclopropenones, and cyclobutenones. All reactions proceed with high atom-efficiency via ruthena- or rhodacyclicintermediates. In addition, rhodium-catalyzed [2 + 2 + 2] cocyclization of alkynes with isocyanates as well as novel ruthenium-catalyzed [2 + 2 + 1] cocyclization of alkynes, isocyanates, and carbon monoxide have been disclosed.

Novel catalytic reactions via ruthena- or rhodacyclic intermediates have been developed by our research group. We initiated our study from (1) ruthenium-catalyzed [2+2] cycloaddition of alkynes with alkenes, followed by developing (2) intramolecular Pauson-Khand-type reaction of 1,6-enynes, (3) hydroquinone synthesis, (4) cyclocotrimerization reactions, and (5) codimerization of styrenes with ethylene. Another approach to construct novel functional monomers, such as cyclopentenones, pyranopyrandiones, and substituted phenols, involves cleavage of carbon-carbon bonds in cyclobutenediones, cyclopropenones, and cyclobutenones. All reactions may proceed with high atom-efficiency via ruthena- or rhodacyclic intermediates, represented by ruthenacyclopentene, (maleoyl)ruthenium, and rhodacyclopentenone intermediates. In addition, rhodium-catalyzed [2+2+2] cocyclization of alkynes with isocyanates as well as novel ruthenium-catalyzed [2+2+1] cocyclization of alkynes, isocyanates, and carbon monoxide have been disclosed. 1 Introduction 2 Ruthenium-Catalyzed Cycloaddition of Alkynes with Alkenes 2.1 [2+2] Cycloaddition of Alkynes with 2-Norbornenes 2.2 Intramolecular Pauson-Khand-Type Reaction of Enynes with Carbon Monoxide 2.3 Cross-Carbonylation of Alkynes with 2-Norbornenes or Electron-Deficient Alkenes to Hydroquinones 2.4 Synthesis of Benzenepolycarboxylates by Cross-Benzannulation of Acetylenedicarboxylates with Allylic Compounds 2.5 [2+2+2] Cocyclization of Three Different Alkynes 2.6 Regio- and Stereoselective Dimerization of Styrenes and Linear Codimerization of Styrenes with Ethylene 3 Ruthenium- and Rhodium-Catalyzed Cleavage of C-C Bonds Leading to Reconstructive Synthesis of Novel Functional Monomers 3.1 Ru-Catalyzed Selective Monodecarbonylative Coupling of Cyclobutenediones with Alkenes to Cyclopentenones 3.2 Ru-Catalyzed Carbonylative Dimerization of Cyclopropenones and Cross-Carbonylation of Cyclopropenones with Alkynes to Pyranopyrandiones 3.3 Ru- and Rh-Catalyzed Ring-Opening Reactions of Cyclobutenones 3.4 Rh-Catalyzed Direct Synthesis of Substituted Phenols from Cyclobutenones and Electron-Deficient Alkenes 4 Ruthenium- and Rhodium-Catalyzed Cocyclization of Alkynes and Isocyanates 4.1 Rh-Catalyzed Cyclocotrimerization of Alkynes and Isocyanates to 2-Pyridones or Pyrimidine-2,4-diones 4.2 Ru-Catalyzed [2+2+1] Cocyclization of Alkynes, Isocyanates, and Carbon Monoxide 5 Summary

A novel zerovalent ruthenium complex with a π-acidic ligand, Ru(η6-cyclooctatriene)(η2-dimethyl fumarate)2 (1), was prepared from Ru(η4-cyclooctadiene)(η6-cyclooctatriene) [Ru(cod)(cot)]. Complex 1 or Ru(cod)(cot) catalyzes various new carbon-carbon bond-forming reactions that include the [2 + 2] cycloaddition of alkenes and alkynes via ruthenacycles, the creation of a new hydrocarbon, pentacyclo[6.6.0.02,6.03,13.010,14]tetradeca-4,11-diene [PCTD], by dimerization of 2,5-norbornadiene via C-C bond cleavage, and the codimerization of alkynes and/or alkenes. Complex 1 was shown to be an excellent mother complex for various zerovalent ruthenium complexes. Complex 1 reacts with amines, phosphines or water to give new zerovalent ruthenium complexes with the ligands. The resulting aqua complexes have a water ligand with an oxygen atom that is a chiral center, i.e., ruthenium complexes with a ‘chiral water’ ligand were prepared and fully characterized.

Ruthenium complex-catalyzed reactions often require highly qualified tuning of reaction conditions with substrates to attain high yield and selectivity of the products. In this review, our strategies for achieving characteristic ruthenium complex-catalyzed co-oligomerization of different alkenes are disclosed: 1) The codimerization of 2-norbomenes with acrylic compounds by new ruthenium catalyst systems of RuCl 3 (tpy)/Zn [tpy = 2,2':6',2"-terpyridine] or [RuCl 2 (η 6 -C 6 H 6 )] 2 /Zn in alcohols, 2) A novel synthesis of 2-alkylidenetetrahydrofurans from dihydrofurans and acrylates by zerovalent ruthenium catalysts, such as Ru(η 4 -cod)(η 6 -cot) [cod = 1,5-cyclooctadiene, cot = 1,3,5-cyclooctatriene] and Ru( η 6 -cot)( η 2 -dmfm) 2 [dmfm = dimethyl fumarate], 3) Regio- and stereoselective synthesis of enamides by Ru(η 6 -cot)(η 2 -dmfm) 2 -catalyzed codimerization of N-vinylamides with alkenes, and 4) Unusual head-to-head dimerization of styrenes and linear codimerization of styrenes with ethylene by Ru(η 6 -cot)(η 2 -dmfm) 2 catalyst in the presence of primary alcohols.

A novel rhodium-catalyzed synthesis of substituted phenols by the ring-opening reaction of cyclobutenones with alkynes as well as electron-deficient alkenes has been developed. Both reactions involve C–C bond cleavage of cyclobutenones, and an (η4-vinylketene)rhodium complex rather than a rhodacyclopentenone is considered to be a key intermediate.