Synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes by cross-coupling induced by transition metals - formation of C-C bonds.

The synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs), by forming a C-C bond, can be achieved by cross-coupling reactions using transition metal catalysts. Two main strategies are described to access these 1,3-disubstituted BCPs, either from nucleophilic BCPs or electrophilic BCPs. Mechanisms are included where relevant.

Heterogeneous Single-Atom Zinc on Nitrogen-Doped Carbon Catalyzed Electrochemical Allylation of Imines.

Organometallic reagents are effective for carbon-carbon bond formation; however, consumption of stoichiometric amounts of metals is problematic. We developed electrochemical allylation reactions of imines catalyzed by nitrogen-doped carbon-supported single-atom zinc, which were fixed on a cathode to afford a range of homoallylic amines efficiently. The system could suppress generation of metallic waste, and the catalyst electrode showed advantages over bulk zinc in terms of activity and robustness. An electrochemical flow reaction was also successfully performed to produce the homoallylic amine continuously with minimum amounts of waste.

[Two Cases of Advanced Recurrent Breast Cancer with Severe Heart Failure Caused By Anthracycline].

Case 1: A 48-year-old woman, had right breast cancer with multiple liver metastases. Seven courses of paclitaxel plus bevacizumab were administered, but due to disease progression, 12 courses of FEC 75(total epirubicin 900 mg/m2)were administered. 2 months after the last FEC administration, the patient developed heart failure and died about 3 months later. Case 2: A 58-year-old woman, was on endocrine therapy after surgery for left breast cancer. Recurrence of lung and bone metastases were appeared 5 years after surgery, 10 courses of FEC 75(total epirubicin 750 mg/m2)were administered due to disease progression. Eight months after the last administration of FEC, the patient developed heart failure and died about 8 months later. Anthracycline induced cardiotoxicity is irreversible and has a severe course. Therefore, anthracycline should be administered with caution.

Development of Metal-Free, Trifluoromethanesulfonic Acid-Immobilized Nitrogen-Doped Carbon Catalysts for Povarov Reactions.

A metal-free, heterogeneous acid catalyst, trifluoromethanesulfonic acid-immobilized nitrogen-doped carbon catalyst, was developed for Povarov reactions. This catalyst exhibited excellent catalytic activity, achieving high turnover frequency (>400 h-1) and good cis-selectivity of the desired 1,2,3,4-tetrahydroquinoline products. The reaction had a broad substrate scope, and the multicomponent Povarov reaction proceeded smoothly with readily accessible aldehydes and anilines. The heterogeneity and reusability of this catalytic system were confirmed. The catalyst was characterized by spectroscopic and microscopic analysis studies.

Effect of Activation Methods of Molecular Sieves on Ketimine Synthesis.

Although the use of molecular sieves for imine synthesis is a common protocol, there have been no comprehensive studies on heat-drying methods. This can be crucial for reproducibility. It was found that molecular sieve 5A dried at 160 °C for 5 h under vacuum efficiently promoted the condensation of various ketones and amines to afford even relatively bulky ketimines. Several control experiments and analyses revealed that only a small amount of Brønsted acid sites was important for the activity, rather than dehydration ability. Other types of molecular sieves could be utilized for the reaction after treatment with water followed by heat drying. A continuous-flow acetalization reaction of alcohols using the activated molecular sieve 5A was also demonstrated.

Nitrogen-Doped Carbon-Incarcerated Zinc Electrodes as Heterogeneous Catalysts for Electrochemical Allylation of Carbonyl Compounds.

Electrochemical allylation reactions of carbonyl compounds using cathodes prepared from nitrogen-doped carbon (NDC)-incarcerated zinc catalysts have been developed. A range of aldehydes and ketones afforded the desired allylic alcohols in high yields with <10 mol % zinc leaching, and the heterogeneous nature of the active species was suggested. Compared with bulk zinc electrodes, NDC-stabilized zinc nanoparticle species were compatible with a broader range of heteroaromatic substrates and enabled the use of an undivided cell.

Development of Trifluoromethanesulfonic Acid-Immobilized Nitrogen-Doped Carbon-Incarcerated Niobia Nanoparticle Catalysts for Friedel-Crafts Acylation.

Heterogeneous trifluoromethanesulfonic acid-immobilized nitrogen-doped carbon-incarcerated niobia nanoparticle catalysts (NCI-Nb-TfOH) that show excellent catalytic performance with low niobium loading (1 mol %) in Friedel-Crafts acylation have been developed. These catalysts exhibit higher activity and higher tolerance to catalytic poisons compared with the previously reported TfOH-treated NCI-Ti catalysts, leading to a broader substrate scope. The catalysts were characterized via spectroscopic and microscopic studies.

Nitrogen-Doped Carbon Enables Heterogeneous Asymmetric Insertion of Carbenoids into Amines Catalyzed by Rhodium Nanoparticles.

Development of stable heterogeneous catalyst systems is a crucial subject to achieve sustainable society. Though metal nanoparticles are robust species, the study of asymmetric catalysis by them has been restricted because methods to activate metal nanoparticles without causing metal leaching were limited. We developed Rh nanoparticle catalysts (NCI-Rh) supported on nitrogen-doped carbon as a solid ligand to interact with metals for asymmetric insertion of carbenoids into N-H bonds cocatalyzed by chiral phosphoric acid. Nitrogen dopants played a crucial role in both catalytic activity and enantioselectivity while almost no catalysis was observed with Rh nanoparticles immobilized on supports without nitrogen dopants. Various types of chiral α-amino acid derivatives were synthesized in high yields with high enantioselectivities and NCI-Rh could be reused in seven runs. Furthermore, we demonstrated the corresponding continuous-flow reaction using a column packed with NCI-Rh. The desired product was obtained efficiently for over 90 h through the reactivation of NCI-Rh and the chiral source could be recovered.

Well-Dispersed Trifluoromethanesulfonic Acid-Treated Metal Oxide Nanoparticles Immobilized on Nitrogen-Doped Carbon as Catalysts for Friedel-Crafts Acylation.

Although strong acid-treated metal oxides are useful heterogeneous superacid catalysts for various organic transformations, they usually have a limited density of acidic sites due to their low surface areas. Herein, heterogeneous trifluoromethanesulfonic acid immobilized nitrogen-doped carbon-incarcerated titanium nanoparticle (NP) catalysts have been developed that are composed of well-dispersed, small Ti NPs (ca 7 nm) that are otherwise difficult to achieve using acid-treated metal oxides. The catalysts showed high activity for Friedel-Crafts acylation with low titanium loading (2 mol%, <1 mg of metal for 1 mmol of substrate). A range of microscopic, spectroscopic and physicochemical studies revealed that the nitrogen-doped carbon immobilized the trifluoromethanesulfonic acid and that the addition of metals further changed the nature of the acidic species and enhanced catalytic activity.

Chiral Rhodium Nanoparticle-Catalyzed Asymmetric Arylation Reactions.

The development of heterogeneous catalyst systems for enantioselective reactions is an important subject in modern chemistry as they can be easily separated from products and potentially reused; this is particularly favorable in achieving a more sustainable society. Whereas numerous homogeneous chiral small molecule catalysts have been developed to date, there are only limited examples of heterogeneous ones that maintain high activity and have a long lifetime. On the other hand, metal nanoparticle catalysts have attracted much attention in organic chemistry due to their robustness and ease of deposition on solid supports. Given these advantages, metal nanoparticles modified with chiral ligands, defined as "chiral metal nanoparticles", would work efficiently in asymmetric catalysis. Although asymmetric hydrogenation catalyzed by chiral metal nanoparticles was pioneered in the late twentieth century, the application of chiral metal nanoparticle catalysis for asymmetric C-C bond-forming reactions that give a high level of enantioselectivity with wide substrate scope was very limited.This Account summarizes recent investigations that we have carried out in the field of chiral rhodium (Rh) nanoparticle catalysis for asymmetric arylation reactions. We initially utilized composites of polystyrene-based copolymers with cross-linking moieties and carbon black incarcerated Rh nanoparticle catalysts for the asymmetric 1,4-addition of arylboronic acids to enones. We found that chiral diene-modified heterogeneous Rh nanoparticles were effective in these reactions, with excellent enantioselectivities and without causing metal leaching, and that bimetallic Rh/Ag nanoparticle catalysts enhanced activity. The catalyst could be easily recovered and reused more than ten times, thus demonstrating the robustness of metal nanoparticle catalysts.We then developed a secondary amide-substituted chiral diene modifier designed as a bifunctional ligand that possesses a metal biding site and a NH group to activate a substrate through hydrogen bonding. This chiral diene was very effective for the Rh/Ag nanoparticle-catalyzed asymmetric arylation of various electron-deficient olefins, including enones, unsaturated esters, unsaturated amides and nitroolefins, and imines to afford the corresponding products in excellent yields and with outstanding enantioselectivities. The system was also applicable for the synthesis of intermediates of various useful compounds. Furthermore, the compatibility of chiral Rh nanoparticles with other catalysts was confirmed, enabling the development of tandem reaction systems and cooperative catalyst systems.The nature of the active species was investigated. Several characteristic features of the heterogeneous nanoparticle systems that were completely different from those of the corresponding homogeneous metal complex systems were found.

Earth-Abundant Bimetallic Nanoparticle Catalysts for Aerobic Ammoxidation of Alcohols to Nitriles.

Heterogeneous nitrogen-doped carbon-incarcerated iron/copper bimetallic nanoparticle (NP) catalysts prepared from nitrogen-containing polymers were developed. These catalysts showed activity higher than that of the corresponding monometallic NPs for aerobic ammoxidation of alcohols to nitriles. The important procedure for high activity in the catalyst preparation was found to be a simultaneous reduction of two metal salts.

Heterogeneous Rh and Rh/Ag bimetallic nanoparticle catalysts immobilized on chiral polymers.

The development of heterogeneous chiral catalysts has lagged far behind that of homogeneous chiral catalysts in spite of their advantages, such as environmental friendliness for a sustainable society. We describe herein novel heterogeneous chiral Rh and Rh/Ag bimetallic nanoparticle catalysts consisting of polystyrene-based polymers with chiral diene moieties. The catalysts enable high-to-excellent yields and enantioselectivities to be obtained in asymmetric 1,4-addition reactions of arylboronic acids with α,ß-unsaturated carbonyl compounds such as ketones, esters, and amides, and in other asymmetric reactions. The catalysts could be readily recovered by simple filtration and reused; they could also be applied to continuous-flow synthesis. We also discuss the nature of possible reaction species based on XPS analysis.

Polysilane-Immobilized Rh-Pt Bimetallic Nanoparticles as Powerful Arene Hydrogenation Catalysts: Synthesis, Reactions under Batch and Flow Conditions and Reaction Mechanism.

Hydrogenation of arenes is an important reaction not only for hydrogen storage and transport but also for the synthesis of functional molecules such as pharmaceuticals and biologically active compounds. Here, we describe the development of heterogeneous Rh-Pt bimetallic nanoparticle catalysts for the hydrogenation of arenes with inexpensive polysilane as support. The catalysts could be used in both batch and continuous-flow systems with high performance under mild conditions and showed wide substrate generality. In the continuous-flow system, the product could be obtained by simply passing the substrate and 1 atm H2 through a column packed with the catalyst. Remarkably, much higher catalytic performance was observed in the flow system than in the batch system, and extremely strong durability under continuous-flow conditions was demonstrated (>50 days continuous run; turnover number >3.4 × 105). Furthermore, details of the reaction mechanisms and the origin of different kinetics in batch and flow were studied, and the obtained knowledge was applied to develop completely selective arene hydrogenation of compounds containing two aromatic rings toward the synthesis of an active pharmaceutical ingredient.

Development of N-Doped Carbon-Supported Cobalt/Copper Bimetallic Nanoparticle Catalysts for Aerobic Oxidative Esterifications Based on Polymer Incarceration Methods.

Heterogeneous nitrogen-doped carbon-incarcerated cobalt/copper bimetallic nanoparticle (NP) catalysts, prepared from nitrogen-containing polymers, were developed, and an efficient catalytic process for aerobic oxidative esterification was achieved in the presence of a low loading (1 mol %) of catalyst that could be reused and easily reactivated. This protocol enabled diverse conditions for the bimetallic NP formation step to be screened, and significant rate acceleration by inclusion of a copper dopant was discovered. The catalytic activity of the bimetallic Co/Cu catalysts is much higher than that for cobalt catalysts reported to date and is even comparable with noble-metal NP catalysts.

Catalytic enantioselective aldol reactions.

Recent developments in catalytic asymmetric aldol reactions have been summarized. Enantioselective aldol reactions are important methods to synthesize ß-hydroxy carbonyl compounds in optical pure form, and as such, numerous successful chiral catalysts were designed and applied for asymmetric aldol reactions. This review article is organized under the categories of: (1) catalytic enantioselective aldol reactions of preformed enolates, (2) catalytic enantioselective direct-type aldol reactions using chiral metal catalysts, (3) catalytic enantioselective direct-type aldol reactions using organocatalysts, (4) catalytic enantioselective aldol reactions in aqueous media. Examples of the aldol reactions that employ simple carbonyl compounds will be also the focus of this review.

Rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes: reaction mechanism and development of homogeneous and heterogeneous catalysts.

Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be converted into various useful species often used as chiral building blocks in drug and natural product synthesis. In the present work, asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes catalyzed by a rhodium complex with a chiral diene bearing a tertiary butyl amide moiety were developed. Just 0.1 mol% of the chiral rhodium complex could catalyze the reactions and give the desired products in high yields with excellent enantioselectivities. The homogeneous catalyst thus developed could be converted to a reusable heterogeneous metal nanoparticle system using the same chiral ligand as a modifier, which was immobilized using a polystyrene-derived polymer with cross-linking moieties, maintaining the same level of enantioselectivity. To our knowledge, this is the first example of asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes in a heterogeneous system. Wide substrate generality and high catalytic turnover were achieved in the presence of sufficient water without any additives such as KOH or KHF2 in both homogeneous and heterogeneous systems. Various insights relating to a rate-limiting step in the catalytic cycle, the importance of water, role of the secondary amide moiety in the ligand, and active species in the heterogeneous system were obtained through mechanistic studies.

Asymmetric Arylation of Imines Catalyzed by Heterogeneous Chiral Rhodium Nanoparticles.

Asymmetric arylation of aldimines catalyzed by heterogeneous chiral rhodium nanoparticles has been developed. The reaction proceeded in aqueous media without significant decomposition of the imines by hydrolysis to afford chiral (diarylmethyl)amines in high yields with outstanding enantioselectivities. This catalyst system exhibited the highest turnover number (700) in heterogeneous catalysts reported to date for these reactions. The reusability of the catalyst was also demonstrated.

Chiral Nanoparticles/Lewis Acids as Cooperative Catalysts for Asymmetric 1,4-Addition of Arylboronic Acids to α,ß-Unsaturated Amides.

Cooperative catalysts consisting of chiral Rh/Ag nanoparticles and Sc(OTf)3 have been developed that catalyze asymmetric 1,4-addition reactions of arylboronic acids with α,ß-unsaturated amides efficiently. The reaction has been considered one of the most challenging reactions because of the low reactivity of the amide substrates. The new catalysts provide the desired products with outstanding enantioselectivities (>98 % ee) in the presence of low loadings (<0.5 mol %) of the catalyst.

Chiral Metal Nanoparticle Systems as Heterogeneous Catalysts beyond Homogeneous Metal Complex Catalysts for Asymmetric Addition of Arylboronic Acids to α,ß-Unsaturated Carbonyl Compounds.

We describe the use of chiral metal nanoparticle systems, as novel heterogeneous chiral catalysts for the asymmetric 1,4-addition of arylboronic acids to α,ß-unsaturated carbonyl compounds, as representative C-C bond-forming reactions. The reactions proceeded smoothly to afford the corresponding ß-arylated products in high to excellent yields and outstanding enantioselectivities with wide substrate scope. Remarkably, the nanoparticle catalysts showed performance in terms of yield, enantioselectivity, and catalytic turnover that was superior to that of the corresponding homogeneous metal complexes. The catalyst can be successfully recovered and reused in a gram-scale synthesis with low catalyst loading without significant loss of activity. The nature of the active species was investigated, and we found that characteristic features of the nanoparticle system were totally different from those of the metal complex system.