Shu̅ Kobayashi

Powerful Amide Synthesis from Alcohols and Amines under Aerobic Conditions Catalyzed by Gold or Gold/Iron, -Nickel or -Cobalt Nanoparticles

Considering the importance of the development of powerful green catalysts and the omnipresence of amide bonds in natural and synthetic compounds, we report here on reactions between alcohols and amines for amide bond formation in which heterogeneous gold and gold/iron, -nickel, or -cobalt nanoparticles are used as catalysts and molecular oxygen is used as terminal oxidant. Two catalysts show excellent activity and selectivity, depending on the type of alcohols used. A wide variety of alcohols and amines, including aqueous ammonia and amino acids, can be used for the amide synthesis. Furthermore, the catalysts can be recovered and reused several times without loss of activity.

Enamides and enecarbamates as nucleophiles in stereoselective C-C and C-N bond-forming reactions.

Because the backbone of most of organic compounds is a carbon chain, carbon-carbon bond-forming reactions are among the most important reactions in organic synthesis. Many of the carbon-carbon bond-forming reactions so far reported rely on nucleophilic attack of enolates or their derivatives, because those nucleophiles can be, in general, readily prepared from the corresponding carbonyl compounds. In this Account, we summarize the recent development of reactions using enamide and enecarbamate as a novel type of nucleophile. Despite their ready availability and their intrinsic attraction as a synthetic tool that enables us to introduce a protected nitrogen functional group, enamide and enecarbamate have rarely been used as a nucleophile, since their nucleophilicity is low compared with the corresponding metal enolates and enamines. A characteristic of enamides and enecarbamates is that those bearing a hydrogen atom on nitrogen are relatively stable at room temperature, while enamines bearing a hydrogen atom on nitrogen are likely to tautomerize into the corresponding imine form. Enamides and enecarbamates can be purified by silica gel chromatography and kept for a long time without decomposition. During the investigation of nucleophilic addition reactions using enamides and enecarbamates, it has been revealed that enamides and enecarbamates bearing a hydrogen atom on nitrogen react actually as a nucleophile with relatively reactive electrophiles, such as glyoxylate, N-acylimino ester, N-acylimino phosphonate, and azodicarboxylate, in the presence of an appropriate Lewis acid catalyst. Those bearing no hydrogen atom on nitrogen did not react at all. The products initially obtained from the nucleophilic addition of enamides and enecarbamates are the corresponding N-protected imines, which can be readily transformed to important functional groups, such as ketones by hydrolysis and N-protected amines by reduction or nucleophilic alkylation. In the nucleophilic addition reactions of enamides and enecarbamates to aldehydes, it was unveiled that the reaction proceeds stereospecifically, that is, (E)-enecarbamate gave anti product and (Z)-enecarbamate afforded syn product with high diastereoselectivity (>97/3). This fact can be rationalized by consideration of a concerted reaction pathway via a hydrogen-involved cyclic six-membered ring transition state. In the addition reactions to N-acylimino phosphonates, much higher turnover frequency was observed when enamides and enecarbamates were used as a nucleophile than was observed when silicon enolates were used. When silicon enolates were used, the intermediates bearing a strong affinity for the catalyst inhibited catalyst turnover, resulting in low enantioslectivity because of the dominance of the uncatalyzed racemic pathway. In the case of nucleophilic addition of enamides and enecarbamate, however, a fast intramolecular hydrogen transfer from the enecarbamate nitrogen may prevent the intermediate from trapping the catalyst for a long time, to afford the product with a high enantioselectivity. In conclusion, enamides and enecarbamates, although originally employed as just N-analogues to silicon enolates, have emerged as remarkably useful nucleophiles in a variety of Lewis acid-catalyzed reactions.

Spin trapping of Au-H intermediate in the alcohol oxidation by supported and unsupported gold catalysts.

Electron paramagnetic resonance (EPR) spectroscopy and spin trapping were used to explore the mechanism of alcohol oxidation over gold catalysts. Reaction of secondary alcohols with supported and unsupported gold catalysts (e.g., Au/CeO(2), polymer-incarcerated Au nanoparticles, PPh(3)-protected Au nanoparticles) in the presence of spin traps led to the formation of a hydrogen spin adduct. Using isotope labeling, we confirmed that the hydrogen in the spin adduct originates from the cleavage of the C-H bond in the alcohol molecule. The formation of the hydrogen spin adduct most likely results from the abstraction of hydrogen from the Au surface by a spin trap. These results thus strongly suggest intermediate formation of Au-H species during alcohol oxidation. The role of oxygen in this mechanism is to restore the catalytic activity rather than oxidize alcohol. This was further confirmed by carrying out gold-catalyzed alcohol oxidation in the absence of oxygen, with nitroxides as hydrogen abstractors. The support (e.g., metal oxides) can activate oxygen and act as an H abstractor from the gold surface and hence lead to a faster recovery of the activity. Peroxyl radicals were also observed during alcohol oxidation, consistent with a free-radical autoxidation mechanism. However, this mechanism is likely to be a minor side reaction, which does not lead to the formation of an appreciable amount of oxidation products.

Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes.

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

Alkaline earth metal catalysts for asymmetric reactions.

The group 2 alkaline earth metals calcium (Ca), strontium (Sr), and barium (Ba) are among the most common elements on Earth, abundant in both the sea and the Earths crust. Although they are familiar in our daily lives, their application to organic synthesis has, so far, been limited. Some particularly useful properties of these elements include (i) low electronegativity, (ii) a stable oxidation state of +2, meaning that they can potentially form two covalent bonds with anions, and (iii) the ability to occupy a variety of coordination sites due to their large ionic radius. Furthermore, the alkaline earth metals, found between the group 1 and group 3 elements, show mild but significant Lewis acidity, which can be harnessed to control coordinative molecules via a Lewis acid-base interaction. Taken together, these characteristics make the metals Ca, Sr, and Ba very promising components of highly functionalized acid-base catalysts. In this Account, we describe the development of chiral alkaline earth metal catalysts for asymmetric carbon-carbon bond-forming reactions. Recently prepared chiral alkaline earth metal complexes have shown high diastereo- and enantioselectivities in fundamental and important chemical transformations. We chose chiral bisoxazoline (Box) derivatives bearing a methylene tether as a ligand for chiral modification. These molecules are very useful because they can covalently coordinate to alkaline earth metals in a bidentate fashion through deprotonation of the tether portion. It was found that chiral calcium-Box complexes could successfully promote catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions with high diastereo- and enantioselectivities. Both the calcium-Box complexes and chiral strontium-bis-sulfonamide and chiral barium-BINOLate complexes could catalyze asymmetric 1,4-addition reactions with high enantioselectivities. Furthermore, we designed a calcium-neutral coordinative ligand complex as a new type of chiral alkaline earth metal catalyst. We found that pyridinebisoxazolines (Pybox) worked well: they served as excellent ligands for calcium compounds in 1,4-addition reactions and Mannich reactions. Moreover, they were successful in 1,4-additions in concert with enantioselective protonation, affording the desired products in good to high enantioselectivities. Our results demonstrate that alkaline earth metals are very useful and attractive catalysts in organic synthesis. Moreover, their ubiquity in the environment is a distinct advantage over rare metals for large-scale processes, and their minimal toxicity is beneficial in both handling and disposal.

Remarkable effect of bimetallic nanocluster catalysts for aerobic oxidation of alcohols: combining metals changes the activities and the reaction pathways to aldehydes/carboxylic acids or esters.

Selective oxidation of alcohols catalyzed by novel carbon-stabilized polymer-incarcerated bimetallic nanocluster catalysts using molecular oxygen has been developed. The reactivity and the selectivity were strongly dependent on the combination of metals and solvent systems; aldehydes and ketones were obtained by the gold/platinum catalyst in benzotrifluoride, and esters were formed by the gold/palladium catalyst in methanol. To the best of our knowledge, this is the first example that the reaction pathway has been changed dramatically in gold catalysis by combining with a second metal. The differences in the activity and the selectivity are considered to be derived from the difference in the structure of the bimetallic clusters.

Palladium-catalyzed allylic amination using aqueous ammonia for the synthesis of primary amines.

Palladium-catalyzed allylic amination using aqueous ammonia for the preparation of primary amines has been realized. It is noteworthy that the use of aqueous ammonia is essential and that ammonia gas did not react at all. The first catalytic asymmetric synthesis using aqueous ammonia as a nitrogen source has also been demonstrated.

Polymer-Incarcerated Chiral Rh/Ag Nanoparticles for Asymmetric 1,4-Addition Reactions of Arylboronic Acids to Enones: Remarkable Effects of Bimetallic Structure on Activity and Metal Leaching

Robust and highly active bimetallic Rh nanoparticle (NP) catalysts, PI/CB Rh/Ag, have been developed and applied to the asymmetric 1,4-addition of arylboronic acids to enones without leaching of the metals. We found that the structures of the bimetallic Rh/Ag catalysts and chiral ligands strongly affect their catalytic activity and the amount of metal leaching. PI/CB Rh/Ag could be recycled several times by simple operations while keeping high yields and excellent enantioselectivities. To show the versatility of the PI/CB Rh/Ag catalyst, a one-pot, oxidation-asymmetric 1,4-addition reaction of an allyl alcohol and an arylboronic acid was demonstrated by combining the PI/CB Rh/Ag catalyst with PI/CB Au as an aerobic oxidation catalyst.

Chiral Silver Amide-Catalyzed Enantioselective [3 + 2] Cycloaddition of α-Aminophosphonates with Olefins

The first catalytic asymmetric [3 + 2] cycloadditions of Schiff bases of alpha-aminophosphonates with olefins have been developed. Chiral silver amide complexes bearing (R)-DTBM-SEGPHOS worked well as catalysts for the first time, and proline phosphonic analogues were obtained in high yields with excellent exo- and enantioselectivities.

Catalytic Use of Indium(0) for Carbon−Carbon Bond Transformations in Water: General Catalytic Allylations of Ketones with Allylboronates

We have discovered the unprecedented catalytic use of In(0) for catalytic C-C bond transformations. Remarkably, these general catalytic allylations of ketones proceeded smoothly in water as a sole solvent under mild conditions, and water proved to be essential for these reactions. Both the displayed substrate scope and the functional group tolerance were excellent. Importantly, the In metal catalyst could be easily recovered and reused without loss of catalytic activity. Moreover, when an alpha-substituted allylboronate was used, an unusual constitutional selectivity was observed providing exclusively the formal alpha-adduct. Additionally, the resulting tertiary homoallylic alcohols were obtained with exceptionally high diastereoselectivities. The applicability of this concept to asymmetric catalysis in water by using In(0) combined with a chiral bis(oxazoline) ligand was demonstrated as well.