Given that C-H bonds are ubiquitous in organic compounds, substrate functionalization via C-H bond activation appears as a challenging straightforward method in organic synthesis, eliminating the multiple steps and limitations associated with the preparation of functionalized starting materials. Regioselectivity is the important issue to be addressed in the transformation of C-H bonds because organic molecules can have many different types of C-H bonds. The use of a directing group can largely overcome the issue of regio-control by allowing the catalyst to come into close proximity to the targeted C-H bonds which, in most cases, are ortho C-H bonds. A wide variety of functional groups has been evaluated as directing groups to date in the transformation of C-H bonds. The development of new types of directing groups continues to be important, in terms of exploring novel types of transformations of C-H bonds that cannot be achieved by conventional directing groups. In 2005, Daugulis reported the arylation of unactivated C(sp3)-H bonds using 8-aminoquinoline and picolinamide as a N,N-bidentate directing group in conjunction with Pd(OAc)2 as the catalyst. Encouraged by these promising results, a number of transformations of C-H bonds have since been developed using bidentate directing group systems. In this review, a recent advance on chelation-assisted transformation of C-H bonds by taking advantage of a bidentate directing group is described.
This account describes development of new synthetic reactions utilizing palladium complexes bearing a PSiP-pincer type ligand as a catalyst. The PSiP-palladium complex was designed based on the expectations that 1) the strong trans influence and electron-donating nature of the silicon atom would enhance the reactivity of its trans substituent, 2) the rigid pincer structure based on the phenylene backbones would retard Pd(0) liberation and facilitate rational design of Pd(II)-based catalytic cycle, and 3) rather strained square planar structure of the PSiP-linkage would facilitate structural change to trigonal bipyramidal geometry, allowing facile coordination and activation of substrates. Consequently, we have developed hydrocarboxylation reaction of allenes and 1,3-dienes with CO2 and selective synthesis of monoboryl- and diborylalkenes via dehydrogenative borylation of alkenes with diboron. Both reactions are new type of molecular transformations and are realized by utilizing characteristics of the PSiP-palladium complexes. Furthermore, unique dynamic behaviors of the silicon atom were revealed through the reaction of η2-(Si-H)Pd(0) complex, demonstrating promising utility of the PSiP-pincer ligand in organometallic and synthetic chemistry.
Rhenium and manganese-catalyzed regioselective insertion of unsaturated molecules into aromatic and olefinic C-H bonds have been achieved. In some cases, successive intramolecular nucleophilic cyclization proceeded. We have also succeeded in regioselective insertion of alkynes into a non-strained C-C single bond of 1,3-dicarbonyl compounds using a rhenium or manganese catalyst. In addition, we have succeeded in regio- and stereo-defined cycloaddition reactions. By using a rhodium or palladium catalyst, we have achieved direct and efficient carbon-heteroatom bond formations via C-H bond activation.
In general, biologically active drug lead molecules are structurally complex, bearing multiple functional groups and chiral sp3 carbons. Our aim in developing new catalysis is to promote a concise, robust, and clean drug lead synthesis. To do so requires catalysis allowing for the design of concepually new retrosynthesis independent of functional groups. Here we summarize our first step toward such a goal. First, we describe a Cu(I)-catalyzed enantioselective condensation of ketones and hemiaminals that can produce versatile chiral building blocks for alkaloid synthesis. The hard anion-conjugated soft metal (HASM) catalysis concept is the basis for the reactivity. Second, two Cu-catalyzed cross-dehydrogenative coupling (CDC) reactions are discussed. The radical-conjugated redox catalysis (RCRC) concept leads to the development of a very early example of catalytic asymmetric aerobic CDC. Third, the Rh-catalyzed aldehyde cross aldol reaction and the Co-catalyzed C-4 selective alkylation of pyridines, both of which are mediated by means of hydride transfer, are described. Unique reactivity in the latter two topics is partly due to the redox activity of the transition metal catalysts.
Gold nanoparticles are drawing great attention because of its interesting properties. Although a bulk gold is chemically inert, a nano-sized particles shows completely different characteristics. Therefore, applications of gold nanoparticles for organic transformations are wide-spreading in recent years. We have developed several organic reactions employing metal oxide supported gold nanoparticles. In these reactions, the catalysis are assumed not only by gold nanoparticles but an active species formed from oxide support depending on the reaction conditions. This phenomenon expands the capability of metal oxide supported gold nanoparticles since the catalysis can be modulated by employing a proper metal oxide support.
Efforts to develop an attractive biocatalyst with new chemical reactivity and selectivity indicate that promising strategies involve the construction of artificial metalloenzymes generated by incorporation of a metal-containing moiety into a protein scaffold. In this article, we present three recent results focusing on the modification of proteins with artificial metal complexes. First, an artificial hydrogenase model containing a synthetic diiron carbonyl cluster, (µ-S2)[FeI(CO)3]2, held by a native cysteine-containing motif in the cytochrome c protein is described. The diiron carbonyl core anchored by coordination within the protein matrix works well as a catalyst for H2 evolution. Second, a hybrid catalyst containing a rhodium complex with a maleimide moiety at the peripheral position of the cyclopendiene ligand is described. The rhodium complex was inserted into a β-barrel protein scaffold of a mutant of aponitrobindin via a covalent linkage. The hybrid protein acts as a polymerization catalyst and preferentially yields trans-poly(phenylacetylene)(PPA). Finally, an artificial hemoprotein containing an iron porphycene, a structural isomer of hemin, within a heme pocket, is reported. The reconstituted horseradish peroxidase catalyzes the H2O2-dependent oxidation of thioanisole, of which the initial rate is 12-fold faster than that observed for native myoglobin.
Polyquinoxaline-based helically chiral phosphine ligands PQXphos, bearing chiral side chains, were synthesized via living aromatizing copolymerization of o-diisocyanobenzene monomers. The chiral reaction environment of PQXphos is created on the basis of its single-handed helical structure, leading to high enantioselectivities in palladium-catalyzed asymmetric hydrosilylation of styrenes (up to 98% ee), Suzuki-Miyaura coupling (up to 98% ee), and silaborative C-C cleavage of meso-methylenecyclopropanes (up to 97% ee). While most common organic solvents induce right-handed helix to (R)-PQXphos bearing (R)-2-butoxymethyl side chains, 1,1,2-trichloroethane and some solvents induce left-handed helix to it. The inverted, left-handed (R)-PQXphos also showed high enantioselectivities for the production of enantiomers of the products obtained with right-handed (R)-PQXphos. PQXphos formed insoluble polymer complex through coordination to palladium. The insoluble palladium complex of PQXphos was reused 8 times, while keeping catalyst activity and enantioselectivity. In the silaborative desymmetrization of methylenecyclopropanes, PQXphos showed not only high enantioselectivity, but also high catalyst activity in comparison with the corresponding low-molecular-weight ligand.
In the past decade, chiral Brønsted acid catalysis has become a leading tool to achieve catalytic asymmetric transformations. As a source of Brønsted acids, poorly acidic hydrogen bonding donors like (thio)ureas and alcohols had been used in the early study, and strongly acidic phosphoric acids then emerged as an indispensable option. We became interested in the use of chiral carboxylic acids, as they have a distinct acidity which cannot be provided by other Brønsted acids. To this end, we developed axially chiral dicarboxylic acids bearing two carboxylic acids at the 2,2’-positions of a binaphthyl unit, and succeeded in applying these catalysts to a variety of asymmetric transformations.
An inventive approach to the development of chiral Brønsted acid catalysts which possess strong acid functionalities has been accomplished. Because of their unique structural and chemical features, phosphoric acids have become the focus of our attention as potential chiral Brønsted acid catalysts, among the various organic Brønsted acids surveyed. An acidic functionality is available even with the introduction of a ring system which effectively restricts the conformational flexibility of the chiral backbone. In addition, substituents can be introduced to the ring system to provide an efficient chiral environment for enantioselective transformations. Furthermore the phosphoryl oxygen would function as a Brønsted basic site and hence it is anticipated that it would convey acid/base dual function even to monofunctional phosphoric acid catalysts. It can be considered that an efficient substrate recognition site would be constructed around the activation site due to the steric and electronic influence of the substituents introduced at the ring system as well as the acid/base dual function. In this context, we developed 1,1’-bi-2-naphthol (BINOL)-derived monophosphoric acids as chiral Brønsted acid catalysts. The chiral phosphoric acids thus developed functioned as efficient enantioselective catalysts for a variety of carbon-carbon bond forming reactions via activation of a series of functionalities, affording products in an enantioselective manner. In this account article, we review our recent achievements in developing enantioselective reactions using the chiral phosphoric acid catalysts.
We have designed and synthesized novel bifunctional hydrogen-bond (HB) donor catalysts bearing a benzothiadiazine or a quinazoline scaffold, whose HB-donating activity as well as recognition modes of the substrates were found to be significantly different from thiourea-typed organocatalysts by comparison of their 1H NMR studies, X-ray crystallographic analyses, spectrophotometric analyses, and computational investigations. We found that quinazoline-typed catalysts were effective for the highly enantioselective hydrazination of 1,3-dicarbonyl compounds and that benzothiadiazine-type catalysts showed great activity for the asymmetric isomerization of alkynoates to allenoates. In both cases, these newly developed catalysts were much more efficient than thiourea-typed organocatalysts, indicating that the HB-donating moiety of the catalysts was important for the recognition and activation of the substrates to facilitate the reaction.
Cyclodextrins (CDs) initiate ring-opening polymerizations of lactones selectively to give polyesters in high yields. The order of the polymer yield of β-butyrolactone (β-BL) with CDs is α-CD≅β-CD»γ-CD>no CD. On the other hand, that of δ-valerolactone (δ-VL) is β-CD>γ-CD»α-CD>no CD. The yields of the polyesters depend on the cavity size of CDs and structures of lactones, indicating that the reaction took place via inclusion of lactones in the CD cavity. The included monomer in the CD cavity is activated by the formation of hydrogen bonds between the hydroxyl group of CDs and the carbonyl oxygen of monomers in the initiation step. Moreover, CDs threaded onto the polymer are essential for the polymerization propagation step. The polyrotaxane structure prevents the polymer chain from forming random coil conformation. The formation of the polyrotaxane structure keeps the catalytic space of β-CD at the end of polymer. However, an unfixed CD on the polymer chain would leave the active site of β-CD as polymerization proceeds by an insertion of esters between β-CD and the growing chain. To prevent CDs threaded onto the polymer from leaving the active site CD, a molecular clamp CD is covalently bound close to the active β-CD to form the CD dimer. One of CD rings in the dimer functions as the active binding site for the monomer. The other acts as an artificial molecular clamp to grow a higher molecular weight polymer chain. These CD dimers efficiently initiate polymerization to produce polyesters. This behavior is similar to a sliding DNA clamp-clamp loader complex, which plays an important role in propagating DNA in biological systems.
Organic nitroxyl radicals have attracted attention as useful catalysts for alcohol oxidation under mild, safe, and environmentally benign conditions. We have pursued the development of ideal alcohol oxidation methods on the basis of azaadamantane-type nitroxyl radical catalysts (AZADOs) , which we have developed as a highly efficient alcohol oxidation catalyst. By tuning the electrochemical and steric properties of nitroxyl radical catalysts, 5-F-AZADO (4) and Nor-AZADO (5) were identified as suitable catalysts for aerobic oxidation. These catalysts realize highly efficient aerobic alcohol oxidation systems with a remarkably broad range of substrate applicabilities under mild and simple conditions. Nor-AZADO (5) was also found to effectively catalyze alcohol oxidation with diisopropyl azodicarboxylate (DIAD) as the cooxidant as well as oxidation from silyl enol ether to 1,2-diketone.
Transition metal catalysts have inevitably been used for C(sp2)-C(sp2) bond forming reactions of aryl halides with sp2-carbon nucleophiles. On the other hand, we have recently developed such a kind of reactions with no aid of transition metal catalysis, utilizing single electron transfer (SET) mechanism. Here, a single electron acts as a catalyst to promote the reaction of aryl halides (Ar-X) with arenes, styrenes or aryl Grignard reagents (ArMgBr) to give biaryls, stilbenes or biaryls, respectively. The common intermediates are anion radicals ([Ar-X]•−) of aryl halides and those ([Ar-R]•−) of coupling products. [Ar-X]•−, generated through SET from a base or ArMgBr to Ar-X, reacts directly with ArMgBr, whereas less reactive arenes and styrenes react with Ar•, generated by decomposition of [Ar-X]•−. All the reactions include, in the last step, SET from [Ar-R]•− to Ar-X to give Ar-R and regenerate [Ar-X]•−.