Nickel-Photoredox-Catalyzed Stereoconvergent Coupling of Alkenyl Halides and Nitrogen-Containing Heterocycles.

Nitrogen-containing heterocycles possessing N-alkenyl substituents are an important structural motif. However, the synthetic methods reported thus far cannot selectively synthesize the Z stereoisomer on the basis of the stereochemistry of the substituted alkenes. Herein, we report the stereoconvergent coupling of heterocycles and alkenyl halides consisting of a mixture of E/Z stereoisomers, which selectively afforded the thermodynamically less stable Z-coupling product. Mechanistic studies suggest that a nickel photoredox catalyst facilitates the formation of N-centered heteroarene radicals.

Electrochemical Epoxidation Catalyzed by Manganese Salen Complex and Carbonate with Boron-Doped Diamond Electrode.

Epoxides are essential precursors for epoxy resins and other chemical products. In this study, we investigated whether electrochemically oxidizing carbonate ions could produce percarbonate to promote an epoxidation reaction in the presence of appropriate metal catalysts, although Tanaka and co-workers had already completed a separate study in which the electrochemical oxidation of chloride ions was used to produce hypochlorite ions for electrochemical epoxidation. We found that epoxides could be obtained from styrene derivatives in the presence of metal complexes, including manganese(III) and oxidovanadium(IV) porphyrin complexes and manganese salen complexes, using a boron-doped diamond as the anode. After considering various complexes as potential catalysts, we found that manganese salen complexes showed better performance in terms of epoxide yield. Furthermore, the substituent effect of the manganese salen complex was also investigated, and it was found that the highest epoxide yields were obtained when Jacobsen's catalyst was used. Although there is still room for improving the yields, this study has shown that the in situ electrochemical generation of percarbonate ions is a promising method for the electrochemical epoxidation of alkenes.

Variation of the Emission Efficiency and Wavelength from Fluorescent Zinc Salen Complexes upon Systematic Structural Modifications.

Understanding the photophysical properties of metal salen complexes is not straightforward because the emission efficiency is altered irregularly upon structural modifications. The present study prepared zinc salen complexes with systematic structural variations to pinpoint critical factors to determine the emission efficiency. One of the important experimental observations is the regiochemistry of a phenolate substituent affecting emission efficiency from a salicylidene fluorophore, which is nicely assigned as arising from the photoexcited electronic structure of metal salen complexes. Another significant finding is the thermal fluctuation of a salen ligand arising from the mismatched ligand-metal interaction, which has a significant impact on fluorescence lifetime. The present study sheds light on hidden factors that alter photophysical properties of a metal salen complex, which provide valuable insights into designing new photoactive salen ligands.

Aerobic Direct Dioxygenation of Terminal/Internal Alkynes to α-Hydroxyketones by an Fe Porphyrin Catalyst.

We herein report a new synthetic method for the preparation of α-hydroxyketones by the dioxygenation of alkynes. The reaction proceeds at room temperature under the action of Fe porphyrin and pinacolborane under air as a green oxidant to produce α-hydroxyketones. The mild reaction conditions allow chemoselective oxidation with functional group tolerance. Terminal alkynes in addition to internal alkynes are applicable, affording unsymmetrical α-hydroxyketones that are difficult to obtain by any reported dioxygenation of unsaturated C-C bonds.

Nickel-Catalyzed [5+2] Cycloaddition of 10π-Electron Aromatic Benzothiophenes with Alkynes To Form Thermally Metastable 12π-Electron Nonaromatic Benzothiepines.

The nickel-catalyzed formal [5+2] cycloaddition of five-membered benzothiophenes and alkynes giving seven-membered benzothiepines via unprecedented dearomatization is reported. The reaction involves the carbothiolation of alkynes with sulfur-containing aromatic heterocycles affording sulfur-containing heterocyclic compounds via ring expansion. As a result, this method facilitates divergent access to thermally metastable benzothiepines. The structure of the thianickelacycle intermediate, which is formed via oxidative addition of the C-S bond in benzothiophenes to nickel(0), was confirmed by in situ X-ray absorption fine structure spectroscopy and density functional theory calculation.

Cationic Cobalt Porphyrin-Catalyzed Allylation of Aldehydes with Allyltrimethylsilanes.

Cationic cobalt porphyrin-catalyzed allylation of aldehydes with allyltrimethylsilanes is developed. The formation of the aldehyde-cobalt porphyrin complex, the key intermediate for the addition of allylsilanes, is confirmed by theoretical studies and synchrotron-based X-ray absorption fine-structure measurements. Facile dissociation of the product by allylation from the cobalt complex regenerates the active complex with the aldehyde. The readily obtainable [Co(TPP)]SbF6 complex serves as an efficient catalyst for this allylation.

Asymmetric Aza-Diels-Alder Reaction with Ion-Paired-Iron Lewis Acid-Brønsted Acid Catalyst.

The development and use of a multiple-activation catalyst with ion-paired Lewis acid and Brønsted acid in an asymmetric aza-Diels-Alder reaction of simple dienes (non-Danishefsky-type electron-rich dienes) was achieved by utilizing the [FeBr2 ]+ [FeBr4 ]- combination prepared in situ from FeBr3 and chiral phosphoric acid. Synergistic effects of the highly active ion-paired Lewis acid [FeBr2 ]+ [FeBr4 ]- and a chiral Brønsted acid are important for promoting the reaction with high turnover frequency and high enantioselectivity. The multiple-activation catalyst system was confirmed using synchrotron-based X-ray absorption fine structure measurements, and theoretical studies. This study reveals that the developed catalyst promoted the reaction not only by the interaction offered by the ion-paired Lewis acid and the Brønsted acid but also noncovalent interactions.

Diastereoselective Synthesis of 1,3-Oxazolidines via Cationic Iron Porphyrin-catalyzed Cycloaddition of Aziridines with Aldehydes.

An efficient iron porphyrin Lewis acid-catalyzed cycloaddition of aziridines with aldehydes has been developed to provide oxazolidines with high regio- and diastereoselectivity. The cycloaddition proceeds in toluene with 1 mol % of the iron catalyst at 25 °C. A theoretical study and synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the aziridine-iron porphyrin complex, which is the key intermediate for the generation of the 1,3-dipole synthon.

FeCl3 as an Ion-Pairing Lewis Acid Catalyst. Formation of Highly Lewis Acidic FeCl2+ and Thermodynamically Stable FeCl4- To Catalyze the Aza-Diels-Alder Reaction with High Turnover Frequency.

The aza-Diels-Alder reaction of nonactivated dienes and imines was realized through the action of the ion-paired Lewis acid catalyst [FeCl2]+[FeCl4]- generated by the in situ disproportionation of FeCl3. The uniquely high reactivity of [FeCl2]+[FeCl4]- was attributed to both the highly Lewis acidic FeCl2+ and thermodynamically stable FeCl4- acting as an ion-paired catalyst. Synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the disproportionation and structure of the resulting ion-paired iron complex. A theoretical study was performed to analyze the catalytic reaction and better understand the "ion-pairing effect" which transforms simple FeCl3 into a high turnover frequency Lewis acid catalyst in the aza-Diels-Alder reaction of nonactivated dienes and imines.

Nickel-catalyzed intermolecular carboiodination of alkynes with aryl iodides.

Nickel-catalyzed intermolecular carboiodination of alkynes with aryl iodides to form highly substituted and functionalized alkenyl iodides has been developed. The reaction involves radical-mediated formal alkyne insertion into the carbon-nickel bond and carbon-iodine reductive elimination facilitated by Ni(iii) species.

Pseudomonas aeruginosa overexpression system of nitric oxide reductase for in vivo and in vitro mutational analyses.

Membrane-integrated nitric oxide reductase (NOR) reduces nitric oxide (NO) to nitrous oxide (N2O) with protons and electrons. This process is essential for the elimination of the cytotoxic NO that is produced from nitrite (NO2-) during microbial denitrification. A structure-guided mutagenesis of NOR is required to elucidate the mechanism for NOR-catalyzed NO reduction. We have already solved the crystal structure of cytochrome c-dependent NOR (cNOR) from Pseudomonas aeruginosa. In this study, we then constructed its expression system using cNOR-gene deficient and wild-type strains for further functional study. Characterizing the variants of the five conserved Glu residues located around the heme/non-heme iron active center allowed us to establish how the anaerobic growth rate of cNOR-deficient strains expressing cNOR variants correlates with the in vitro enzymatic activity of the variants. Since bacterial strains require active cNOR to eliminate cytotoxic NO and to survive under denitrification conditions, the anaerobic growth rate of a strain with a cNOR variant is a good indicator of NO decomposition capability of the variants and a marker for the screening of functionally important residues without protein purification. Using this in vivo screening system, we examined the residues lining the putative proton transfer pathways for NO reduction in cNOR, and found that the catalytic protons are likely transferred through the Glu57 located at the periplasmic protein surface. The homologous cNOR expression system developed here is an invaluable tool for facile identification of crucial residues in vivo, and for further in vitro functional and structural studies.

Drastic Redox Shift and Electronic Structural Changes of a Manganese(III)-Salen Oxidation Catalyst upon Reaction with Hydroxide and Cyanide Ion.

Flexible redox properties of a metal complex are important for redox catalysis. The present study shows that the reaction of a manganese(III) salen complex, which is a well-known oxidation catalyst, with hydroxide ion gives a transient manganese(III) species with drastically lowered redox potential, where the redox difference is -1.21 V. The reaction with cyanide ion gives a stable manganese(III) species with almost the same spectroscopic and redox properties, which was characterized as an anionic [MnIII(salen)(CN)2]- of low-spin S = 1 state, in contrast to the starting MnIII(salen)(OTf) having usual high-spin S = 2 manganese(III). The present study has thus clarified that the drastic redox shift comes from an anionic six-coordinate [MnIII(salen)(X)2]- species where X is either OH- or CN-. Resonance Raman measurements show that the stretching band of the imino group shifts from 1620 to 1597 cm-1 upon conversion from MnIII(salen)(OTf) to [MnIII(salen)(CN)2]-, indicative of lowered C═N double bond character for [MnIII(salen)(CN)2]-. The observed deformation of a salen ligand is a clear indication of an increased electron population on the imino π*-orbital upon formation of low-spin manganese(III). It was proposed that the electronic structure of [MnIII(salen)(CN)2]- may contain only limited contribution from valence tautomeric [MnIV(salen- •)(CN)2]-, in which the imino group of a salen ligand is reduced by one-electron via intramolecular electron transfer from low-spin manganese(III). The present study has clarified an unexpected new finding that a salen ligand works as a reservoir for negative charge to stabilize low-spin manganese(III).

Ruthenium-Porphyrin-Catalyzed [4 + 2] Cycloaddition of α,ß-Unsaturated Imines and Aldehydes.

A new efficient synthetic route to unsymmetrically substituted dihydropyridine scaffolds via dehydrative [4 + 2] cycloaddition of N-tosylated α,ß-unsaturated imines with aldehydes has been developed. This transformation is enabled by (i) the remarkable catalytic ability of the cationic Ru(IV) porphyrin complex to activate both the imino and carbonyl groups and (ii) the hydrophobic nature of the porphyrin ligand, which helps realize robust Lewis acidity in the dehydrative cycloaddition.

Reverse Catalase Reaction: Dioxygen Activation via Two-Electron Transfer from Hydroxide to Dioxygen Mediated By a Manganese(III) Salen Complex.

Although atmospheric dioxygen is regarded as the most ideal oxidant, O2 activation for use in oxygenation reactions intrinsically requires a costly sacrificial reductant. The present study investigated the use of aqueous alkaline solution for O2 activation. A manganese(III) salen complex, Mn(III)(salen)(Cl), in toluene reacts with aqueous KOH solution under aerobic conditions, which yields a di-µ-oxo dimanganese(IV) salen complex, [Mn(IV)(salen)]2(µ-O)2. The (18)O isotope experiments show that (18)O2 is indeed activated to give [Mn(IV)(salen)]2(µ-(18)O)2 via a peroxide intermediate. Interestingly, the (18)OH(-) ion in H2(18)O was also incorporated to yield [Mn(IV)(salen)]2(µ-(18)O)2, which implies that a peroxide species is also generated from (18)OH(-). The addition of benzyl alcohol as a stoichiometric reductant selectively inhibits the (18)O incorporation from (18)OH(-), indicating that the reaction of Mn(III)(salen)(Cl) with OH(-) supplies the electrons for O2 reduction. The conversion of both O2 and OH(-) to a peroxide species is exactly the reverse of a catalase-like reaction, which has a great potential as the most efficient O2 activation. Mechanistic investigations revealed that the reaction of Mn(III)(salen)(Cl) with OH(-) generates a transient species with strong reducing ability, which effects the reduction of O2 by means of a manganese(II) intermediate.

Nickel-Catalyzed Reactions Directed toward the Formation of Heterocycles.

Heterocycles have garnered significant attention because they are important functional building blocks in various useful molecules, such as pharmaceuticals, agricultural chemicals, pesticides, and materials. Several studies have been conducted regarding the preparation of heterocyclic skeletons with an emphasis on selectivity and efficiency. Three strategies are typically employed to construct cyclic molecules, namely, cyclization, cycloaddition, and ring-size alterations. Although each method has certain advantages, cycloaddition may be superior from the viewpoint of divergence. Specifically, cycloadditions enable the construction of rings from several pieces. However, the construction of heterocycles via cycloadditions is more challenging than the construction of carbocycles. For heterocycle construction, simple pericyclic reactions rarely work smoothly because of the large HOMO-LUMO gap unless well-designed combinations, such as electron-rich dienes and aldehydes, are utilized. Thus, a different approach should be employed to prepare heterocycles via cycloadditions. To this end, the use of metallacycles containing heteroatoms is expected to serve as a promising solution. In this study, we focused on the preparation of heteroatom-containing nickelacycles. Because nickel possesses a relatively high redox potential and an affinity for heteroatoms, several methods were developed to synthesize heteronickelacycles from various starting materials. The prepared nickelacycles were demonstrated to be reasonable intermediates in cycloaddition reactions, which were used to prepare various heterocycles. In this Account, we introduce the following four methods to prepare heterocycles via heteronickelacycles. (1) Direct oxidative insertion of Ni(0) to α,ß-unsaturated enone derivatives: treatment of 3-ethoxycarbonyl-4-phenyl-3-buten-2-one with Ni(0) afforded an oxa-nickelacycle, which reacted with alkynes to give pyrans. (2) Substitution of a part of a cyclic compound with low-valent nickel, accompanied by elimination of small molecules such as CO, CO2, and acetophenone: treatment of phthalic anhydride with Ni(0) in the presence of ZnCl2 afforded the oxanickelacycle, which was formed via decarbonylative insertion of Ni(0) and reacted with alkynes to give isocumarins. (3) Cyclization to a nickelacycle, accompanied by two C-C σ-bond activations: insertion of Ni(0) into an arylnitrile, followed by aryl cyanation of an alkyne, gave alkenylnickel as an intermediate. The alkenylnickel species subsequently underwent an intramolecular nucleophilic attack with an arylcarbonyl group to form a cyclized product with concomitant cleavage of the C-C σ-bond between the carbonyl and aryl groups. (4) Assembly of several components to form a heteroatom-containing nickelacycle via cycloaddition: a new [2 + 2 + 1] cyclization reaction was carried out using an α,ß-unsaturated ester, isocyanate, and alkyne via a nickelacycle. On the basis of these four strategies, we developed new methods to prepare heterocyclic compounds using nickelacycles as the key active species.

A Triphenylamine with Two Phenoxy Radicals Having Unusual Bonding Patterns and a Closed-Shell Electronic State.

Reported herein is the structure and the electronic properties of a novel triphenylamine derivative having two phenoxy radicals appended to the amino nitrogen atom. X-ray single crystal analysis and the magnetic resonance measurements demonstrates the unexpected closed-shell electronic structure, even at room temperature, of the molecule and two unusual C-N bonds with multiple-bond character. The theoretical calculations support the experimentally determined molecular geometry with the closed-shell electronic structure, and predicted a small HOMO-LUMO gap originating from the nonbonding character of the HOMO. The optical and electrochemical measurements show that the molecule has a remarkably small HOMO-LUMO gap compared with its triphenylamine precursor.

Nickel-catalysed synthesis of tetrasubstituted vinyl sulfides from thiocarbamates and internal alkynes.

The thiocarbamoylation of internal alkynes to produce tetrasubstituted ß-aminocarbonyl vinyl sulfides was demonstrated using a nickel catalyst. This reaction was successful with a wide variety of substituents, and gave the syn-adducts exclusively.

Nickel-catalyzed reaction of thioisatins and alkynes: a facile synthesis of thiochromones.

A new synthetic method for thiochromones was developed by using nickel-catalyzed decarbonylative cycloaddition of readily available thioisatins with alkynes. This reaction proceeded under very mild conditions and has quite high functional group compatibility.

Factors affecting hydrogen-tunneling contribution in hydroxylation reactions promoted by oxoiron(IV) porphyrin π-cation radical complexes.

Hydrogen atom transfer with a tunneling effect (H-tunneling) has been proposed to be involved in aliphatic hydroxylation reactions catalyzed by cytochrome P450 and synthetic heme complexes as a result of the observation of large hydrogen/deuterium kinetic isotope effects (KIEs). In the present work, we investigate the factors controlling the H-tunneling contribution to the H-transfer process in hydroxylation reaction by examining the kinetics of hydroxylation reactions at the benzylic positions of xanthene and 1,2,3,4-tetrahydronaphthalene by oxoiron(IV) 5,10,15,20-tetramesitylporphyrin π-cation radical complexes ((TMP(+•))Fe(IV)O(L)) under single-turnover conditions. The Arrhenius plots for these hydroxylation reactions of H-isotopomers have upwardly concave profiles. The Arrhenius plots of D-isotopomers, clear isosbestic points, and product analysis rule out the participation of thermally dependent other reaction processes in the concave profiles. These results provide evidence for the involvement of H-tunneling in the rate-limiting H-transfer process. These profiles are simulated using an equation derived from Bell's tunneling model. The temperature dependence of the KIE values (k(H)/k(D)) determined for these reactions indicates that the KIE value increases as the reaction temperature becomes lower, the bond dissociation energy (BDE) of the C-H bond of a substrate becomes higher, and the reactivity of (TMP(+•))Fe(IV)O(L) decreases. In addition, we found correlation of the slope of the ln(k(H)/k(D)) - 1/T plot and the bond strengths of the Fe═O bond of (TMP(+•))Fe(IV)O(L) estimated from resonance Raman spectroscopy. These observations indicate that these factors modulate the extent of the H-tunneling contribution by modulating the ratio of the height and thickness of the reaction barrier.

Diastereoselective construction of trans-fused octalone framework via ruthenium-porphyrin-catalyzed cycloaddition.

Lewis acid catalyzed cycloaddition of cyclohexenone and butadiene affords trans-fused octalone with high regio- and diastereoselectivity. The use of the ruthenium porphyrin complex as the Lewis acid catalyst is key to the reaction. The cycloaddition proceeds in toluene with 1 mol % of the ruthenium catalyst at 25 °C.