Naohiko Yoshikai

Low-Valent Iron-Catalyzed C−C Bond Formation−Addition, Substitution, and C−H Bond Activation

The use of iron as a catalyst for organic synthesis has been increasingly attracting the interest of chemists from economical and ecological points of view. While Fe(III) and Fe(II) catalysts have long been used as Lewis acids for synthesis, we have been interested in exploration of catalysis based on rather unexplored organoiron chemistry since the late 1990s. This Perspective summarizes a series of iron-catalyzed C-C bond formation reactions developed by us, which include (asymmetric) carbometalation of olefins, cross-coupling of alkyl halides, and activation of sp(2) and sp(3) C-H bonds.

Iron-Catalyzed Direct Arylation through Directed C−H Bond Activation

An iron-catalyzed C-C bond formation reaction of a nitrogen-containing aromatic compound with an arylzinc reagent takes place at 0 degrees C in a good to quantitative yield. The reaction involves a C-H bond activation directed by a neighboring nitrogen atom. The important additives in this reaction are 1,10-phenanthroline, tetramethylethylenediamine, and 1,2-dichloro-2-methylpropane, in the absence of which a very low product yield was observed.

Palladium-catalyzed aerobic oxidative cyclization of N-aryl imines : indole synthesis from anilines and ketones

We report here an operationally simple, palladium-catalyzed cyclization reaction of N-aryl imines, affording indoles via the oxidative linkage of two C-H bonds under mild conditions using molecular oxygen as the sole oxidant. The process allows quick and atom-economical assembly of indole rings from inexpensive and readily available anilines and ketones and tolerates a broad range of functional groups.

Hydroxyphosphine ligand for nickel-catalyzed cross-coupling through nickel/magnesium bimetallic cooperation.

We report here that hydroxyphosphine ligands (PO ligands) significantly accelerate nickel-catalyzed cross-coupling reactions of unreactive aryl electrophiles and Grignard reagents. The new catalytic system based on the nickel-PO-Grignard combination allows facile activation of unreactive aryl halides such as fluorides, chlorides, polyfluorides, and polychlorides as well as phenol derivatives such as carbamates and phosphates to give the corresponding cross-coupling products in good to excellent yields. We ascribe the high catalytic activity to a nickel phosphine/magnesium alkoxide bimetallic species that forms from the nickel precatalyst, the PO ligand, and the Grignard reagent and undergoes activation of the aryl-X bond by a cooperative push-pull action of the nucleophilic nickel and Lewis acidic magnesium centers. This mechanistic conjecture was corroborated by kinetic isotope effect experiments and density functional theory calculations. Being distinct from the conventional three-centered mechanism for oxidative addition, the proposed mechanism for the C-X bond activation offers a new concept for the design of cross-coupling reactions as well as other homogeneous catalyses involving activation of electrophilic substrates.

Cobalt-Catalyzed Hydroarylation of Alkynes through Chelation-Assisted C−H Bond Activation

Ternary catalytic systems consisting of cobalt salts, phosphine ligands, and Grignard reagents promote addition of arylpyridines and imines to unactivated internal alkynes with high regio- and stereoselectivities. Deuterium-labeling experiments suggest that the reaction involves chelation-assisted oxidative addition of the aryl C-H bond to the cobalt center and insertion of the C-C triple bond into the Co-H bond, followed by reductive elimination of the resulting diorganocobalt species.

Iron‐Catalyzed Chemoselective ortho Arylation of Aryl Imines by Directed CH Bond Activation

No Fe-ar: Iron catalyzes an imine-directed C-H bond activation to introduce an ortho-aryl group to an acetophenone-derived imine using a diarylzinc reagent (see scheme), whereas palladium catalyzes the conventional substitution reaction . The title reaction features mild and selective C-H bond activation in the presence of aryl bromide, chloride, or sulfonate groups, and 1,2-dichloroisobutane is essential to achieve such selectivity.

Regioselectivity-Switchable Hydroarylation of Styrenes

Cobalt-phosphine and cobalt-carbene catalysts have been developed for the hydroarylation of styrenes via chelation-assisted C-H bond activation, to afford branched and linear addition products, respectively, in a highly regioselective fashion. Deuterium-labeling experiments suggested a mechanism involving reversible C-H bond cleavage and olefin insertion steps and reductive elimination as the rate- and regioselectivity-determining step.

Modular Pyridine Synthesis from Oximes and Enals through Synergistic Copper/Iminium Catalysis

We describe here a [3+3]-type condensation reaction of O-acetyl ketoximes and α,β-unsaturated aldehydes that is synergistically catalyzed by a copper(I) salt and a secondary ammonium salt (or amine). This redox-neutral reaction allows modular synthesis of a variety of substituted pyridines under mild conditions with tolerance of a broad range of functional groups. The reaction is driven by a merger of iminium catalysis and redox activity of the copper catalyst, which would initially reduce the oxime N-O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediate to the pyridine product.

Cobalt-Catalyzed, Room-Temperature Addition of Aromatic Imines to Alkynes via Directed C–H Bond Activation

A quaternary catalytic system consisting of a cobalt salt, a triarylphosphine ligand, a Grignard reagent, and pyridine has been developed for chelation-assisted C-H bond activation of an aromatic imine, followed by insertion of an unactivated internal alkyne that occurs at ambient temperature. The reaction not only tolerates potentially senstitive functional groups (e.g., Cl, Br, CN, and tertiary amide), but also displays a unique regioselectivity. Thus, the presence of substituents such as methoxy, halogen, and cyano groups at the meta-position of the imino group led to selective C-C bond formation at the more sterically hindered ortho positions. Under acidic conditions, the hydroarylation products of dialkyl- and alkylarylacetylenes underwent cyclization to afford benzofulvene derivatives, while those of diarylacetylenes afforded the corresponding ketones in moderate to good yields. A mechanistic investigation into the reaction with the aid of deuterium-labeling experiments and kinetic analysis has indicated that oxidative addition of the ortho C-H bond is the rate-limiting step of the reaction. The kinetic analysis has also shed light on the complexity of the quaternary catalytic system.

Iron-Catalyzed C−C Bond Formation at α-Position of Aliphatic Amines via C−H Bond Activation through 1,5-Hydrogen Transfer

C-C bond formation reactions that take place through organoiron species sometimes exhibit radical-like character. The reaction of N-(2-iodophenylmethyl)dialkylamine with a Grignard or diorganozinc reagent in the presence of a catalytic amount of Fe(acac)(3) gives the product resulting from arylation, alkenylation, or alkylation of the sp(3) C-H bond next to the amine group in good to excellent yield. Mechanistic studies including labeling experiments indicate that the reaction involves radical translocation triggered by the formation of a radical-like species by removal of the iodide group.