Kenichiro Itami

CH Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

Potassium t-Butoxide Alone Can Promote the Biaryl Coupling of Electron-Deficient Nitrogen Heterocycles and Haloarenes

The biaryl coupling of electron-deficient nitrogen heterocycles and haloarenes can be promoted by potassium t-butoxide alone, without the addition of any exogenous transition metal species. Electron-deficient nitrogen heterocycles such as pyridine, pyridazine, pyrimidine, pyrazine, and quinoxaline are arylated with haloarenes. Control experiments support a radical-based mechanism. Taking these findings into account, radical processes may be partially involved in the reported transition-metal-catalyzed arylation reactions employing t-butoxide bases and haloarenes under elevated temperatures or under microwave irradiation.

Synthesis of Extended π‐Systems through C–H Activation

Activation of aromatic CH bonds by a transition metal catalyst has received significant attention in the synthetic chemistry community. In recent years, rapid and site-selective extension of π-electron systems by C-H activation has emerged as an ideal methodology for preparing organic materials with extended π-systems. This Review focuses on recently reported π-extending C-H activation reactions directed toward new optoelectronic conjugated materials.

Selective Synthesis of [12]Cycloparaphenylene

Shape-persistent, nanosized macrocycles that are composed of only spand sp-hydridized carbon atoms on their perimeter (conjugated molecular loops and belts) have attracted significant attention because of their potential applications in materials science and supramolecular chemistry. 2] Particularly interesting and challenging among these are aromatic belts and rings as exemplified by the V gtle belts, cyclophenacenes, 6] cycloparaphenylenes, and cyclacenes [10, 11] . Adding to their sheer aesthetic appeal, these unusual hydrocarbons represent structural models for carbon nanotube segments, and can be envisioned as potential precursors in the preparation of structurally uniform armchair or zigzag carbon nanotubes (Scheme 1). However, despite extensive trials the synthesis of these molecules remains a formidable challenge. In 2005, as a part of our research program exploring new synthetic methods and properties of oligoarenes and nanocarbons, we initiated a synthetic study of these aromatic belts/rings that aims at contributing to a bottom-up organic synthesis of structurally uniform single-walled carbon nanotubes. We selected cycloparaphenylene as a first target in view of a comparatively straightforward approach to their synthesis through aryl–aryl bond formation. Despite its structural simplicity, no successful synthesis had been reported at the inception of our work. Very recently, Bertozzi and co-workers have accomplished the elegant first synthesis of [9]-, [12]-, and [18]cycloparaphenylenes and coined them as “carbon nanohoops”. Herein, we report a selective synthesis of [12]cycloparaphenylene (1) through stepwise palladiumcatalyzed coupling reactions.

Nickel-Catalyzed C–H/C–O Coupling of Azoles with Phenol Derivatives

The first nickel-catalyzed C-H bond arylation of azoles with phenol derivatives is described. The new Ni(cod)(2)/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C-H/C-O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine.

Direct C-H arylation of (hetero)arenes with aryl iodides via rhodium catalysis.

A new method for the catalytic C-H arylation of heteroarenes and arenes that manifests high activity paired with reasonably broad scope was developed. Under the catalytic influence of RhCl(CO){P[OCH(CF3)2]3}2 and Ag2CO3, the direct C-H arylation of heteroarenes/arenes with aryl/heteroaryl iodides took place to afford a range of biaryls in good to excellent yields with high regioselectivity. Thiophenes, furans, pyrroles, indoles, and alkoxybenzenes are applicable in this arylation protocol.

Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates

Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)(2)/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAc)(2)/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.

Synthesis of Cycloparaphenylenes and Related Carbon Nanorings: A Step toward the Controlled Synthesis of Carbon Nanotubes

Since their discovery in 1991, carbon nanotubes (CNTs) have attracted significant attention because of their remarkable mechanical, electronic, and optical properties. Structural uniformity of the CNT is critically important because the sidewall structures (armchair, zigzag, and chiral) determine many of the significant properties of CNTs. Ideally researchers would synthesize CNTs with a defined target sidewall structure and diameter, but the current synthetic methods, such as arc discharge and chemical vapor deposition, only provide CNTs as the mixtures of various structures. Purification of these mixtures does not allow researchers to isolate a structurally uniform CNT, which is the bottleneck for fundamental studies and advanced applications of these materials. Therefore, the selective and predictable synthesis of structurally uniform CNTs would represent a critical advance in both nanocarbon science and synthetic chemistry. This Account highlights our efforts toward the bottom-up synthesis of structurally uniform carbon nanotubes (CNTs). We envisioned a bottom-up synthesis of structurally uniform CNTs through a controlled growth process from a short carbon nanoring (template) that corresponds to the target structure of CNTs. Our simple retrosynthetic analysis led to the identification of cycloparaphenylenes (CPPs), acene-inserted CPPs, and cyclacenes as the shortest sidewall segments of armchair, chiral, and zigzag CNTs, respectively. With this overall picture in mind, we initiated our synthetic studies of aromatic rings/belts as an initial step toward structurally uniform CNTs in 2005. This research has led to (i) a general strategy for the synthesis of CPPs and related carbon nanorings using cyclohexane derivatives as a benzene-convertible L-shaped unit, (ii) a modular, size-selective, and scalable synthesis of [n]CPPs (a shortest segment of armchair CNTs), (iii) the X-ray crystal structure analysis of CPPs, (iv) the design and synthesis of acene-inserted CPPs as the shortest segment of chiral CNTs, and (v) the first synthesis of cyclo-1,4-naphthylene, a π-extended CPP. We believe this work will serve as important initial steps toward a controlled synthesis of CNTs.

Programmed Synthesis of Tetraarylthiophenes through Sequential C−H Arylation

A general protocol for the programmed synthesis of tetraarylthiophenes has been established. The utilization of three catalysts, RhCl(CO){P[OCH(CF(3))(2)](3)}(2), PdCl(2)/P[OCH(CF(3))(2)](3), and PdCl(2)/bipy, enables regioselective sequential arylations at the three C-H bonds of 3-methoxythiophene with iodoarenes. Interesting metal- and ligand-controlled regiodivergent C-H arylations have been uncovered during this study. The installation of fourth aryl groups to the thus-generated 2,4,5-triaryl-3-methoxythiophenes has been accomplished through a sequence of demethylation, triflation, and Suzuki-Miyaura coupling.

Decarbonylative C–H Coupling of Azoles and Aryl Esters: Unprecedented Nickel Catalysis and Application to the Synthesis of Muscoride A

A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.