Kirika Ueda

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.

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.

Oxidative Biaryl Coupling of Thiophenes and Thiazoles with Arylboronic Acids through Palladium Catalysis: Otherwise Difficult C4‐Selective CH Arylation Enabled by Boronic Acids

Heteroarenes equipped with aryl groups (heterobiaryls) are often found in biologically active compounds, organic materials, and pharmaceuticals. In recent years, the direct C H arylation of heteroarenes catalyzed by a transition-metal complex 2] has emerged as a practical alternative to the wellestablished Pd-catalyzed cross-coupling reactions. Although tremendous efforts in the synthetic community including our groups have culminated in a wealth of useful and highly active catalysts, considerable room remains for further investigations. In particular, the development of a unique catalytic system that can preferentially activate and arylate an otherwise less reactive C H bond on heteroarenes is critically important from both scientific and practical points of view. For example, the Pd-catalyzed arylation of C H bonds of thiophenes with haloarenes is known to occur preferentially at the positions a to the sulfur atom (C2 and/or C5) following the typical reactivity profile of the thiophene ring (Scheme 1, top reaction). 7] Except for very rare cases, 8] selective and preferential arylation at the positions b to the sulfur atom (C3 and/or C4) does not take place. This is also true for the arylation of thiazoles, and a catalytic system that can preferentially arylate the least reactive C4 positions has not been forthcoming. We herein report that the Pd-catalyzed oxidative C H arylation of thiophenes and thiazoles with arylboronic acids manifests the otherwise difficult C4 regioselectivity (Scheme 1, bottom reaction). The present finding is significant not only because the regioselective outcome is complementary to that of the arylation using haloarenes, but also because it demonstrates the remarkable mechanistic difference between these two seemingly related Pd-catalyzed direct arylation processes. In early experiments, we found that the C H arylation of 2-ethylthiophene (1a) with phenylboronic acid (2a) took place in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO), Pd(OAc)2, and 2,2’-bipyridyl (bipy) in 1,2-dichloroethane (DCE) at 80 8C (Table 1, entry 1). Very surprisingly, we identified 2-ethyl-4-phenylthiophene (3aa) to be the sole coupling product under these conditions (69% yield). The corresponding C5-phenylation product (4aa) was not identified. Based on these promising initial results we decided to further optimize the reaction conditions (Table 1). After we had found that the bipy is necessary for the reaction to occur (entry 2), we screened various nitrogen-based bidentate ligands such as bipy derivatives (L1–L3), phenanthrolines (L4–L6), and TMEDA (L7) in the reaction of 1a with 2a (entries 3–9). Although L4 and L6 were found to be equally effective ligands in terms of yield and regioselectivity, we selected bipy as the standard ligand for subsequent experiments in view of its efficiency, cost, and simplicity. With a,a,atrifluorotoluene as a solvent, a slightly higher yield (76 %) was obtained (entry 10) and the reaction also proceeded at lower temperatures, remarkably even at room temperature (entry 11). Replacing TEMPO with other oxidants such as p-benzoquinone, (diacetoxyiodo)benzene, and copper(II) chloride resulted in a much lower reaction efficiency (entries 12–14). Higher concentrations of 1a in a,a,atrifluorotoluene resulted in higher yields while the high regioselectivity was maintained (entries 15 and 16). Reducing the catalyst loading to 5 or 2 mol% Pd(OAc)2 led to a slight Scheme 1. Reagent-controlled regiodivergency in the Pd-catalyzed C H arylation of thiophenes and thiazoles.

β-Selective C–H Arylation of Pyrroles Leading to Concise Syntheses of Lamellarins C and I

The first general β-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C-H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of pyrrole-derived natural products and pharmaceuticals. As such, we have successfully synthesized polycyclic marine pyrrole alkaloids, lamellarins C and I, by using this β-selective arylation of pyrroles with aryl iodides (C-H/C-I coupling) and a new double C-H/C-H coupling as key steps.

Mechanistic Studies on the Pd-catalyzed Direct CH Arylation of 2-Substituted Thiophene Derivatives with Arylpalladium Bipyridyl Complexes

Direct C-H phenylation of 2-ethylthiophene and 2-chlorothiophene with PhPdI(bipy) complex to form either the corresponding 4-phenyl or 5-phenylthiophene derivative is studied under stoichiometric conditions using various Lewis acids as additives. It is shown that reactions occur via the corresponding cationic Pd complex (PhPdbipy(+)) and that the counteranion determines the regioselectivity. High-level DFT calculations reveal that C-C bond formation occurs via a carbopalladation pathway and not via electrophilic palladation. These calculations give some indications regarding the regioselectivity of the thiophene arylation.

CHAPTER 8:Cross-Dehydrogenative-Coupling Reactions without Metals

Cross-dehydrogenative-coupling (CDC) reactions without metal promoters are summarized in this chapter. This includes CDC reactions using various oxidants such as hypervalent iodonium salts, peroxides and quinones. CDC reactions mediated by electrochemical methods, light irradiation, organocatalysts, and enzymes are also described in this chapter.