Metalation Dictates Remote Regioselectivity: Ruthenium-Catalyzed Functionalization of meta C_(Ar)—H Bonds

摘要

In the last few decades, methods for the transition-metal-catalyzed functionalization of aromatic C—H bonds have been extensively studied, thus resulting in powerful new tools for synthesis in academia and in industry. Amongst the many challenges, controlling the regioselectivity in the C—H activation step is indispensable for designing efficient functionalization processes. Often, the most acidic C—H bond in an arene can be functionalized preferentially, such as in the functionalization of electron-poor heteroarenes or in direct arylation reactions which proceed by a concerted metalation-deprotonation (CMD) pathway. The most frequently used approach, however, involves the use of directing groups which allow access to ortho-functionalized aromatic compounds by a chelation-assisted cyclometalation. In contrast, the development of a general catalytic transformation at the meta and para position of aromatic compounds with high levels of selectivity remains a challenge. Recent breakthroughs in this area have been the development of two main strategies for meta functionalization (Figure 1). Firstly, Hartwig et al. and Smith el al. reported the one-pot iridiitm-calalyzed boryla-tion and functionalization reactions of 1,3-disubstitutcd arenes at C5. Regioselectivity was shown to be dictated by a minimization of the steric bulk around the catalyst (Figure 1a). Sterics have also been suggested as the controlling factor in some palladium-mediated processes. In a second strategy, regiocontrol is achieved through coordination of the transition-metal catalyst to a directing group, thus facilitating the approach of the catalyst to induce functionalization of the meta C—H bonds (Figure 1 b). This type of functionalization was demonstrated by Yu et al. who designed a removable directing group for palladium-catalyzed olefination reactions of meta OH bonds and proceed through the formation of a macropalladacyclc (Figure 1 b). Coordination to a copper-(III) catalyst and a subsequent Heck-type mechanism has also been invoked to explain the regioselectivity in the copper-catalyzed meta-selective arylation of anilides and β-aryl carbonyl compounds reported by Gaunt et al. (Figure 1b), even though the exact mechanism of this reaction remains unclear.