Functionalization of Heteroarenes via Palladium/Norbornene-Catalyzed Double C-H Activation.

ConspectusElectron-rich five-membered heteroarenes, such as pyrroles, furans, indoles, and thiophenes, are prevalent in small-molecule drugs and other functional organic compounds. Consequently, methods that enable rapid and modular construction of densely substituted heteroaromatic frameworks are of high importance. From the synthetic efficiency standpoint, direct introduction of two or more functional groups into heteroarene cores would greatly increase complexity, facilitate structural diversification, and streamline preparation of target compounds. Direct C-H functionalization has emerged as one of the most step-economical strategies for synthesis of complex aromatic compounds. Despite that substantial progress has been achieved in site-selective functionalization of C-H bond at a single position, the regio- and site-selective installation of two distinct carbon substituents at adjacent positions remains a formidable challenge. On the other hand, palladium/norbornene (Pd/NBE) cooperative catalysis has emerged as a powerful platform for vicinal difunctionalization of arenes. The classical Pd/NBE reactions use aryl halides as substrates, which are initiated by Pd(0)-mediated oxidative addition. Recently, the Pd(II)-initiated variants triggered by C-H palladation offer unique advantages of employing less functionalized substrates and accommodating milder operational conditions. However, application of the Pd/NBE catalysis to the double C-H functionalization of electron-rich five-membered heteroarenes has not been a trivial task, due to competing heteroatom coordination, substrate sensitivity under oxidative conditions, and undesired side reactions such as ipso protonation. In this Account, we provide a concise summary of our systematic efforts in developing the Pd/NBE-catalyzed vicinal difunctionalization of diverse heteroarenes via double C-H activation in the past six years. Depending on the general catalytic mechanism, these reactions can be classified into "oxidative" and "redox-neutral" difunctionalization reactions. We will focus on describing the reaction scope, the proposed mechanism, the product selectivity, and current limitations of these reactions. In particular, we will discuss the design and use of structurally modified NBEs that enable these transformations, as well as the mechanistic insights into their roles in controlling reactivity and selectivity. The major topics covered include: (1) oxidative C2,C3-difunctionalization of thiophenes and furans, which are enabled by C2-amide-substituted NBEs; (2) oxidative C2,C3-difunctionalization of indoles, enabled by C1-substituted NBEs; (3) oxidative C2,C3-difunctionalization of pyrroles and its application to the total synthesis of leuconoxine-type alkaloids; and (4) redox-neutral C2,C3-difunctionalization of pyrroles, thiophenes, and furans. It is anticipated that this Account could offer a clear overview on the state of art in the field of the Pd/NBE-catalyzed difunctionalization of heteroarenes. Additionally, the scope and limitations outlined here would provide guidance to readers for choosing suitable conditions when using these reactions. Moreover, the mechanistic insights gained in these studies may have valuable implications for developing more general difunctionalization reactions via double C-H activation.