Study On The Pd-Catalyzed N-Chelation-Directed Sp~2C-H Bond Activation

In recent years, Pd-catalyzed coupling reactions have been widely used in the preparation of natural products, biologically active compounds, organic electronic materials, and some fine chemicals. Meanwhile, the direct carbon-hydrogen bond activation/functionalization has emerged as a viable strategy for the synthesis of natural products and other pharmaceutical compounds. Compared with the classical coupling reaction, the C-H bond activation avoids pre-functionalized materials, greatly reducing the reaction steps, improving the reaction efficiency and achieving the atom economicy. Although the C-H bond activation has obvious advantages, it also brings new challenges. Since one molecule of the organic compound containing a plurality of similar dissociation energy C-H bond, achieving the high regioselectivity of C-H bond functionalization has become a major problem. In general, the directing group can selectively enabled C-H bond functionalization through coordinating with palladium. Therefore, the introduction of suitable directing-groups has been widely investigated and has become a hot topic in organic synthesis recently. In this research work, Pd-catalyzed sp2C-H bond activation reactions and the derivatization using amide as the directing group are able to be conducted:1. The synthesis of isoindolinones by a palladium-catalyzed cascade reaction was achieved, which involves the cleavage of three C-H bonds and one N-H bond as well as the formation of one C-C bond and one C-N bond. The reaction proceeds through the palladium-catalyzed ortho sp2C-H activation directed by the CONHOMe group of benzamides and the intramolecular oxidative amidation leading to the isoindolinone products as the E-isomers rather than the Z-isomers reported in the literature.2. An unexpected and novel approach to construct sp2C-sp3C bond has been developed via N-O bond cleavage without any external catalysts or additives. To the best of our knowledge, there is still no precedent for a catalyst-free radical-based approach to construct sp2C-sp3C bond just under thermal heating conditions. Compared with those metal-catalyzed reactions, this is a novel, very simple, highly effective and environmentally friendly process and would be a very attractive radical process towards new bond formation.3. The palladium-catalyzed ortho-arylation of benzamides by aryl iodides has been demonstrated with the simplest amide CONH2as a directing group for the first time. This protocol can be applied to various benzamides and aryl iodides with both electron-donating and electron-withdrawing groups. In addition, the synthesized biphenyl-2-carboxamides can be further transformed to other biphenyl derivatives such as carboxylic acids, nitriles, carbamates, and amines.4. We have demonstrated the Pd-catalyzed regioselective ortho-acyloxylation of N-nitrosoanilines using N-nitroso as a directing group for the first time. Our protocol can be applied to a wide range of N-nitrosoanilines with both electron-donating and electron-withdrawing groups. The obtained products can be further manipulated to bring out2-(methylamino)phenols, which can be used to synthesize important pharmaceutical drugs and drug precursors.