Palladium-Catalyzed Cross-Coupling And Decarbonylative Cross-Coupling Reactions For Synthesis Of Heterocycles

Heterocycles are the cyclic molecules possessing one or more heteroatom(s) such as nitrogen, oxygen, sulfur, and so on. They are not only found in alkaloids, nucleic acids, antibiotics, and other biologically active molecules but also the essential components of many drugs. Palladium-catalyzed cross-coupling reactions are one of the powerful tools for formation of carbon-carbon bond and they play an important role in contemporary organic synthesis. Palladium-catalyzed cross-coupling reactions can be used for construction of heterocyclic skeletons. They are also the effective methods for derivatization by introducing new substituents on to the existing heterocycles. This thesis studies on the preparation of derivatives of 1,4-benzoxazines and generation of novel isoindolin-1-ones via palladium-catalyzed cross-coupling and decarbonylative intramolecular cross-coupling reactions, respectively.Chapter 1 gives a brief introduction on the classical cross-coupling reactions mediated by palladium catalysts and their applications in carbon-carbon bond formation. An emphasis is placed on Suzuki-Miyaura cross-coupling reaction which is covered in this thesis research. A more detail treatment is made for palladium-catalyzed decarbonylative cross-coupling reactions, including the reaction scope, the reaction mechanisms, and the examples in the current literature. As the reverse reaction pathway, the carbonylative cross-coupling reaction is also mentioned. Applications of palladium-catalyzed cross-coupling reactions both in construction of heterocyclic skeletons and in preparation of heterocyclic derivatives are illustrated with selected examples.The results of synthesis of 1,4-benzoxazine derivatives are described in chapter 2. By using the aromatic amide-derived phosphine (Aphos) ligands developed in our laboratories, the catalyst system consisting of Aphos-Pd(OAc)2 demonstrates excellent activity for Suzuki-Miyaura cross-coupling reactions of five 6-chloro-1,4-benzoxazines with three representative aryl boronic acids under mild reaction conditions (60℃,≤24 h), affording fifteen 6-aryl-1,4-benzoxazines in excellent yields. These results highlight the generality of Aphos-Pd(OAc)2 precatalyst for derivatization of aryl chlorides.The key results of this thesis are presented in chapters 3 and 4, which deal with palladium-catalyzed decarbonylative intramolecular cross-coupling reactions. Details on discovery of this new reaction protocol, reaction condition optimization, reaction mechanism study, and synthesis of isoindolin-1-ones are disclosed. Starting from 4-(2'-bromobenzyl)-1,4-benzoxazin-2,3-diones, a number of N-(2'-hydroxyaryl)-isoindolin-1-ones are formed via palladium-catalyzed decarbonylative intramolecular cross-coupling process. Moreover, by mimicking structural similarity with validation by experimentation, N-(2-bromobenzyl)oxanilic acid phenyl esters are confirmed to undergo the same palladium-catalyzed decarbonylative intramolecular cross-coupling reaction to furnish N-arylisoindolin-l-ones. These results suggest good generality of this decarbonylative cross-coupling reaction.The experimental section, compound characterization data, and references are found at the end of the thesis, together with copies of both 1H and 13C NMR spectra of the new compounds synthesized during this thesis research.