Palladium-Catalyzed Cross-Coupling And Microwave-Assisted Cascade Reactions For Synthesis Of Heterocycles

Heterocyle is one of the most important organic compounds widespread in alkaloids, nucleic acids, antibiotics and other biologically active molecules and is also key substructure featured in many drugs. Therefore, to search methods for fast and effective heterocyclic synthesis remains long-time a hot topic. Palladium-catalyzed cross-coupling reaction provides a powerful means to construct carbon-carbon bond and plays an important role in contemporary organic synthesis. Also, it can be used for construction of heterocyclic skeletons and derivatization of heterocyclic compounds. Ugi-4CR and post-Ugi annulations cascade reactions offers another way to build heterocyclic structure. This thesis studies on construction of1,4-benzoxazine skeleton via "one-pot" Ugi-4CR and O-alkylation reaction, preparation of derivatives of1,4-benzoxazines via Suzuki-Miyaura coupling reaction and generation of novel isoindolin-1-ones via palladium catalyzed decarboxylative coupling reaction.Chapter1briefly introduces Suzuki-Miyaura coupling reaction, decarboxylative intramolecular cross-coupling and their applications in carbon-carbon bond formation. In Chapter2, after a concise review of medicinal value and synthetic methods of1,4-benzoxazines, the research to synthesize and derivative3,4-dihydro-3-oxo-2H-1,4-benzoxazines is covered. Starting from2-aminophenols, through reductive N-alkylation with2-bromobenzaldehyde and O-alkylation annulations with2-bromo alkanoates under microwave irradiation,3,4-dihydro-3-oxo-2H-1,4-benzoxazines are established. Then, in the catalytic system of Pd(OAc)2-Aphos, and K3PO4.3H2O,3,4-dihydro-3-oxo-2H-1,4-benzoxazines react with aryl boronic acid via Suzuki cross-coupling reaction to furnish the derivative products with good yields.In Chapter3, after a brief introduction of isoindolin-1-ones, an attempted investigation on isoindolin-1-ones preparation via the palladium-catalyzed decarboxylative intramolecular cross-coupling reaction is presented. With 2-Bromobenzaldehyde and aniline as starting materials, through a series of amine condensation, imine addition, acylation and finally palladium-catalyzed decarboxylative intramolecular cross-coupling reaction, isoindolin-1-ones can be obtained. After detailed experiment and analysis, the mechanism of the reaction is proposed.Chapter4firstly covers the development of multicomponent reactions and the application of Ugi-4CR and post Ugi annulations in heterocyclic chemistry, then describes the results on establishment of the microwave-assisted "one-pot" reaction of Ugi-4CR and intramolecular O-alkylation reaction for synthesis of3,4-dihydro-3-oxo-2H-1,4-benzoxazines. Compare the microwave-assisted to the room temperature syntheses, it reveals that the microwave-assisted protocol can significantly accelerate the reaction and shorten the reaction time from hours to30min or so with the yields similar or slightly lower.The experimental section, characterization of all new compounds, cited references and copies of original1H and13C NMR spectra are found at the end of the thesis.