Synthesis Of The Chinese Medicine Active Ingredients Of Arylthiophenes Catalyzed By α-amino Imine Palladium Complexes

In the 21 st century, more and more people are concerned about the health. It is recognized that the traditional Chinese medicine play important effect on the disease prevention and therapy. The structure of Chinese medicine active ingredients is very complicated that it is difficult for separation, purification and synthesis, which limits the international application of Chinese medicine. Nowdays, the tools for separation and purification has been greatly developed, and some sturcutre of the ingredients of traditional Chinese medicines have been definited. It is found that the aromatic heterocyclic motifies such as arylated thiophenes are unviersly existed, such as pluchea indica less, achillea millefolium, tagetes erecta, eclipta prostrate, chamomilia. The palladium-catalyzed direct C-H bond arylation has become one of the most important methods for the construction of carbon-carbon bonds in the past decade, which is known as broad functional group tolerance and without the need of synthesis of organometallic coupling partners in traditional palladium-catalyzed Suzuki, Stille, Kumada, Hiyama, and Negishi cross-couplings, It is found that the phosphine-based ligands are necessary in these reactions, however, they are not readily available, air-sensitive and toxic. Moreover, a high palladium loading of 5-10 mol% are required.To overcome the disadvantages of the catalytic instability and environmental concerns, we envisioned that a strong binding of the electron-rich and bulky steric N,N-based α-amino imine palladium complexes would help the palladium retain its ligand and retard the catalyst decomposition, Herein, we describe six generally applicable bulky α-amino imine palladium complexes for the efficient cross-coupling reactions between a variety of thiophenes with(hetero)aryl bromides.1. Synthesis of α-amino imine palladium complexesDiketone was reacted with anilines in the presence of catalytic acid to obtain six α-diimines. Then treatment of α-diimines with trimethylaluminum and subsequent hydrolysis provided the ligands in good yield. Then the coordination reactions were conducted by treatment of the ligands with PdCl2 in reflux methanol to provide the palladium complexes C1-C6.2. Studies on the catalytic properties of α-amino imine palladium complexesThe activities of benzothiophene and 4-bromobenzonitrile as the model reaction on palladium complex screening were conducted. It is found that the bulky C5 was the most efficient precatalyst, a veriety of the aryl bromides, regardless of electron-rich and electron-withdrawing substrates as well as the sterically hindered substrates were successfully converted into corresponding desired cross-coupling products. The optimal reaction condition was carried out by the K2CO3 as base, PivOH as additive and DMAc as solvent. Using 2-methyl thiophene and bromonaphthalene under the optimal conditions with 0.5 mol% Pd loading, 99% yield was obtained.3. In this thesis, six α-amino imine ligands L1-L6, palladium complexes C1-C6 and coupling products were confirmed by 1HNMR, 13 CNMR. The Crystal structures of C1 and C3 have been examined by X-ray.