Studies On Copper-catalyzed Cross-Coupling Reactions And Applications In Synthesis Of Heterocyclic Compounds

Aromatic carbon-heteroatom bond formation is a crucial research topic for investigation on synthetic methodology. A vast number of aryl (thio)ether, amine and heterocycles could be found as subunits in the structures of natural products and pharmaceutical molecules. Therefore, assembly of aromatic carbon-heteroatom bond by a more efficient and economical way is an eternal target pursued by organic chemists.Copper-catalyzed cross-coupling reaction is an important tool for building aromatic carbon-heteroatom bond, which is characterized as high efficiency, low toxicity and low cost. Recently, application of this protocol in tandem synthesis of heterocycles is emerged as a hotspot. Our team discovered that a proper ortho-substitution on aryl halide could be involved in copper catalytic cycle, which leaded to many benefits, such as lower reaction temperature, lower catalyst loading and increased chemical yield. Based on this envision, we selected rationally designed substrates and successively developed several methods to synthesize heterocyclic compounds, including quinoxalin-2(1H)-ones, quinazolin-4(3H)-ones, dibenzo[b,f][1,4](ox/thi) azepin-1(10H)-ones and3-aminoindazoles. This dissertation includes five chapters and the details are summarized below:In Chapter1, the background and significant progress of copper-catalyzed cross-coupling reaction has been briefly reviewed. Since Ullmann reported the first copper-catalyzed example, many research groups, such as Buchwald’s, Taillefer’s and our teams have made continuous dedications in this field. A series of ligands were developed to promote different type of cross-coupling reactions, which have been successfully applied in the synthesis of heterocyclic compounds.In Chapter2, a new protocol for the synthesis of quinoxalin-2(1H)-one derivatives is described. Aryl halides possessing ortho assisted group and cyclic amino acids were selected as substrates to undergo copper-catalyzed coupling, followed by hydrolysis and cyclization in one-pot transformation to afford quinoxalin-2(1H)-ones. It was observed that the chiral feature, inherited from enantiopure amino acid, could be almost preserved under optimized conditions.In Chapter3, a new protocol for the synthesis of quinazolin-4(3H)-one derivatives is described.2-bromo-N-phenylbenzamide is a versatile candidate and it exhibits outstanding ortho-subsitutent effect in copper-catalyzed reactions. This type of substrates was coupled with amide compounds, followed by dehydrative cyclization to afford quinazolin-4(3H)-one products. This method exhibited outstanding merits than previous process, such as broad application in organic synthesis, mild reaction condition and high level of yield. Moreover, this protocol could be applied in the synthesis of Methaqualone, a psychotropic drug and Dictyoquinazol A, a natural product.In Chapter4, a new protocol for the synthesis of dibenzo[b,f][1,4](ox/thi) azepin-11(10H)-ones is described. The one-pot reaction of2-bromo (thio)phenol and2-bromo-N-phenylbenzamide via twice cross-couplings afforded dibenzo [b,f][1,4](ox/thi)azepin-11(10H)-ones. This facile methodology allows rapid access to a variety of bioactive compounds such as Sintamil, a known psychotropic drug. Furthermore, an unwilling side product derived by Smiles rearrangement was observed by the use of substituted2-bromo thiophenol as coupling partner. Thus a preliminary investigation was conducted to unveil the effect of ligand and substitutent on the selectivity of products.In Chapter5, a new protocol for the synthesis of3-aminoindazoles was described. The one-pot process was started from2-bromobenzonitrile, via copper-catalyzed coupling with hydrazine derivatives and followed by intramolecular cyclization to give3-aminoindazoles. This method can conveniently provide diverse3-aminoindazoles by varying their substituents at the1-position and the phenyl ring part.