Copper-Catalyzed Functionization Of Indoles

Since indoles exist abundantly in many biologically active natural products, functional materials and pharmaceutical compounds, their synthesis and further functionalization are of considerable importance. In the past few years, the development of environmentally benign and cheap copper catalysts has aroused much attention in the studies of indole functionalization. Recently, there has been remarkable progress in copper-catalyzed indole functionalization with inexpensive, readily available, insensitive-to-air and low-toxicity copper catalysts.This dissertation mainly focused on the studies of copper catalyzed indoles and2-arylindoles functionalization reaction, and falled into four parts as follows.1. Copper-catalyzed activation of dioxygen:oxidative cyclization of2-arylindolesWe have developed a copper-catalyzed method for the dimerization of2-arylindoles. A series of unusual six-ring-fused heterocycles containing indole and quinoline skeletons was successfully synthesized by a copper-catalyzed reaction from2-arylated indoles. Two new bonds were regioselectively formed via C-H and C-H coupling.18O-Labelled experiments revealed that the dioxygen is not only the oxidant but also the reactant. This transformation provides a novel route for accessing fused nitrogen-containing heterocycles. The use of an inexpensive copper catalyst and O2or air as the oxidant is a practical advantage. The incorporation of an oxygen atom into the organic frameworks from atmospheric molecular oxygen (O2) offers the most ideal oxidation process.2. Copper-catalyzed sequential Ullmann N-arylation and aerobic oxidative C-H animation:a convenient route to indolo[1,2-c]quinazoline derivativesIn recent years, domino reactions have emerged as powerful tools for the synthesis of polyheterocycles3and reaction sequences that involve direct C-H activation are especially attractive. An efficient synthesis of indolo[1,2-c]quinazoline derivatives has been developed by copper-catalyzed sequential Ullmann N-arylation and aerobic oxidative C-H amination. The protocol uses readily available2-(2-halophenyl)-1H-indoles and (aryl)methanamines as the starting materials to afford indolo[1,2-c]quinazolines, which are the core units of hinckdentine A. The protocol uses environmentally friendly air as the oxidant, cheap Cu(OAc)2as the catalyst, and readily available reagents as the starting materials without the use of ligands. The accessibility and generality of this process make it highly valuable in view of the medicinal importance of these polyheterocycles.3. Highly regioselective synthesis of fused seven-membered rings through copper-catalyzed cross-couplingDibenz[b,f][1,4]oxazepine derivatives are pharmacologically active substances. However, the preparation of these seven-membered compounds usually needs several steps and harsh reaction conditions. The search for new and efficient strategies for the regioselective synthesis of this type of compounds is of great importance. Copper-catalyzed C-O-and C-N-coupling reactions are powerful tools in pharmaceutical synthesis and have been extensively investigated in the last decade. Many heterocyclic molecules have been prepared by the use of the copper-catalyzed coupling strategy. However, the application of copper catalyzed transformation for seven-membered heterocycles is rarely reported. We herein report a highly regioselective synthesis of indole-fused dibenzo[b,f][1,4]oxazepines that involves the copper-initiated C-N and C-O coupling of2-(2-halophenyl)-1H-indoles and2-halophenols in one-pot. Aryl chlorides can be successfully applied to the synthesis of these seven-membered compounds, which enhances the practical application of the methodology. Notably, this transformation involves Smiles rearrangement (1,5-hydrogen shift), which leads to the completely different regioselectivity from the classical cross-coupling of copper catalysis.4. K2CO3promoted direct sulfenylation of indoles:a facile approach of3-sulfenylindoles3-Sulfenylindoles represent pharmaceutically and biologically important structures. In the past decades, a lot of significant synthetic methods for the construction of3-sulfenylindoles have been developed. However, in many of these transformations, harsh reaction conditions and limitations, such as low yield or low functional group tolerance restrict their synthetic practice. We have demonstrated an easy and efficient K2CO3-promoted C(3)-H sulfenylation of free (N-H) indoles. In the presence of K2CO3, the reactions were performed well under mild conditions without extrusion of air and moisture, and the corresponding3-sulfenylindoles were obtained in good to excellent yields. This novel method provides a complementary, environment-friendly, and easy operation approach to accessing3-sulfenylindole derivatives.