Br(?)nsted Acid-Catalyzed Intramolecular Cyclization Of Perfluoroalkylated 3-Indolylmethanols For The Construction Of Perfluoroalkylated Polycycles

Indoles and their derivatives are extremely important nitrogen-containing heterocyclic alkaloids that are widely found in pharmaceutical molecules and natural products,which have a variety of biological activities such as antibacterial,antiviral and anticancer,with important applications in medicine,pesticides and materials.Indenoindoles have been widely used as precursors for the total synthesis of many natural products and have shown a wide range of biological activities.They are also frequently used as catalysts for the polymerisation of metal complexes and as materials for organic electroluminescent devices due to their electron-rich properties and powerful charge-transfer capabilities.For fluorine atoms are strongly electronegative,lipophilic and stable,the introduction of them into drug molecules can significantly improve the physicochemical properties and biological activity of drugs,and is becoming a common method for drug screening.Among various fluorinated components,trifluoromethyl is considered to be the key drug component and multifunctional synthesizer;perfluoroalkyl occupied a unique position in organic and materials chemistry due to its strong electron absorption,large spatial site resistance,good lipophilicity and stability.Although a variety of efficient strategies have been developed for the preparation of indenoindoles,they often require transition metal catalysts or materials that are multi-step and not easily synthesised;furthermore,the synthesis of perfluoroalkyl indenoindoles has not been reported.Therefore,It is of great importance to develop a new method with mild conditions,simple operation and simple synthesis of materials for the synthesis of 10-perfluoroalkylated indeno[1,2-b]indoles.The major work of this thesis includes the following two chapters:(1)Construction of 10-perfluoroalkylated indeno[1,2-b]indoles via Br(?)nsted acid-catalyzed dehydrative Nazarov-type cyclization of perfluoroalkylated indolylmethanolsA new method for hexafluoroisopropanol/Br(?)nsted acid co-catalyzed perfluoroalkylated3-indolylmethanols dehydrative intramolecular Nazarov-type cyclization for the synthesis of10-perfluoroalkylated indeno[1,2-b]indoles is developed.Using sulfonyl-protected perfluoroalkylated indolylmethanols as the starting material to explore the effects of different catalysts,solvents and other factors on the reaction.Substrate expansion was carried out under optimal conditions to synthesize a series of structurally novel 10-perfluoroalkylated indeno[1,2-b]indoles.Subsequent ten-gram-scale experiments as well as product transformations demonstrated the synthetic utility of the present protocol.Finally,a plausible reaction mechanism was proposed.Furthermore,the method can be further extended to the efficient synthesis of trifluoromethylated thieno[1,2-b]indoles by using trifluoromethylated 2-thiophenyl-3-indolyl as starting materials.(2)Synthesis of 3-perfluoroalkylated benzothieno[b]cyclopentenonesHexafluoroisopropanol/Br(?)nsted acid co-catalysed perfluoroalkylated 3-indolyl(2-benzothiophenyl)methanols dehydrative Nazarov-type cyclization and subsequent hydrophilic nucleophilic addition/C2-N1 cleavage cascade reaction was developed,provding3-perfluoroalkylated benzothieno[b]cyclopentenones in high to excellent yields under mild reaction conditions.Benzothiophenes are an extremely important sulfur-containing heterocyclic compounds with unique electron-rich properties,as well as an useful intermediate in organic synthesis whose structures are commonly found in pharmaceutical and biologically active molecules.Cyclopentenones are not only important backbones for many biologically important molecules,but are also essential structural motifs for the synthesis of biologically active functional molecules.Although many methods for the synthesis of benzothiophene derivatives or cyclopentenones have been disclosed,methods for the synthesis of perfluoroalkylated benzothieno[b]cyclopentenones have not yet been reported.In this chapter,with perfluoroalkylated 3-indolyl(2-benzothiophenyl)methanols as the starting material to explore the effects of different catalysts,solvents and other factors on the reactions.Substrate scope was next evaluated under the established optimal conditions,furnishing a diverse array of3-perfluoroalkylated benzothieno[b]cyclopentenones.Subsequent scale-up experiments and further product transformations demonstrated the synthetic utility of the present protocol.Finally,we proposed a possible reaction mechanism on the basis of controlled experiments.In this thesis,an efficient synthetic method for the construction of novel10-perfluoroalkylated indeno[1,2-b]indoles and 3-perfluoroalkylated benzothieno[b]cyclopentenones that relies on hexafluoroisopropanol/Br(?)nsted acid co-catalyzed perfluoroalkylated3-indolylmethanols dehydrative intramolecular Nazarov-type cyclization tandem reaction have been developed.The method is easy to operate and does not require any metal catalyst.The reaction can be scaled up to ten-gram scale,without a significant decrease in product yields,demonstrating the robustness and practicability of the present protocol.In addition,we envision the present protocol will find broad applicability in the field of chemical synthesis,fluorochemistry as well as material science.