Synthesis of Trifluoromethyl Derivatives of Quinoline and Isoquinoline

Abstract

Trifluoromethyl derivatives of quinoline and isoquinoline were synthesized using phosphonium salts with a trifluoroacetamide group in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene. The quinoline skeleton was formed from a phenethylphosphonium salt with a trifluoroacetamide NH proton, whereas the isoquinoline formation required masking of the amide proton of trifluoroacetamide in the benzylphosphonium structure.Fluorinated aromatic compounds are found in various bioactive compounds, such as pharmaceuticals and pesticides. This is because the introduction of a fluorine group or a trifluoromethyl group into organic molecules causes significant changes in the chemical and pharmaceutical properties of the parent molecules. 1 Currently, the trifluoromethyl group is one of the most common fluorine-containing substituents found in commercial pharmaceuticals and agrochemicals. 2,3 Considerable efforts have been made developing synthetic strategies for introducing trifluoromethyl groups into organic skeletons. Two primary methods have been reported: (i) direct trifluoromethylating reactions using various trifluoromethylating reagents 4 and (ii) the use of pre-functionalized CF3 group-containing building blocks. 5 Various organofluorine compounds can be obtained by the first method using different types of trifluoromethylating reagents based on their electronic properties, such as radicality, 6 electrophilicity, 7 and nucleophilicity. 8 However, this method requires multi-step synthesis, and the trifluoromethylating reagents are sometimes difficult to handle, expensive, or both. Some studies used the second method with fluorinated building blocks, such as β-trifluoromethyl-α,β-unsaturated carbonyl compounds, which have attracted tremendous attention in recent years because of their availability and versatility. 9 By contrast, we have used trifluoroacetic acid derivatives, such as trifluoroacetic anhydride (TFAA), as a