Metal- and additive-free TfOH catalyzed chemoselective O- and S-trifluoroethylation of oxindoles, isoindolines and thio-oxindoles

Abstract

Fluorine-containing moieties are of great interest in the development of new synthetic methods due to their considerable medicinal value. Thus, researchers have explored direct trifluoroethylation using CF₃CH₂-containing precursors; however, the high cost, prolonged synthesis time, toxic nature, and instability towards transition metal catalysis of these precursors pose challenges. As an alternative, conducting trifluoroethylation by in situ production of 2,2,2-trifluorodiazoethane (CF₃CHN₂) from CF₃CH₂NH₂·HCl in solution is a comparatively easy, safe, and greener approach. However, previous reports using 2,2,2-trifluorodiazoethane in solution also demonstrate the use of transition metal-catalyzed pathways under harsh reaction conditions and hazardous solvents. Herein, we have developed a triflic acid (a commercially available and cheap Brønsted acid) catalyzed protocol for O-trifluoroethylation of 3,3-disubstituted, monosubstituted, unsubstituted, and chalcone-based oxindoles and isoindolines, and S-trifluoroethylation of thio-oxindoles in the presence of in situ generated 2,2,2-trifluorodiazoethane in solution. This highly efficient metal- and additive-free strategy offers a mild and feasible approach to achieve chemoselective trifluoroethylation with good to excellent yields in a very short reaction time (10 minutes). This methodology has a broad substrate scope, making it a versatile approach that can be effectively employed for all types of cyclic amides. Additionally, the method is scalable for larger operations. The calculation of various green chemistry metrics, such as high atom economy (93%), high carbon efficiency (100%), high reaction mass efficiency (74%), and low E-factor(0.40 kg waste per kg product), confirms the eco-friendliness of this approach. The EcoScale evaluation showcases the simplicity, effectiveness, and eco-friendliness of this approach.