Metal‐Free Synthesis of Fluorinated Indoles Enabled by Oxidative Dearomatization

Abstract

Nitrogen heterocycles are found in a majority of approved small-molecule pharmaceuticals, and the number of approved fluorinated drugs is increasing each decade. Therefore, new approaches for accessing fluorinated nitrogen heterocycles are of great significance. A novel, scalable, and metal-free method for accessing a wide range of fluorinated indoles is described. This oxidative-dearomatization-enabled approach assembles 2-trifluoromethyl NH-indole products from simple commercially available anilines with hexafluoroacetylacetone in the presence of an organic oxidant. The nature of the aniline N-capping group is critical for the success of this new reaction. Furthermore, the indole products contain a 3-trifluoroacetyl group, which can be exploited to access a plethora of useful functional groups.

An aerobic copper-mediated domino process for the synthesis of 3-(trifluoromethylseleno)indoles

“…11–14 Taking cues from the positive effect of fluorinated substituents, it was envisioned that introducing fluorine-containing groups on the indole rings could increase their bioactivity. In this context, a flourish of activity in the development of synthetic approaches to fluorinated, 15 trifluoromethylated 16–22 or trifluoromethylthiolated 23–37 indoles has recently been witnessed in the literature. Despite these great significances, the synthesis of trifluoromethylselenolated indoles is rarely explored and is mainly relied on strategies employing electrophilic or radical trifluoromethylselenolation of existing indole cores.…”

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

“…[2] Owing to the strong electron-withdrawing property of fluoroalkyl groups, the fluorinated alcohols possess some unique properties: (1) Generally, there are two versions of reactions participated by fluorinated alcohols: the reactions catalyzed by additional promoters with fluorinated alcohols as solvents and the reactions performed without any catalysts. In the former version, numerous notable works have been achieved, in which transition metal complexes (Co, [3] Fe, [4] Cu, [5] Pd, [6] Ru, [7] Ir, [8] ), Brønsted acids, [9] hypervalent iodines [10] and electrochemical activation [11] have been applied as catalysts, additives or novel driving-force. With the assistance of fluorinated alcohols' unique properties, reactive intermediates of the above reactions can be stabilized by the distinctive solvent microstructure.…”

Direct Access to Functionalized Indoles via Single Electron Oxidation Induced Coupling of Diarylamines with 1,3-Dicarbonyl Compounds

“…12 Later, Njardarson and co-workers reported a metal-free synthesis of fluorinated indoles via an oxidative dearomatization−rearomatization strategy (eq 2) with the use of phenyliodine(III) diacetate as the oxidant. 13 However, due to the low oxidative potential, anilines can easily undergo dehydrogenative dimeriza-tion to form azo compounds under oxidative conditions. 14 So, it is understandable that preinstallation of enamines from anilines and 1,3-dicarbonyl compounds or the use of N-protected anilines is essential for the indole syntheses in these two examples (eqs 1 and 2).…”

“…For instance, the Glorius group reported a palladium-catalyzed oxidative cyclization of enamines for the synthesis of indoles (Scheme , eq 1) . Later, Njardarson and co-workers reported a metal-free synthesis of fluorinated indoles via an oxidative dearomatization–rearomatization strategy (eq 2) with the use of phenyliodine­(III) diacetate as the oxidant . However, due to the low oxidative potential, anilines can easily undergo dehydrogenative dimerization to form azo compounds under oxidative conditions .…”