Synthesis of CF₃CH₂-Containing Indolines by Transition-Metal-Free Aryltrifluoromethylation of Unactivated Alkenes

Abstract

With an unactivated double bond as the radical acceptor, allyl amines underwent a metal-free trifluoromethylation/cyclization cascade with CFSONa (Langlois' reagent), affording CFCH-containing indolines and tetrahydroisoquinolines, whose practical syntheses are significant challenges. This protocol features mild conditions, low cost, and a broad substrate scope.

Synthesis of Polychloromethyl-Containing Indolines via Metal-Free Radical Arylpolychloromethylation of Unactivated Alkenes

“…Substrates were synthesized according to the literature procedure. [32] 4.2 General procedure A 35-mL oven-dried Schlenk tube, equipped with a magnetic stirring bar, was charged with N-(2-methylallyl)-N-phenylacetamide (1a1) (95 mg, 0.5 mmol), DCP (405 mg, 1.5 mmol), and CHCl 3 (5.0 mL). The reaction mixture was stirred at 120 ℃ for 3 h, then it was quenched with saturated aqueous Na 2 S 2 O 3 (2.0 mL) and water (20.0 mL), and extracted with CH 2 Cl 2 (10.0 mL) three times.…”

“…[25～28] However, access to indolines is mainly restricted to indole dearomatization reaction, [29 ～ 31] and methodologies from acyclic substrates are rather limited. [32～34] Recently, we developed several protocols for the incorporation of various functional groups (i.e., CF 3 CH 2 , [32] phosphonoalkyl, [33] and cyanoalkyl [34] ) into the indoline framework by using N-allyl anilines as olefinic radical acceptors. Herein, we report a metal-free polychloromethylation/cyclization cascade of unactivated alkenes, which provides a direct access to polychloromethylated indolines.…”

An External-Catalyst-Free Trifluoromethylation/Cyclization Strategy To Access Trifluoromethylated-Dihydroisoquinolinones/Indolines with Togni Reagent II

“…CF 3 radical. 24 In contrast, without addition of any additional oxidant, our newly developed external-catalyst-free trifluoromethylation/cyclization methodology allowed more fragile Naryl-N-allylacetamides to be employed as our reactants, such as the one attached with the methylthio group, showing high functional tolerance. Additionally, all our related syntheses toward trifluoromethylated N-acetylindolines were achieved within half the reaction time of what Liang's method required, showing a much higher reaction efficiency.…”

“…Moreover, N -allyl- N -phenylacetamide was also applicable for this reaction, affording product 5l in a good yield. With respect to the synthetic method toward trifluoromethylated N -acetylindolines, Liang’s group just reported a cascade synthetic method to access some trifluoromethylated N -acetylindolines but using CF 3 SO 2 Na rather than Togni-II as the trifluoromethylating reagent; however, a strong oxidant (1.5 equiv of K 2 S 2 O 8 ) was required by this reaction for oxidizing CF 3 SO 2 Na to release SO 2 and the CF 3 radical . In contrast, without addition of any additional oxidant, our newly developed external-catalyst-free trifluoromethylation/cyclization methodology allowed more fragile N -aryl- N -allylacetamides to be employed as our reactants, such as the one attached with the methylthio group, showing high functional tolerance.…”

Cu‐Mediated Synthesis of Indolines and Dihydroisoquinolinones through Arylperfluoroalkylation of Unactivated Alkenes

“…In 2016, Cheng and Yuan group have reported the Pd‐catalyzed arylperfluoroalkylation for the synthesis of heterocycles. In 2018, our group developed the synthesis of CF 3 CH 2 ‐containing indolines by transition‐metal‐free aryltrifluoromethylation of unactivated alkenes. Inspired by recent advances in difunctionalization of unactivated alkene,[3a], and in continuation of our interest in the synthesis of biologically active compounds, we speculate that R f acts as a free radical initiator mediated by copper without ligand and N ‐allyl acts as a free radical acceptor to achieve the construction of fluorinated indoline structures by free radical cascade reaction.…”