Ga(OTf)₃-Catalyzed Temperature-Controlled Regioselective Friedel–Crafts Alkylation of Trifluoromethylated 3-Indolylmethanols with 2-Substituted Indoles: Divergent Synthesis of Trifluoromethylated Unsymmetrical 3,3′-and 3,6′-Bis(indolyl)methanes

Abstract

An unprecedented Ga­(OTf)3-catalyzed, temperature-controlled regiodivergent alkylation of 2-substituted indoles with trifluoromethylated 3-indolylmethanols is described that provides structurally diverse unsymmetrical 3,3′- and 3,6′-bis­(indolyl)­methanes with a CF3-containing quaternary carbon center in good to excellent yields under mild conditions. In addition, this present protocol could be successfully extended to the synthesis of difluoromethylated 3,3′- and 3,6′-bis­(indolyl)­methanes with excellent efficiency.

Reaction of indoles with aromatic fluoromethyl ketones: an efficient synthesis of trifluoromethyl(indolyl)phenylmethanols using K2CO3/n-Bu4PBr in water

“…Particularly, the Friedel-Crafts alkylation of 3-indolylmethanols with indoles has become a useful method for the preparation of 3,3'-, and 3,6'-DIMs, which are known to possess a wide variety of biological activities, including anti-inflammatory, and anticancer effects. Therefore, we decided to synthesize DIMs from 3a, which reacted with indole (1b) or 2-phenylindole (1k) in the presence of Ga(OTf) 3 in ACN at room temperature or at 80 °C as reported by Y. Ling et al [32]. As indicated in Scheme 2, the desired unsymmetrical 3,3'-DIM (9: 81%) and 3,6'-DIM (10: 77%) with quaternary center were afforded in good yields.…”

Reaction of indoles with aromatic fluoromethyl ketones: An efficient synthesis of trifluoromethyl-indolyl-phenylethanols using K2CO3/nBu4PBr in water

“…This could be due to the dilution of catalytic system in each cycle. Therefore, we decided to synthesize DIMs from 3a, which reacted with indole (1b) or 2phenylindole (1k) in the presence of Ga(OTf)3 in ACN at room temperature or at 80 o C reported by Ling, Y. et al [15]. As indicated in Scheme 2, the desired unsymmetrical 3,3'-DIMs (9: 81%) and 3,6'-DIMs (10: 77%) with quaternary center were afforded in good yields.…”

“…99% 91% 87% 84% 15 Scheme 2. Synthesis of trifluoromethylated unsymmetrical 3,3'-and 3,6'-DIMs (9)(10)(11).…”

Fluorinated Alcohols: Magic Reaction Medium and Promoters for Organic Synthesis

“…In 2015, our group disclosed a kind of fluorinated alcohol mediated S N 1-type reactions of 3-indolylmethanols 11 [17] with diverse nucleophiles 12 such as indoles (12 a-b), active methylenes (12 c), silyl enol ether (12 d), anthrone (12 f), arenes (12 g, 12 h), thiol (12 e) and thiophenol (12 i) (Scheme 4). [18a] In this reaction, dual H-bonds were formed between TFE and 3-indolylmethanol as shown in transition state 14, in which the CÀ O bond was significantly weakened and could be easily cleaved to furnish alkylideneindoleninium intermediate 15.…”