Brønsted Acid‐Catalyzed Intramolecular α‐Arylation of Ketones with Phenolic Nucleophiles via Oxy‐Allyl Cation Intermediates

Abstract

Nucleophilic addition to the oxy‐allyl cation intermediate has emerged as a promising methodology for functionalization of the α‐position of carbonyl compounds in an umpolung fashion. However, a structure of available carbon nucleophiles to trap the catalytically generated oxy‐allyl cation has been limited to highly nucleophilic ones. Herein, we report the Brønsted acid‐catalyzed α‐arylation of ketones employing less explored phenolic nucleophiles as carbon nucleophiles in the oxy‐allyl cation catalysis, affording ketones bearing an all carbon quaternary center at the α‐position.

A general approach to 2,2-disubstituted indoxyls: total synthesis of brevianamide A and trigonoliimine C

“… 13 a Initial efforts to employ a catalytic amount of p -toluenesulfonic acid ( p -TsOH, 10 mol%) in several common solvents (entries 3–5) at 0 °C to room temperature showed that a key issue was simple elimination of the ethoxy group (presumably via an iminium ion) to give ( Z )-enamine 26 . 19 We found, however, that the fluoroalcohol solvents 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), which are known to stabilize cationic intermediates, 20 gave none of the elimination byproduct and provided excellent yields of the desired aryl coupling product 25 (HFIP: 99%; TFE: 98%; entries 1 and 2). In fact, upon screening different acids in TFE, we found that acid identity was not especially important, with several Brønsted acids and Lewis acids (entries 6–10) all providing product to varying degrees ( e.g.…”

CuCl2‐Mediated Oxidative Intramolecular α‐Arylation of Ketones with Phenolic Nucleophiles via Oxy‐Allyl Cation Intermediates

“…Recently, we have reported the Brønsted acid‐catalyzed intramolecular α‐arylation of ketones with phenolic nucleophiles via oxy‐allyl cation intermediates (Scheme 1b) [6k] . However, ketone substrates require a hydroxy group as a leaving group at the α‐position to generate the oxy‐allyl cation intermediate, and the difficulty in their synthesis limits the synthetic utility of this transformation.…”

2,2-Disubstituted Indoxyls via Oxidative Dearomatization: Generalization to 2-Alkylindoles and Application to Alkaloid Synthesis

“…Reasoning that stabilization of the intermediate iminium ion might be crucial to an efficient coupling, we turned to fluoroalcohol solvents which are known to stabilize cationic intermediates. 18 In particular, we took inspiration from a report 19 by Maruoka and coworkers wherein they had faced similar difficulties in an acid catalyzed intramolecular arylation of ⍺-hydroxyketones like 32 (Scheme 4). These authors obtained significant amounts of an alkene elimination product (34) alongside desired 33 before finding that fluoroalcohol solvents like 2,2,2-trifluoroethanol (TFE) or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) suppressed this unwanted dehydration.…”