Etsuko Tokunaga

Trifluoromethanesulfonyl Hypervalent Iodonium Ylide for Copper-Catalyzed Trifluoromethylthiolation of Enamines, Indoles, and β-Keto Esters

A novel electrophilic-type trifluoromethylthiolation reagent, a trifluoromethanesulfonyl hypervalent iodonium ylide, was designed and reacted well with various nucleophiles to afford the desired CF3S-substituted products. In situ reduction of the trifluoromethanesulfonyl group to give the trifluoromethylthio group, which is the key step in this process, was realized in the presence of copper(I) chloride.

Cu-Mediated Chemoselective Trifluoromethylation of Benzyl Bromides Using Shelf-Stable Electrophilic Trifluoromethylating Reagents

Copper-mediated chemoselective trifluoromethylation at the benzylic position by the use of shelf-stable electrophilic trifluoromethylating reagents 3 in good to high yields under mild conditions is described for the first time. The generality of this trifluoromethylation for a wide variety of benzyl bromides facilitates the rapid creation of structural diversity of medicinal candidates in drug discovery.

Organocatalytic Asymmetric Synthesis of Trifluoromethyl‐substituted Diarylpyrrolines: Enantioselective Conjugate Cyanation of β‐Aryl‐β‐trifluoromethyl‐disubstituted Enones

Ether way: the cinchona-alkaloid-catalyzed title reaction was achieved in high yields with high to excellent ee values for the first time, and affords key intermediates for the biologically important 2 having a trifluoromethylated all-carbon quaternary chiral center. Ether-type catalysts (1) are more efficient in this transformation than the conventional hydroxy analogues.

Enantioselective Friedel−Crafts Reaction of β-Trifluoromethylated Acrylates with Pyrroles and Its Application to the Synthesis of Trifluorinated Heliotridane

The first chiral Lewis acid catalyzed enantioselective Friedel-Crafts alkylation of pyrroles with beta-CF(3) acrylates has been investigated, which afforded various types of chiral trifluoromethylated compounds in excellent yields (90-99%) with high ees (up to 99% ee). With the aid of the Friedel-Crafts reaction adduct, optically active trifluorinated heliotridane was successfully constructed.

Regioselective synthesis of pyrazole triflones based on triflyl alkyne cycloadditions.

The regioselective synthesis of pyrazole triflones has been achieved by 1,3-dipolar cycloaddition of triflyl alkynes and hydrazonoyl chloride in the presence of Hünigs base. Pyrazolo[5,1-a]isoquinoline triflones were also regioselectively synthesized for the first time via tandem 1,3-dipolar cycloaddition/oxidative aromatization between triflyl alkynes and C,N-cyclic azomethine imines.

Iodoarene-catalyzed fluorination and aminofluorination by an Ar-I/HF·pyridine/mCPBA system

We have developed the iodoarene-catalyzed nucleophilic fluorination of β-dicarbonyl compounds and intramolecular aminofluorination of ω-amino-alkenes using the same reaction conditions. The key for this reaction is the in situ generation of a hypervalent iodine compound ArIF2 by hydrogen fluoride, mCPBA and a catalytic amount of iodoarene. Preliminary trials of catalytic asymmetric nucleophilic fluorination were conducted.

Synthesis of Indole and Biindolyl Triflones: Trifluoromethanesulfonylation of Indoles with Tf2O/TTBP (2,4,6-tri-tert-butylpyridine) System

A convenient synthesis of indole triflones is reported. N-Alkyl, aryl and N-H indole triflones were obtained in 82-96% yields by the Tf(2)O/TTBP System. Biindolyl triflones were accessed in 51-81% yields for the first time by simple treatment of the resulting indole triflones with a base and without any use of organometallic chemistry. An environmentally friendly solvent, Solkane 365/227, can be substituted for this process without any loss of efficiency.

Regioselective synthesis of heteroaryl triflones by LDA (lithium diisopropylamide)-mediated anionic thia-Fries rearrangement.

Novel heteroaryl triflones including oxindole, pyrazolone, pyridine, and quinoline derivatives have been regioselectively synthesized by LDA-mediated thia-Fries rearrangement for the first time. These reactions are also the first examples of the application of anionic thia-Fries rearrangement in heteroaromatic compounds.

Kinetic Resolution of Allyl Fluorides by Enantioselective Allylic Trifluoromethylation Based on Silicon‐Assisted CF Bond Cleavage

Two birds, one stone! The first kinetic resolution of allyl fluorides was achieved by the development of an organocatalyzed enantioselective allylic trifluoromethylation. Two kinds of chiral fluorinated compounds, which incorporate C*F and C*CF3 units, respectively, can thus be accessed by a single transformation.

S-((phenylsulfonyl)difluoromethyl)thiophenium salts: carbon-selective electrophilic difluoromethylation of β-ketoesters, β-diketones, and dicyanoalkylidenes.

S-((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho-ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF2 H group to sp(3) -hybridized carbon nucleophiles such as of β-ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF2 H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.