In Situ Generation of Electrophilic Trifluoromethylthio Reagents for Enantioselective Trifluoromethylthiolation of Oxindoles

Abstract

An organocatalytic asymmetric trifluoromethylthiolation reaction via in situ generation of active electrophilic trifluoromethylthio species involving trichloroisocyanuric acid and AgSCF3 as a practical and easily handled electrophilic SCF3 source for CSP(3)-SCF3 bond formation was developed. Reactions with this one-pot version strategy occurred in good yields and excellent stereoselectivities to access enantiopure oxindoles bearing a SCF3-substituted quaternary chiral center. The straightforward process described here makes use of simple starting materials and proceeds under mild conditions, which will be useful in medicinal chemistry and diversity-oriented syntheses.

Enantioselective Trifluoromethylthiolating Lactonization Catalyzed by an Indane‐Based Chiral Sulfide

“…This property can greatly enhance the transmembrane permeability of drug candidates. [16] These reactions were based on the use of electrophilic SCF 3 reagents in combination with nucleophilic b-ketoesters or 3-aryl oxindoles as the substrates and cinchona alkaloids or chiral copper complexes as the catalyst, and proposed to proceed through an S N 2pathway (Scheme 1a). [3][4][5][6][7][8][9][10][11][12] However,t hese achievements mainly focused on the preparation of achiral SCF 3containing compounds.A lthough chiral SCF 3 -containing molecules might lead to further advances in drug discovery, methods for the enantioselective introduction of the SCF 3 group remain rare.T od ate,o nly af ew examples have been reported by the groups of Rueping, [13] Shen, [14] Gade, [15] and Tan.…”

Enantioselective Trifluoromethylthiolating Lactonization Catalyzed by an Indane‐Based Chiral Sulfide

“…[3][4][5][6][7][8][9][10][11][12] However,t hese achievements mainly focused on the preparation of achiral SCF 3 -containing compounds.A lthough chiral SCF 3 -containing molecules might lead to further advances in drug discovery, methods for the enantioselective introduction of the SCF 3 group remain rare.T od ate,o nly af ew examples have been reported by the groups of Rueping, [13] Shen, [14] Gade, [15] and Tan. [16] These reactions were based on the use of electrophilic SCF 3 reagents in combination with nucleophilic b-ketoesters or 3-aryl oxindoles as the substrates and cinchona alkaloids or chiral copper complexes as the catalyst, and proposed to proceed through an S N 2pathway (Scheme 1a). Owing to the lack of an appropriate setup to achieve high enantioselectivity,n oo ther catalytic processes for the formation of chiral SCF 3 -containing compounds have been developed, specifically for enantioselective alkene trifluoromethylthiolation.…”

“…[18] Owing to the involvement of ac halcogenide in the catalytic cycle,w e envisioned that chiral trifluoromethylated products could be formed through chiral chalcogenide catalysis (Scheme 1b). Compared to the asymmetric incorporation of SCF 3 groups by S N 2p athways, [13][14][15][16] the enantioselective trifluoromethylthiolation of alkenes is more challenging.According to studies of enantioselective alkene bromo-and chalcofunctionalizations by the groups of Denmark [19] and Yeung, [20] the enantioselectivities can be heavily affected by two issues:racemization of the iranium ion through olefin-to-olefin degeneration and the racemization derived from which nucleophilic partners may capture the thiiranium or seleniranium species.T oovercome these possible racemization problems,wec onsidered the use of abifunctional catalyst that would stabilize the intermediary iranium ion. Thep roposed bifunctional catalyst possesses achalcogenide group as the Lewis base and an NH moiety as the hydrogen-bond donor.H erein, we report an efficient approach for the asymmetric trifluoromethylthiolation of alkenes that is based on the use of such an indane-based chiral bifunctional sulfide catalyst and an ew electrophilic SCF 3 reagent.…”

Electrophilic trifluoromethylthiolation of thiols with trifluoromethanesulfenamide

“…Functionalization of allylic alcohols furnished the corresponding triuoromethyl sulfoxides via a [2,3]-sigmatropic rearrangement. 53 A combination of AgSCF 3 and trichloroisocyanuric acid was utilized as an in situ electrophilic SCF 3 source in enantioselective catalytic functionalization of oxindoles 54 and in the synthesis of 3-((triuoromethyl)thio)-4H-chromen-4-ones. 55 Carbonyl compounds 56 and arenes 57 were triuoromethylthiolated with a new N-((triuoromethyl)thio) benzenesulfonamide type of reagent.…”