The incorporation of a SCF3 group into organic molecules is a topic of great interest, especially for the pharmaceutical and agrochemical industries.1 Due to its high lipophilicity and high electron-withdrawing character (Hansch lipophilicity parameter πR =1.44 vs πR= 0.88 for CF3),2 the SCF3 moiety represents a powerful opportunity to influence the pharmacokinetics properties of a drug molecule increasing the transmembrane permeation. In the last few decades, numerous methods for the introduction of a trifluoromethylthio group into organic compounds have been reported;3 however, only few examples of efficient methods to introduce catalytically and directly the SCF3 group in alpha- position of a carbonyl function were reported. In this contest, we have developed a novel approach for the organocatalytic α-trifluoromethylthiolation of unactivated ketones, starting from the corresponding silylenol ethers using N-(trifluoromethylthio)saccharin as trifluoromethylthiolating reagent that is activated by the presence of catalytic amounts of a Lewis base (Figure 1). Tetrahydrothiophene was identified as the best organocatalyst and it was successfully employed to promote the synthesis of different α-trifluoromethylketones; the reaction has been performed under a traditional batch methodology and under continuous flow conditions. In general, yields obtained using the traditional batch process were higher than those observed when the reaction was performed in micro(meso)reactors. However, short reaction times, higher productivity and higher space time yields were observed when a flow system process was employed. Preliminary DFT calculations were also performed in order to elucidate the mechanism of the reaction; recent experimental results and a proposed catalytic cycle of the reaction will be presented and discussed.

Organocatalytic α-trifluoromethylthiolation of carbonyl compounds / S. Rossi, M. Benaglia - In: Atti del 38. Convegno Nazionale della Divisione di Chimica OrganicaPrima edizione. - [s.l] : EDISES, 2018 Sep. - ISBN 9788833190150. - pp. 215-215 (( Intervento presentato al 38. convegno Convegno Nazionale della Divisione di Chimica Organica della Società Chimica Italiana tenutosi a MIlano nel 2018.

Organocatalytic α-trifluoromethylthiolation of carbonyl compounds

S. Rossi
;
M. Benaglia
2018-09

Abstract

The incorporation of a SCF3 group into organic molecules is a topic of great interest, especially for the pharmaceutical and agrochemical industries.1 Due to its high lipophilicity and high electron-withdrawing character (Hansch lipophilicity parameter πR =1.44 vs πR= 0.88 for CF3),2 the SCF3 moiety represents a powerful opportunity to influence the pharmacokinetics properties of a drug molecule increasing the transmembrane permeation. In the last few decades, numerous methods for the introduction of a trifluoromethylthio group into organic compounds have been reported;3 however, only few examples of efficient methods to introduce catalytically and directly the SCF3 group in alpha- position of a carbonyl function were reported. In this contest, we have developed a novel approach for the organocatalytic α-trifluoromethylthiolation of unactivated ketones, starting from the corresponding silylenol ethers using N-(trifluoromethylthio)saccharin as trifluoromethylthiolating reagent that is activated by the presence of catalytic amounts of a Lewis base (Figure 1). Tetrahydrothiophene was identified as the best organocatalyst and it was successfully employed to promote the synthesis of different α-trifluoromethylketones; the reaction has been performed under a traditional batch methodology and under continuous flow conditions. In general, yields obtained using the traditional batch process were higher than those observed when the reaction was performed in micro(meso)reactors. However, short reaction times, higher productivity and higher space time yields were observed when a flow system process was employed. Preliminary DFT calculations were also performed in order to elucidate the mechanism of the reaction; recent experimental results and a proposed catalytic cycle of the reaction will be presented and discussed.
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/629813
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