Deoxygenative Tri- and Difluoromethylthiolation of Carboxylic Acids with Benzothiazolium Reagents

Abstract

Deoxygenative syntheses of fluorinated thioesters directly from carboxylic acids have been developed employing benzothiazolium reagents. The process using BT-SCF3 represents an attractive approach toward these SCF3-containing compounds that avoids the use of metal –SCF3 salts or preactivated acyl electrophiles. Moreover, the in situ activation of BT-SCF2H allows for an unprecedented nucleophilic difluoromethylthiolation reaction. DFT calculations support a mechanistic scenario involving a four-membered transition state where acyl substitution occurs without the formation of an unstable free –SCF2H anion.

Deoxygenative nucleophilic difluoromethylselenylation of carboxylic acids and alcohols with BT-SeCF2H

“…With BT-SeCF2H in hand, we sought to investigate its reactivity as a nucleophilic difluoromethylselenylating reagent. Inspired by the successful application of BT-SCF2H in deoxygenative substitution reactions of carboxylic acids, 13 BT-SeCF2H (1.25 eq.) was first reacted with n-dodecanoic acid 3a and NaH (2 eq.)…”

“…These BT-reagents can be prepared from relatively inexpensive starting materials and serve as practical sources of fluoroalkylchalcogenyl anions in synthetically appealing deoxygenative functionalisation reactions of readily available aliphatic alcohols 12 and carboxylic acids. 13,14 In addition to perfluoroalkyl derivatives such as BT-SRF (RF = CnF2n-1) and BT-SeCF3, recent work showed that the partially fluorinated analogue BT-SCF2H could be successfully engaged in efficient deoxygenative difluoromethylthiolation reactions, providing (difluoromethyl)thioesters directly from carboxylic acids under mild conditions. 13 Inspired by these results, we considered whether a (difluoromethyl)selenium analogue could be accessed and, if so, whether it would act as a source of hitherto unexplored − SeCF2H anions for nucleophilic transformations.…”

“…13,14 In addition to perfluoroalkyl derivatives such as BT-SRF (RF = CnF2n-1) and BT-SeCF3, recent work showed that the partially fluorinated analogue BT-SCF2H could be successfully engaged in efficient deoxygenative difluoromethylthiolation reactions, providing (difluoromethyl)thioesters directly from carboxylic acids under mild conditions. 13 Inspired by these results, we considered whether a (difluoromethyl)selenium analogue could be accessed and, if so, whether it would act as a source of hitherto unexplored − SeCF2H anions for nucleophilic transformations. Herein, we report the successful synthesis of BT-SeCF2H and its application as a reagent in unprecedented deoxygenative difluoromethylselenylation reactions (Scheme 1b).…”

Stable and easily available sulfide surrogates allow a stereoselective activation of alcohols

“… 12 Hopkinson recently demonstrated that benzothiazolium reagents can be used in trifluoromethyl(alkyl) sulfide synthesis or fluorinated thioester synthesis. 13 However, to the best of our knowledge, a successful chiral thioether synthesis using isothiouronium salts involving a configuration inversion of enantiopure secondary alcohols has not been reported. Additionally, we believe that the straightforward reactivity of uronium salts could prove advantageous in a range of synthetic contexts ranging from late-stage modification to enabling preparation of thioethers carrying sensitive functional groups.…”

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols

“…In 2019, we reported a new reagent for nucleophilic trifluoromethylthiolation based on the benzothiazolium motif: BT-SCF 3 [36][37][38]. This easily handled solid, which is stable at least over several months under ambient conditions, could be engaged in efficient deoxygenative trifluoromethylthiolation reactions of readily available aliphatic alcohols.…”