Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

Abstract

1,1-Difluorinated sulfonamides are known to have improved anti-inflammatory activity and enzyme inhibitory potency than their non-fluorinated counterparts, where two geminal fluorine atoms can give rise to electronic perturbation of the nearby polar groups and improve their biological activity. However, as methods for their stereoselective synthesis are scarce, such entities remain entirely unexplored. Here, we outline an efficient method for stereoselective introduction of difluoro(aminosulfonyl)methyl group (CF 2 SO 2 NH 2 ) into carbonyls, imines, and alkyl halides with a new (R)-2-pyridyl difluoromethyl sulfoximine reagent, which provides an unique solution for synthesis of chiral ,-difluorinated sulfonamides with a quaternary stereocenter. Its potency is illustrated by the synthesis of fluorinated analogues of bioactive compounds such as 2-OH-SA, one of antagonists for GABA B receptor in guinea pig ileum, and the late-stage modification of complex molecules such as haloperidol, ebastine, cholesterol and (+)--tocopherol derivatives.Stereoselective difluoro(aminosulfinyl)methylation to yield chiral sulfinylamides are presented, showcasing other uses of this new reagent.

Dynamic Kinetic Resolution-Enabled Highly Stereoselective Nucleophilic Fluoroalkylation to Access Chiral β-Fluoro Amines

“…However, the reaction time was up to 2 days at −80 °C, and enaminalizable ketimines were not compatible (Figure c-i). Hu and co-workers synthesized β-fluoro amines via diastereoselective fluoromethylation of chiral N - tert -butylsulfinyl ketimines, but with a racemic carbon center at the β-position (due to the difficult differentiation of H/F atoms), and the yield is moderate (Figure c-ii). , In addition, an enzyme-catalyzed kinetic resolution was also reported, but the drawback is the limitation of the 50% maximal yield (Figure c-iii). , Our group was recently devoted to the development of nucleophilic fluoroalkylations by employing sulfoximine as the stereocontrol reagent. − Herein, a new method for asymmetric synthesis of β-fluoro amines with a sulfoximine reagent is reported (Figure c-iv). Our concept relies on the dynamic kinetic resolution of α-fluoro carbanions, which delivers chiral amines with a fluorinated carbon stereogenic center at the β-position.…”

Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon

“…The growing interest in selective synthesis of fluorinated compounds is evident based on their prevalence in natural products, agrochemicals, and pharmaceuticals. [ 1 ] Thus, a variety of catalytic methods have been disclosed, [ 2 , 3 ] including radical processes, [ 4 ] nucleophilic [ 5 ] or electrophilic additions, [ 6 ] and other transformations. [ 7 ] In this area, an appealing task is the introduction of a difluoromethylene unit, [ 8 ] which has demonstrated broad applications in medicinal chemistry and material science.…”

Reagent-Controlled Highly Stereoselective Difluoromethylation: Efficient Access to Chiral α-Difluoromethylamines from Ketimines

“…For instance, Hu group reported the stereoselective addition reaction between tert -butyl sulfinyl protected imines and phenyl difluoromethyl sulfone or TMSCF 2 H to generate the enantiomerically enriched α-difluoromethyl amine [ 14 , 15 ] (shown in Figure 1 C(i)), which served as an example of substrate-controlled Mannich addition. Recently, we have been devoted to the development of nucleophilic fluoroalkylation by using fluoroalkyl sulfoximine reagents [ 16 , 17 , 18 , 19 , 20 ]. In this context, we were interested in developing a reagent-controlled stereoselective Mannich reaction instead of a substrate-controlled version [ 21 , 22 , 23 ].…”