From Difluoromethyl 2‐Pyridyl Sulfone to Difluorinated Sulfonates: A Protocol for Nucleophilic Difluoro(sulfonato)methylation

Abstract

An efficient method for the synthesis of alkyl α,α‐difluorosulfonates has been developed. The selection of the 2‐pyridyl group as the aryl substitute on the sulfone is critically important for the success of this transformation (see scheme). The synthetic application of fluorinated sulfones is extended and a unique solution is provided for a long‐standing challenge in nucleophilic difluoro(sulfonato)methylation reactions.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…[184,185] Selected examples include Pefabloc (4-(2-aminoethyl)benzenesulfonyl fluoride, AEBFS), an irreversible serine protease inhibitor, [186,187] 5'-(4-fluorosulfonylbenzoyl)adenosine (FSBA), an ATP-binding protein inhibitor, [188,189] SF-p1yne, a clickable covalent probe for scavenger mRNA-decapping enzyme (DcpS protein), [190] or dansyl fluoride, a fluorescent specific serine-type protease inhibitor (Figure 5B). [191] Other applications of sulfonyl fluorides are also worth mentioning, e. g. as catalysts, [192] monomers, [193][194][195] and reagents in organic synthesis [196][197][198][199] (e. g. pyridine-2-sulfonyl fluoride for deoxyfluorination, [200][201][202][203] or 2,2-difluoro-2-(fluorosulfonyl) acetates for alkene gem-difluorocyclopropanation [204][205][206] ).…”

Synthesis of Enantiopure Benzo Fused Cyclic Sulfoximines Through Stereoselective [3+2] Cycloaddition between N‐tert‐Butanesulfinyl [(2‐Pyridyl)sulfonyl]‐difluoromethyl Ketimines and Arynes

“…We next turned our attention to investigate the transformations of cyclic sulfoximines 3 . Initial attempt to prepare difluorinated sulfinate salt through direct removal of the 2‐pyridyl group from 3a with EtSNa/EtSH [35] gave the de‐ tert ‐butylated difluorinated sulfinate salt as the side product, which is difficult to separate from the desired product. Thereafter, we decided to remove the tert ‐butyl group first before conducting the depyridination reaction.…”

Synthesis and applications of sodium sulfinates (RSO2Na): a powerful building block for the synthesis of organosulfur compounds

“…In early 2018, the Rueping, Manolikakes, and Molander groups independently reported Ni/photoredox dual catalysis for constructing aryl-and heteroaryl sulfones under blue LED irradiation at room temperature without any base. Rueping and co-workers elegantly employed a powerful sulfonylation of a series of aryl, heteroaryl, and vinyl bromides and iodides, as well as more challenging aryl chlorides with a range of aryl and heteroaryl sulnates under the catalytic inuence of NiCl.glyme, Ir-PC (33) and dtbbpy (34) to give a broad spectrum of the corresponding sulfones in moderate to good yields (Table 15; entry-13). 240 Similarly, the Manolikakes group used the NiCl 2 -$6H 2 O/Ru(bpy) 3 Cl 2 $6H 2 O dual catalyst system for a crosscoupling of various aryl and heteroaryl iodides with different aryl and alkyl sulnates to afford a wide range of aryl sulfones in moderate to good yields (Table 15; entry-14).…”