A Heck–Matsuda Process for the Synthesis of β‐Arylethenesulfonyl Fluorides: Selectively Addressable Bis‐electrophiles for SuFEx Click Chemistry

Abstract

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, β-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43–97% yield. The β-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

Palladium‐Catalyzed Fluorosulfonylvinylation of Organic Iodides

“…We have demonstrated ESF as an essential building block to prepare the otherwise difficult to access compounds, 2-arylethenesulfonyl fluorides, through a Heck-Matsuda process [Figure 1b(1)]. [7] 2-Arylethenesulfonyl fluorides represent a rare family of selectively addressable bifunctional electrophiles. Sulfonyl fluorides and vinyl sulfonates (or sulfone) can be readily prepared from 2-arylethenesulfonyl fluorides, via Michael addition and SuFEx, respectively, which are both important classes of electrophiles and potential covalent pharmacophores (Figure 1c).…”

“…For simple aryl iodides, the corresponding 2-arylethenesulfonyl fluorides were obtained in similar or better yields with those obtained via a previously described Heck-Matsuda protocol. [7] It is notable that a phenolic hydroxyl group ( 3p , 3x , 3ac , and 3ag ) is well tolerated in this process, which was incompatible in the Heck-Matsuda process. Not surprisingly, the catalytic system distinguished between iodide and other potential reactive halides ( 3h , 3t for Br and 3g for Cl).…”

Sulfonyl Fluorides (SFs): More Than Click Reagents?

“…In 2016, Sharpless and co‐workers first reported the orthogonal reaction of the double bond in ethenesulfonyl fluoride (ESF) with aryldiazonium tetrafluoroborate salts as coupling partners in a palladium‐catalyzed Heck–Matsuda reaction. This method proceeds in a single step, and offered access to a large variety of structurally diverse β‐arylethenesulfonyl fluorides (Scheme ) …”

Pd-Catalyzed Mizoroki-Heck Reactions Using Fluorine-Containing Agents as the Cross-Coupling Partners

“…In 2016, Wu and Sharpless described a Pdcatalyzed Heck-Matsuda process for the synthesis of the otherwise difficult to access β-arylethenesulfonyl fluorides (Scheme 8) [60]. In this reaction, ethenesulfonyl fluoride (51) underwent β-arylation with the stable and readily prepared arenediazonium tetrafluoroborates (50) in the presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride (52) in 43-97% yield.…”

“…In this reaction, ethenesulfonyl fluoride (51) underwent β-arylation with the stable and readily prepared arenediazonium tetrafluoroborates (50) in the presence of catalytic palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride (52) in 43-97% yield. The products 52 proved to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group could be exclusively attacked by nucleophiles under defined conditions, making these simple cores attractive for covalent drug discovery [60]. Pd-Catalyzed intramolecular cyclization of O- (3,3-difluoroallyl)phenyl triflate (41) and 3,3-difluoroallyl ketone oximes (46) by the Mizoroki-Heck reactions of the polarized carbon-carbon double bonds of the 1,1-difluoro-1-alkene moieties was accomplished (Scheme 7) [45,57,58].…”