Sulfur(VI) Fluoride Exchange (SuFEx): Another Good Reaction for Click Chemistry

Abstract

Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used S(VI) electrophiles, and the parent sulfuryl chloride, O2 S(VI) Cl2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S(VI) Cl bond is exceedingly sensitive to reductive collapse yielding S(IV) species and Cl(-) . Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2 -F and SO2 F2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2 CH-SO2 -F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2 F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.

Crystal structure of methyl 1-(2-(fluorosulfonyl)ethyl)-2-oxocyclopentanecarboxylate, C9H13FO5S

“…The moiety has sparked interest in drug discovery, as it has shown to be an inhibitor for numerous proteins [11,12]. Recently, the SF functional group has been included as a click reagent [13]. Despite this, there are very few references in the literature which highlight the SF group as synthetic intermediates.…”

Palladium‐Catalyzed Fluorosulfonylvinylation of Organic Iodides

“…By employing three highly connective molecules, sulfuryl fluoride (SO 2 F 2 ), [1] thionyl tetrafluoride (O=SF 4 ), [2] and ethenesulfonyl fluoride (CH 2 =CH-SO 2 F, ESF, 1), [1], [3], [4] we are able to readily gain SuFEx-abilities for the compounds from nature's nucleophile pool or from the petrochemicals, and finally achieve functions in service of multiple disciplines [5], [6] via catalytic SuFEx protocols ( Figure 1a). Searching for new S VI -F functional groups and developing reliable methods for their installations are considered the major challenge for evolving the current SuFEx chemistry.…”

“…[18] With the silver(I) salt boost, we have now extended the fluorosulfonylvinylation reaction to aryl, heteroaryl and alkenyl iodides [ Figure 1b(3)]. (1) Examination of the examples in Table 1 reveals that our Heck-type reaction has a broad scope for aryl iodides compromising various types of functional groups. Under mild reaction conditions and simple operation, catalytic Pd(OAc) 2 and stoichiometric AgTFA effected the transformations of aryl iodides (2a-2ap) to corresponding vinyl sulfonyl fluorides (3a-2ap) in good to excellent yields.…”

Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub

“…[5,6] In 2014, we reported a new embodiment of ideal click chemistry: SuFEx (Sulfur(VI) Fluoride Exchange)-a technology for creating molecular connections with absolute reliability and unprecedented efficiency through a sulfur(VI)-hub. [7] SuFEx reliably allows the flawless substitution of S VI -F with aryl silyl ethers to give S VI -O bonds, and with amines to give S VI -N-bonds. While the mechanistic details are yet to be fully elucidated, these transactions are made possible by a special coaction between the hydrogen-bonding environment of fluoride ion, and the kinetic and thermodynamic properties of the bonds to sulfur(VI) and silicon centers.…”

“…Under SuFEx conditions the latent reactivity of the otherwise stable S VI -F bond is roused to react with SuFExable substrates. [7,15] While SuFEx is still an emerging technology it has already found diverse applications including, for example: the synthesis of tosylates [9] and sulfonyl azides;, [10] application in polymer chemistry [11] and post polymerization modification; [12,13] Suzuki coupling of aryl- and heteroaryl-fluorosulfates with boronic acids. [15] Of particular significance, however, is the potential for SuFEx in biochemical applications-we have growing evidence to believe that proteins provide molecular and dynamic electrostatic field environments that sulfur(VI) fluoride linkages are adept at reading and reacting to.…”