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SuFEx Reaction
The addition of amines or alcohols to compounds containing sulfonyl fluorides is known as a sulfur(VI)-fluorine exchange reaction (SuFEx reaction). While the reaction itself had been known since the 1930s, its application rapidly expanded after Sharpless et al. systematized the SuFEx reaction as a click chemistry approach in 2014.1) Today, the SuFEx reaction finds widespread use in fields such as drug discovery, chemical biology, and materials science.2-4)
The SuFEx reaction possesses two key characteristics: (1) sulfonyl fluoride compounds exhibit high chemical stability, and (2) the reaction does not require metal catalysts. These two features make the SuFEx reaction a highly reliable click reaction with numerous applications.
Advantages of SuFEx Reaction
The bond dissociation energy of the S(VI)-F bond (90 kcal/mol) is significantly higher than that of the S(VI)-Cl bond (46 kcal/mol). This makes sulfonyl fluoride compounds remarkably stable against redox reactions, hydrolysis, and heat. Meanwhile, amines and alcohols can react with the S(VI)-F bond under mild conditions when combined with appropriate activators. Since no toxic metal catalysts are required, the SuFEx reaction serves as an excellent tool in drug discovery and molecular biology applications.5)
SuFEx Hub Synthetic Reagents
Compounds active in SuFEx reactions are referred to as "SuFEx Hubs." In addition to sulfonyl fluorides, SuFEx hubs containing oxysulfonyl fluorides or sulfamoyl fluorides have also been reported. By combining SuFEx Hubs with nucleophiles, it is possible to construct diverse molecular libraries much like assembling Lego blocks.
While sulfuryl fluoride (SO2F2) is useful for synthesizing SuFEx hubs, its highly toxic gaseous nature makes alternative solid SO2F2 equivalents, such as DABSO (Product No. B3960) and SuFEx-IT (Product No. F1447), more preferable.
These SuFEx hub synthetic reagents enable direct introduction of SO2F group at the desired site. Other types of SuFEx hub synthetic reagents have also been reported.
Synthesis of SuFEx Hubs using Ethenesulfonyl Fluoride (Product No. V0143)
Sulfonyl fluoride groups can be introduced through Michael addition-type reactions with nucleophilic substituents or via cross-coupling reactions with aromatic compounds.
Synthesis of SuFEx Hubs using Methanedisulfonyl Difluoride (Product No. M4103)
It reacts with aromatic aldehydes to readily synthesize α,β-unsaturated sulfonyl fluorides.2) Furthermore, when reacted with β-substituted α,β-unsaturated aldehydes, it produces unique SuFEx hubs known as α,β,γ,δ-unsaturated-α,α-disulfonyldifluorides.6)
Synthesis of SuFEx Hubs using 2-Chloroprop-2-ene-1-sulfonyl Fluoride (Product No. C4286)
The compound undergoes a three-component reaction with alcohol and CS2 to yield allylsulfonyl fluoride containing xanthate derivatives.7) When reacted with carboxylic acids, it forms enol esters containing sulfonyl fluoride groups. Reactions with phenols and thiols have also been reported, making it useful for synthesizing diverse SuFEx hubs.8)
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References
- 1) Sulfur(VI) fluoride exchange (SuFEx): another good reaction for click chemistry
- 2) The growing applications of SuFEx click chemistry
- 3) Sulfur fluoride exchange
- 4) A Practical Guide to SuFEx Chemistry: An Overview of S(VI)-SuFEx Linkers and Their Reactivity
- 5) Sulfur(vi) fluorides as tools in biomolecular and medicinal chemistry
- 6) Olefination with Sulfonyl Halides and Esters: Synthesis of Unsaturated Sulfonyl Fluorides
- 7) Stereoselective addition of phenols to 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF) for the synthesis of a class of novel vinyl sulfonyl fluorides
- 8) A protocol for selective synthesis of thiol-functionalized allylic sulfonyl fluorides
