Alkyl Sulfonyl Fluorides Incorporating Geminal Dithioesters as SuFEx Click Hubs via Water-Accelerated Organosuperbase Catalysis

Abstract

Sulfur(VI) fluoride exchange (SuFEx) is recognized as another emerging tool for click chemistry. The preparation of the functionalized alkyl sulfonyl fluorides as key SuFEx hubs via C(sp 3 )− C(sp 3 ) bond formation is exceptionally challenging. We report herein a new efficient method for accessing alkyl sulfonyl fluorides incorporating γ-geminal dithioester via phosphazene catalysis. The aqueous, neutral organosuperbase catalytic system amplifies the reactivity by taking advantage of the hydrophobic amplification. SuFEx-active products are applied to the click connection of bioactive molecules. Density functional theory studies show that the selective outcome of the product is guided by an ion-pair organosuperbase catalyst assembly that is potentially stabilized by a hydrogen-bonding interaction between the catalyst and the DTM in the C(sp 3 )−C(sp 3 ) bond-forming transition structure.

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…Other transformations. Sulfonyl fluorides with (protected) COOH group, especially at the α position, are prone to decarboxylation via Krapcho-type (thio)ester decomposition, [61] ketone cleavage of acetoacetic ester, [64] or thermal decomposition of free carboxylic acid (Scheme 24). [186][187][188][189] Several amino sulfonyl fluorides or the corresponding isocyanates were synthesized by the modified Curtius rearrangement reaction of SO 2 F-substituted carboxylic acids with diphenyl phosphoroyl azide (DPPA) (Scheme 25).…”

“…Being a strong electron‐withdrawing group, the SO 2 F fragment is considered as one of the best double bond activators for the nucleophilic conjugate (Michael) addition [60] . Indeed, alkenyl sulfonyl fluorides readily react with a huge variety of C ‐, [60–64] N ‐, [43,62,64–67] S ‐, [25,64,67,68] or P ‐nucleophiles [69] (Scheme 4). For example, Michael addition to the simplest vinyl sulfonyl fluoride was used for the preparation of [ 18 F]‐labelled amino acids [70] and modification of s ‐tetrazine building blocks [71] .…”

“…Other transformations . Sulfonyl fluorides with (protected) COOH group, especially at the α position, are prone to decarboxylation via Krapcho‐type (thio)ester decomposition, [61] ketone cleavage of acetoacetic ester, [64] or thermal decomposition of free carboxylic acid (Scheme 24). [186–189] …”

Sustainable Organocatalytic Processes to Access Alkyl SuFEx Click Hubs and Tetrasubstituted Carbon Centers: Potential Libraries for Multidisciplinary Applications

“…In addition, SuFEx ligations of bioactive compounds were successfully executed (Scheme 2C). 17 and -Geminal Dithioester-Incorporated Sulfonyl Fluorides 18 Next, we reported a method using a high-turnover phosphazene superbase catalyst-promoted thia-Michael addition reaction to obtain -sulfidosulfonyl fluorides. -Sulfidosulfonyl fluorides have recently been highlighted as critical structural scaffolds possessing diverse biological properties.…”

Enantioselective Addition of Dialkyl Malonates to β-Arylethenesulfonyl Fluorides under High-Pressure Conditions

“…The same author also reported reactions with malononitrile and cyanomalonate, which resulted in substituted cyclopropanes . Only recently has water-accelerated phosphazene-catalyzed addition of di thio malonates been demonstrated in a racemic variant . However, under these conditions, an adduct with dibenzyl malonate was formed in only trace amount (<3% of yield), despite presence of advantageous biphasic medium and superbase catalysis.…”