Calcium Bistriflimide-Mediated Sulfur(VI)–Fluoride Exchange (SuFEx): Mechanistic Insights toward Instigating Catalysis

Abstract

We report a mechanistic investigation of calcium bistriflimide-mediated sulfur(VI)–fluoride exchange (SuFEx) between sulfonyl fluorides and amines. We determine the likely pre-activation resting state—a calcium bistriflimide complex with ligated amines—thus allowing for corroborated calculation of the SuFEx activation barrier at ∼21 kcal/mol, compared to 21.5 ± 0.14 kcal/mol derived via kinetics experiments. Transition state analysis revealed: (1) a two-point calcium-substrate contact that activates the sulfur(VI) center and stabilizes the leaving fluoride and (2) a 1,4-diazabicyclo[2.2.2]octane additive that provides Brønsted-base activation of the nucleophilic amine. Stable Ca–F complexes upon sulfonamide formation are likely contributors to inhibited catalytic turnover, and a proof-of-principle redesign provided evidence that sulfonamide formation is feasible with 10 mol % calcium bistriflimide.

Enantiospecific Synthesis of Aniline-Derived Sulfonimidamides

“…The TS has a late character, which is manifested by a significant elongation of the S···F bond to 2.23 Å (∑covalent radii = 1.62 Å), shortening of r (S···N) to 1.97 Å, and a strong Ca–F interaction (2.27 Å) at a seven-coordinate Ca center (Table S12 of the Supporting Information). The core geometry of our TS resembles that computed by Ogba, Ball, and co-workers for the corresponding reaction with sulfonyl fluorides . The coordination of the F atom to the Ca center is accompanied by elongation of the calcium triflimide Ca–O bonds {from 2.39 Å in [Ca­(NTf 2 ) 2 ( 1 )] to 2.46 Å in transition state TS1 }.…”

“…This coordination mode contrasts with findings of Ogba, Ball, and co-workers on the activation of sulfonyl fluorides (RSO 2 F) with the Ca­(NTf 2 ) 2 /DABCO system. They observed that Ca­(NTf 2 ) 2 coordinates to RSO 2 F through a sulfonyl group, with the corresponding RSO 2 F···Ca­(NTf 2 ) 2 adduct being 3 kcal/mol less stable than the corresponding tetrahydrofuran (THF)···Ca­(NTf 2 ) 2 complex (computed with explicit and implicit THF solvation) . In their case, in contrast to that under the current study for sulfonimidoyl fluorides, no chelation was observed.…”

Linkage Chemistry of S(VI) Fluorides

“…Accordingly, 9c). [42] DABCO is therein functioned as a base to promote the SÀ N ligation of amine. The fluoride scavenger TMDS (1,1,3,3-tetra-methyldisiloxane) could destabilize the CaÀ F bond and allow Ca 2 + to enter the next cycle.…”

“…It was postulated that DABCO initially catches S(VI) fluoride to form N ‐sulfonyl‐DABCO salt as an active intermediate in the presence of the calcium activator, but the pathway is subsequently proved to be disfavored by DFT calculation with an energy barrier of 51.2 kcal/mol. Accordingly, the groups of Ogba and Ball cooperatively proposed a new reaction model for the Ca‐activated N ‐SuFEx linkage, where Lewis acid Ca(NTf 2 ) 2 not only activates the oxygen but stabilizes the fluoride at the fluorosulfonyl group as shown in transition state Ts‐3 (Scheme 9c) [42] . DABCO is therein functioned as a base to promote the S−N ligation of amine.…”

FSO2N3-Enabled Synthesis of Tetrazoles from Amidines and Guanidines

“…Despite being resistant to hydrolysis, reduction, and thermal decomposition in most conditions, the very stable S­(VI)–F group is reinvigorated under the right circumstances, e.g ., activated by protons or silicons, to exchange with O, N, C-nucleophiles to form S­(VI)–N, S­(VI)–O, and S­(VI)–C bonds . A series of SuFEx catalysts have been identified to facilitate the SuFEx process, including tertiary amines, guanidines, bifluorides, and Lewis acids such as calcium bistriflimide [Ca­(NTf 2 ) 2 ]. , The unique reactivity, the ready accessibility of synthons and the diverse connectivity to deliver functions have bestowed SuFEx reactions with broad utilization in chemical biology, material science, , synthetic methodologies, and drug discoveries …”