Sulfur(VI) fluorides as tools in biomolecular and medicinal chemistry.

Recent advances in the synthesis of sulfur(VI)-fluorides has enabled incredible growth in their application in biomolecular chemistry. This review aims to serve as a primer highlighting synthetic strategies toward a diversity of S(VI) fluorides and their application in chemical biology, bioconjugation, and medicinal chemistry.

Facile synthesis of sulfonyl fluorides from sulfonic acids.

Herein, we demonstrate two complementary strategies for the syntheses of sulfonyl fluorides using sulfonic acids and their salts. One strategy involves the conversion of sulfonic acid sodium salts to sulfonyl fluorides using thionyl fluoride in 90-99% yields in one hour. Lessons learned from the mechanism of this reaction also have enabled a complementary deoxyfluorination of sulfonic acids using Xtalfluor-E® - a bench stable solid - allowing for the conversion of both aryl and alkyl sulfonic acids and salts to sulfonyl fluorides in 41-94% yields. Notably, using Xtalfluor-E® enabled milder conditions and the use of both sulfonic acids and their sodium salts.

Synthesis of 2-arylpyridines by the Suzuki-Miyaura cross-coupling of PyFluor with hetero(aryl) boronic acids and esters.

The Suzuki-Miyaura cross-coupling of pyridine-2-sulfonyl fluoride (PyFluor) with hetero(aryl) boronic acids and pinacol boronic esters is reported. The reactions can be performed using Pd(dppf)Cl2 as the catalyst, at temperatures between 65 and 100 °C and in the presence of water and oxygen. This transformation generates 2-arylpyridines in modest to good yields (5%-89%).

Sulfondiimidamides unlocked as new S(VI) hubs for synthesis and drug discovery.

Despite their promise as drug targets, access to nitrogen-rich S(VI) compounds has been a significant synthetic challenge. In this issue of Chem, Zhang and Willis explore a new class of S(VI) compounds-sulfondiimidamides-providing robust strategies toward their synthesis, derivation, and promise as new sulfonamide bioisosteres.

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

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.

The Emerging Applications of Sulfur(VI) Fluorides in Catalysis.

The past decade has witnessed remarkable growth of catalytic transformations in organic sulfur(VI) fluoride chemistry. This Perspective concentrates exclusively on foundational examples that utilize catalytic strategies to synthesize and react S(VI) fluorides. Key mechanistic studies that aim to provide insight toward future catalytic systems are emphasized.

SuFEx Activation with Ca(NTf2)2: A Unified Strategy to Access Sulfamides, Sulfamates, and Sulfonamides from S(VI) Fluorides.

A method to activate sulfamoyl fluorides, fluorosulfates, and sulfonyl fluorides with calcium triflimide and DABCO for SuFEx with amines is described. The reaction was applied to a diverse set of sulfamides, sulfamates, and sulfonamides at room temperature under mild conditions. Additionally, we highlight this transformation to parallel medicinal chemistry to generate a broad array of nitrogen-based S(VI) compounds.

One-pot fluorosulfurylation of Grignard reagents using sulfuryl fluoride.

Herein, we report a new method for the one-pot syntheses of sulfonyl fluorides. Addition of an alkyl, aryl, or heteroaryl Grignard to a solution of sulfuryl fluoride at ambient temperature affords the desired sulfonyl fluorides in 18-78% yield. Furthermore, this method is applicable for in situ sequential reactions, whereby the Grignard reagent can be converted to the corresponding diarylsulfone, sulfonate ester, or sulfonamide in a one-pot process.

Sulfonamide Synthesis via Calcium Triflimide Activation of Sulfonyl Fluorides.

A method using calcium triflimide [Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides toward nucleophilic addition with amines is described. The reaction converts a wide array of sterically and electronically diverse sulfonyl fluorides and amines into the corresponding sulfonamides in good yield.

Pd-Catalyzed Conversion of Aryl Iodides to Sulfonyl Fluorides Using SO2 Surrogate DABSO and Selectfluor.

A one-pot Pd-catalyzed conversion of aryl iodide to aryl sulfonyl fluorides using DABSO and Selectfluor has been developed generating aryl sulfonyl fluorides in good to excellent yields. The reaction results in the generation of electronically and sterically diverse sulfonyl fluorides. Additionally, sulfonyl fluorides can be converted to aryl sulfonamides and sulfonic esters using Cs2CO3 under mild conditions.

C-H bond activation at palladium(IV) centers.

This communication describes the first observation and study of C-H activation at a Pd(IV) center. This transformation was achieved by designing model complexes in which the rate of reductive elimination is slowed relative to that of the desired C-H activation process. Remarkably, the C-H activation reaction can proceed under mild conditions and with complementary site selectivity to analogous transformations at Pd(II). These results provide a platform for incorporating this new reaction as a step in catalytic processes.

Mechanistic and computational studies of oxidatively-induced aryl-CF3 bond-formation at Pd: rational design of room temperature aryl trifluoromethylation.

This article describes the rational design of first generation systems for oxidatively induced Aryl-CF(3) bond-forming reductive elimination from Pd(II). Treatment of (dtbpy)Pd(II)(Aryl)(CF(3)) (dtbpy = di-tert-butylbipyridine) with NFTPT (N-fluoro-1,3,5-trimethylpyridinium triflate) afforded the isolable Pd(IV) intermediate (dtbpy)Pd(IV)(Aryl)(CF(3))(F)(OTf). Thermolysis of this complex at 80 °C resulted in Aryl-CF(3) bond-formation. Detailed experimental and computational mechanistic studies have been conducted to gain insights into the key reductive elimination step. Reductive elimination from this Pd(IV) species proceeds via pre-equilibrium dissociation of TfO(-) followed by Aryl-CF(3) coupling. DFT calculations reveal that the transition state for Aryl-CF(3) bond formation involves the CF(3) acting as an electrophile with the Aryl ligand serving as a nucleophilic coupling partner. These mechanistic considerations along with DFT calculations have facilitated the design of a second generation system utilizing the tmeda (N,N,N',N'-tetramethylethylenediamine) ligand in place of dtbpy. The tmeda complexes undergo oxidative trifluoromethylation at room temperature.

Oxidation of a cyclometalated Pd(II) dimer with "CF3+": formation and reactivity of a catalytically competent monomeric Pd(IV) aquo complex.

The reaction of [(bzq)Pd(OAc)](2) (bzq = benzo[h]quinoline) with "CF(3)(+)" reagents to afford the monomeric Pd(IV) aquo complex (bzq)Pd(CF(3))(OAc)(2)(OH(2)) is demonstrated. Heating this Pd(IV) adduct at 60 °C for 12 h leads to highly chemoselective aryl-CF(3) bond-forming reductive elimination. The rate and yield of this transformation are both significantly enhanced by the addition of Brønsted and Lewis acidic additives. The mechanism of C-CF(3) bond formation from (bzq)Pd(CF(3))(OAc)(2)(OH(2)) has been studied, and the major pathway is proposed to involve pre-equilibrium acetate dissociation followed by C-CF(3) coupling. Finally, this monomeric Pd(IV) complex is shown to be a kinetically competent intermediate for C-H trifluoromethylation with "CF(3)(+)" reagents. Collectively, these studies provide valuable insights about the speciation, nuclearity, and reactivity of Pd intermediates in catalytic C-H trifluoromethylation reactions.

Aryl-CF(3) bond-forming reductive elimination from palladium(IV).

This communication describes oxidatively induced Ar-CF(3) bond-forming reductive elimination from new Pd(II) complexes of general structure (L approximately L)Pd(II)(Ar)(CF(3)). The electrophilic fluorinating reagent N-fluoro-2,4,6-trimethylpyridinium triflate promotes these reactions in good to excellent yields. The palladium(IV) intermediate ((t)Bu-bpy)Pd(IV)(CF(3))(F)(OTf)(C(6)H(4)F) has been isolated, characterized, and demonstrated to undergo high yielding Ar-CF(3) coupling upon thermolysis. This work provides an attractive conceptual framework for the development of Pd(II/IV)-catalyzed arene trifluoromethylation reactions.

Synthesis and reactivity of palladium(II) fluoride complexes containing nitrogen-donor ligands.

This article describes the synthesis, characterization, and reactivity of palladium(II) fluoride complexes containing sp(2) and sp(3) nitrogen-containing supporting ligands. Both cis and trans complexes of general structure (N)(N')Pd(II)(R)(F) (R = Ar or CH(3)) as well as cis-(N)(2)Pd(II)(F)(2) are reported. Crystallographic characterization of these molecules has allowed structural comparisons to related phosphine-ligated species. Furthermore, these studies have revealed that nitrogen-donor ligands support some of the longest and the shortest Pd-F bonds reported to date. The thermal decomposition of (N)(N')Pd(II)(R)(F) has also been examined, and no products of C-F bond-forming reductive elimination were obtained in any case.

Synthesis and reactivity of a mono-sigma-aryl palladium(IV) fluoride complex.

This communication describes the rational design and synthesis of the remarkably stable Pd(IV) monoaryl fluoride complex (t-Bu-bpy)Pd(IV)(p-FC(6)H(4))(F)(2)(FHF) (t-Bu-bpy = 4,4'-di-tert-butyl-2,2'-bipyridine). This and related complexes undergo Ar-F bond formation in the presence of "F(+)" sources. This work serves as a foundation for the development of Pd(II/IV)-catalyzed coupling reactions to form aryl fluorides.