Perfluorooxosulfate Salts as SOF4-Gas-Free Precursors to Multidimensional SuFEx Electrophiles.

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well-established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make 'beyond-linear' clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2-mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

De-Risking S-F Bond Formation: A Gas Cylinder-Free Strategy to Access S(IV) and S(VI) Fluorinated Compounds.

The sulfur-fluorine partnership occupies a privileged position in fluorine chemistry given the functional versatility that it imparts to organic structures. Despite this, available methodologies to forge S-F bonds are limited compared to C-F bond formation. Here, we describe a synthetic protocol that selectively enables the oxidative halogenation of aliphatic, aromatic, and heteroaromatic thiols to their corresponding SF4 Cl, SO2 F and SF3 derivatives. Selective oxidation of thiols to either S(IV)-F or S(VI)-F compounds is achieved by employing bench-stable calcium hypochlorite as chlorine surrogate (CLOgen), in the presence of KF as fluoride source. Density functional theory (DFT) calculations provided insight into the mechanistic aspects of the transformation and rationalized the observed isomeric preference towards the SF4 Cl derivatives. Ultimately, this glovebox-free method selectively dispatches three classes of compounds upon reaction condition fine-tuning. Furthermore, first-in-class transformations are reported, including the preparation of aliphatic SF4 Cl intermediates, their transformation into aliphatic sulfur pentafluoride analogs, and post-functionalizations that allow accessing highly complex SF4 -bridged scaffolds.

Ex situ Generation of Thiazyl Trifluoride (NSF3 ) as a Gaseous SuFEx Hub.

Sulfur(VI)-fluoride exchange (SuFEx) chemistry, an all-encompassing term for substitution events that replace fluoride at an electrophilic sulfur(VI), enables the rapid and flexible assembly of linkages around a SVI core. Although a myriad of nucleophiles and applications works very well with the SuFEx concept, the electrophile design has remained largely SO2 -based. Here, we introduce S≡N-based fluorosulfur(VI) reagents to the realm of SuFEx chemistry. Thiazyl trifluoride (NSF3 ) gas is shown to serve as an excellent parent compound and SuFEx hub to efficiently synthesize mono- and disubstituted fluorothiazynes in an ex situ generation workflow. Gaseous NSF3 was evolved from commercial reagents in a nearly quantitative fashion at ambient conditions. Moreover, the mono-substituted thiazynes could be extended further as SuFEx handles and be engaged in the synthesis of unsymmetrically disubstituted thiazynes. These results provide valuable insights into the versatility of these understudied sulfur functionalities paving the way for future applications.

Chemistry of Pentafluorosulfanyl Derivatives and Related Analogs: From Synthesis to Applications.

Pentafluorosulfanyl (SF5 )-containing compounds and corresponding analogs are a highly valuable class of fluorine-containing building blocks owing to their unique properties. The reason for that is the set of peculiar and tremendously beneficial characteristics they can impart on molecules once introduced onto them. Despite this, their application in distinct scientific fields remains modest, given the extremely harsh reaction conditions needed to access such compounds. The recent synthetic approaches via S-F, and C-SF5 bond formation as well as the use of SF5 -containing building blocks embody a "stairway-to-heaven" loophole in the synthesis of otherwise-inaccessible chemical scaffolds only a few years ago. Herein, we report and evaluate the properties of the SF5 group and analogs, by summarizing synthetic methodologies available to access them as well as following applications in material science and medicinal chemistry since 2015.

Enantioselective Hydroamination of Alkenes with Sulfonamides Enabled by Proton-Coupled Electron Transfer.

An enantioselective, radical-based method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are proposed to proceed via N-centered radicals formed by proton-coupled electron transfer (PCET) activation of sulfonamide N-H bonds. Noncovalent interactions between the neutral sulfonamidyl radical and a chiral phosphoric acid generated in the PCET event are hypothesized to serve as the basis for asymmetric induction in a subsequent C-N bond forming step, achieving selectivities of up to 98:2 er. These results offer further support for the ability of noncovalent interactions to enforce stereoselectivity in reactions of transient and highly reactive open-shell intermediates.

Acid-catalyzed oxidative radical addition of ketones to olefins.

Based on a mechanistic study, we have discovered a Brønsted acid catalyzed formation of ketone radicals. This is believed to proceed via thermally labile alkenyl peroxides formed in situ from ketones and hydroperoxides. The discovery could be utilized to develop a multicomponent radical addition of unactivated ketones and tert-butyl hydroperoxide to olefins. The resulting γ-peroxyketones are synthetically useful intermediates that can be further transformed into 1,4-diketones, homoaldol products, and alkyl ketones. A one-pot reaction yielding a pharmaceutically active pyrrole is also described.

Azasulfur(iv) derivatives of sulfite and sulfinate esters by formal S-S bond insertion of dichloramines.

Azasulfur(vi) compounds such as sulfoximines and sulfonimidamides are attractive due to the unique properties of the S[double bond, length as m-dash]N bond. While the synthesis of these carbon-attached sulfonimidoyl derivatives is well-established, the situation is different for their heteroatom-bound counterparts. In this work, we propose azasulfur(iv) esters as platform chemicals that can be derivatized to obtain all types of SVI[double bond, length as m-dash]N functional groups, among these are the poorly accessible, all-heteroatom imidosulfate esters. Using a chloroamination workflow established here, S-S bond-containing structures such as elemental sulfur or diaryl disulfides can be transformed into imidothionyl or sulfinimidoyl chlorides, which are easily esterified or amidated. Thus, chloramines serve as a versatile [N] and [Cl+] source, and by using them in the context reported here, we advance the set of mild synthetic methods as the latest toolbox member to cover even more of the azasulfur(iv) and (vi) chemical space.

An Extrusion Strategy for On-Demand SF5Cl Gas Generation from a Commercial Disulfide.

Herein we report a novel methodology for the ex situ generation of SF5Cl by employing 4,4'-dipyridyl disulfide as a safe commercial reagent, obviating the need for lecture bottles. The method is applicable to certain SF5Cl-involving transformations by using a two-chamber reactor. Moreover, easily applying SF5Cl in different solvents is rendered feasible, while avoiding the use of glovebox techniques. This report also suggests 1H-19F HOESY as a simple and fast stereochemistry indication for chloropentafluorosulfanylated olefins.

Copper-Catalyzed, Aerobic Synthesis of NH-Sulfonimidamides from Primary Sulfinamides and Secondary Amines.

NH-Sulfonimidamides are prepared by copper-catalyzed coupling of primary sulfinamides with secondary amines. Neither a ligand nor an additive is needed, and air is the terminal oxidant. The reactions occur at room temperature, show good functional group tolerance, and lead to products in good yields. A sulfanenitrile is proposed as an intermediate in this oxidative amination.

Acid-Mediated Imidazole-to-Fluorine Exchange for the Synthesis of Sulfonyl and Sulfonimidoyl Fluorides.

Sulfur(VI) fluoride motifs are important entities in organic chemistry. Typically, their syntheses involve the corresponding chlorides, which are often difficult to prepare and characterized by a poor storability due to the inherently weak S-Cl bond. Here, a single-step procedure for the preparation of sulfur(VI) fluorides starting from sulfonyl imidazoles as stable S(VI) reservoirs is described. By using a simple combination of AcOH and potassium bifluoride (KF2H), an imidazole-to-fluorine exchange furnishes a variety of sulfonyl, sulfonimidoyl, sulfoxyl, and sulfamoyl fluorides in good to excellent yields.

Correction: SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.

[This corrects the article DOI: 10.1039/D1SC06267K.].

SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates.

Sulfur(vi) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the ex situ generation of trifluoromethanesulfonyl fluoride (CF3SO2F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the SVI-F connector with a S[double bond, length as m-dash]O → S[double bond, length as m-dash]NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H2O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols vs. amine groups, a phenomenon best explained-using ab initio metadynamics simulations-by a hydrogen bonded termolecular transition state for the CF3SO2F triflylation of amines.

Non-innocent probes in direct sonication: Metal assistance in oxidative radical CH functionalization.

Direct sonication by means of ultrasound horns constitutes a widely used technique in chemical process technology. However, the direct contact between the metal probe and the reaction mixture does not always leave the chemical system unaffected. In this report, we study the tert-butyl hydroperoxide-mediated trifluoromethylation of heterocyclic structures, and the influence of sonication thereon. Metal leaching is observed during the process and further examined, showing that several metals can interfere significantly with the chemical reaction under study. Notably, vanadium metal was found to increase the reaction rate exceptionally well, rendering it a useful additive for this type of reactions. Ultimately, some mechanistic considerations are offered, to provide more insight into the nature of the catalytic effect of leached metals.

Ex Situ Generation of Sulfuryl Fluoride for the Synthesis of Aryl Fluorosulfates.

A convenient transformation of phenols into the corresponding aryl fluorosulfates is presented: the first protocol to completely circumvent direct handling of gaseous sulfuryl fluoride (SO2F2). The proposed method employs 1,1'-sulfonyldiimidazole as a precursor to generate near-stoichiometric amounts of SO2F2 gas using a two-chamber reactor. With NMR studies, it was shown that this ex situ gas evolution is extremely rapid, and a variety of phenols and hydroxylated heteroarenes were fluorosulfated in good to excellent yields.

Discovery of a potent protein kinase D inhibitor: insights in the binding mode of pyrazolo[3,4-d]pyrimidine analogues.

In this study, we set out to rationally optimize PKD inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold. The lead compound for this study was 1-NM-PP1, which was previously found by us and others to inhibit PKD. In our screening we identified one compound (3-IN-PP1) displaying a 10-fold increase in potency over 1-NM-PP1, opening new possibilities for specific protein kinase inhibitors for kinases that show sensitivity towards pyrazolo[3,4-d]pyrimidine derived compounds. Interestingly the observed SAR was not in complete agreement with the commonly observed binding mode where the pyrazolo[3,4-d]pyrimidine compounds are bound in a similar fashion as PKD's natural ligand ATP. Therefore we suggest an alternate binding mode where the compounds are flipped 180 degrees. This possible alternate binding mode for pyrazolo[3,4-d]pyrimidine based compounds could pave the way for a new class of specific protein kinase inhibitors for kinases sensitive towards pyrazolo[3,4-d]pyrmidines.