Covalent inhibitor design is dominated by the use of electrophilic acrylamide warheads. One limitation of acrylamides is that there are limited opportunities to modify their electrophilicity, and hence reactivity, by simple structural changes. Here we show that vinyl sulfonimidamides are effective electophilic groups for reaction with both sulfur- and nitrogen-based biologically relevant nucleophiles. The parent N-H vinyl sulfonimidamides are prepared in a single step from an aryl-ONSO reagent, a vinyl organometallic, and an appropriate amine. Imidic N-functionalisation is straightforward, providing a collection of electrophilic fragments of varied reactivity. We demonstrate that the electrophilicity of these new reagents can be modulated by choice of the imidic N-substituent, and when this is used in combination with alkene substituents, allows for a reactivity range both above and below that of the parent acrylamide.

Aryl sulfinamides are versatile synthetic intermediates for accessing diverse and medicinally relevant S(VI) functionalities, such as sulfonamides and sulfonimidamides. Herein, we report a thianthrenium-enabled, site-selective C-H sulfinamidation procedure via a blue-light-promoted electron-donor-acceptor (EDA) complex to afford the key aryl sulfinamide species. This operationally simple procedure combines site-selective C-H sulfonium salt preparation followed by single-electron transfer (SET) from a photoactive EDA complex formed with readily available amines. The resultant aryl radicals react with sulfinylamine reagents to deliver aryl sulfinamides under mild conditions. The method displays broad generality and regioselectively constructs key aryl sulfinamides from medicinally relevant arenes without using expensive transition metal or photoredox catalysts, highlighting its use as a late-stage functionalization tool for medicinal and drug discovery chemistry.

The study of the stereochemistry of organic sulfur compounds has been ongoing for over a century, with S-chirogenic pharmacophores playing an essential role in drug discovery within bioscience and medicinal chemistry. Traditionally, the synthesis of sulfinamides featuring stereogenic sulfur(IV) centers involves a complex, multistep process that often depends on chiral auxiliaries or kinetic resolution. Here, we introduce an effective and versatile method for synthesizing diverse classes of S-chirogenic sulfinamides through selective aryl and alkenyl addition to sulfinylamines. This process is catalysed by a chiral nickel or cobalt complex under reductive conditions, and eliminating the need for preformed organometallic reagents. The method facilitates the incorporation of a diverse array of aryl and alkenyl halides at the sulfur position, enabling their integration into various biologically significant sulfur pharmacophores. Our detailed mechanistic investigations and density functional theory calculations provide insights into the reaction pathway, particularly highlighting the enantiocontrol mode during addition process.

Sulfinamides, sulfonamides, and sulfonimidamides are valuable motifs in medicinal chemistry, yet methods to synthesize alkyl variants from simple, readily available feedstocks remain scarce. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using commercial iron salts and visible light irradiation, in combination with commercial sulfinylamine reagents, to deliver alkyl sulfinamide products. The method is operationally simple and scalable, exhibits broad functional group tolerance, and is translatable to continuous-flow synthesis. Furthermore, it facilitates late-stage diversification of complex molecules, highlighting its potential utility in medicinal chemistry applications.

The well documented difficulties associated with direct (hetero)-arylation of aza-aromatics (e.g., azines) at the α-position to nitrogen led to a collaborative project between the Willis group at Oxford and the Medicine Design department at Pfizer with the aim of addressing this challenge. The result of this collaboration has been a series of reports detailing the development of 2-aza-aryl sulfinates, as well as related 2-aza-aryl sulfone derivatives, as efficient nucleophilic reagents in palladium-catalyzed coupling reactions with (hetero)-aryl halides. The developed chemistry is routinely used in the medicinal chemistry laboratories at Pfizer, and the patent literature now contains many examples of these methods being embraced across the pharmaceutical industry. Hundreds of pyridyl (and related heterocyclic) sulfinates are now commercially available from multiple vendors. In this microperspective we discuss the development and evolution of these methods and highlight subsequent applications.

Azetidines are four-membered saturated N-heterocycles that are of interest in discovery chemistry. However, the implementation of these structures is limited by their synthetic intractability, resulting from their inherent ring strain. An approach that circumvents this is the intermolecular [2 + 2] photocycloaddition between imines and alkenes. However, this is unworkable with simple acyclic imines and non-activated alkenes, due to the inability to generate suitably reactive imine-derived triplet intermediates. Here we show that simple acyclic imines bearing N-sulfamoyl fluoride substituents generate reactive triplet imines that react with a broad range of alkenes to produce azetidine products in high yields. Mechanistic and computational studies confirm the key role of the sulfamoyl fluoride unit in dictating the [2 + 2] pathway. In addition, the sulfamoyl fluoride substituents offer a convenient reaction site for product functionalization or for traceless removal. The advent of synthetically useful imine-derived triplets should initiate further research and applications of these elusive reactive intermediates. Azetidines are four-membered saturated N-heterocycles that are of interest in drug discovery and medicinal chemistry. Here the authors report how sulfamoyl fluoride substituents tune the reactivity of acyclic imine-derived triplet intermediates for the synthesis of azetidines via a [2 + 2] photocycloaddition reaction with alkenes.

Sulfinamides are versatile, synthetically useful intermediates, and final motifs. Traditional methods to synthesize sulfinamides generally require substrates with preinstalled sulfur centers. However, these precursors have limited commercial availability, and the associated synthetic routes often require harsh reaction conditions and highly reactive reagents, thus severely limiting their application. Herein, we report the synthesis of sulfinamides from aryl and alkenyl (pseudo)halides and N-sulfinylamines, enabled by palladium catalysis. The reactions use mild conditions and are achieved without the use of highly reactive preformed organometallic reagents, resulting in transformations of broad generality and high functional group tolerance. In particular, substrates featuring protic and electrophilic functional groups can be used successfully. The modification of complex aryl cores and natural product derivatives demonstrates the utility of this method.

The asymmetric synthesis of sulfur(IV) functionalities presents a substantial challenge given that direct catalytic methods are underexplored. In this issue of Chem, Chi and co-workers use quinine as the chiral catalyst for the asymmetric conversion of sulfinate salts to high-value sulfinate esters and sulfinamides.

image [7522‐26‐1] C 3 H 9 NOSSi (MW 135.3) InChI = 1S/C3H9NOSSi/c1‐7(2,3)4‐6‐5/h1‐3H3 InChIKey = RFMSRGPUQNDFNS‐UHFFFAOYSA‐N (used as a sulfurdiimidation, sulfinamidation, or sulfinylamination reagent for the synthesis of aza‐sulfur compounds, as a dienophile in Diels–Alder reactions, and as a dipolarophile in (3 + 2) cycloadditions) Alternative Names : 1,1,1‐trimethyl‐ N ‐sulfinylsilanamine, silylamine, 1,1,1‐trimethyl‐ N ‐sulfinyl‐, (sulfinylamino)trimethylsilane, (trimethylsilyl)sulfinylamine, (trimethylsilyl)sulfinylimide, 1,1,1‐trimethyl‐ N ‐sulfinylsilylamine, N ‐(trimethylsilyl)sulfinylimide, N ‐trimethylsilylsulfinylimine, N ‐sulfinyl trimethylsilanamine, ((trimethylsilyl)imino)‐λ 4 ‐sulfanone, and TMS‐NSO. Physical Data : mp −78 °C, 1 bp 108–110 °C (760 mmHg), 1 and = 1.4258. 2 Solubility : miscible with common organic solvents including THF, Et 2 O, CH 2 Cl 2 , CHCl 3 , toluene, and benzene. Form Supplied in : colorless liquid; commercially available. Analysis of Reagent Purity : spectroscopic data: IR, 1,3 Raman, 3 NMR ( 1 H, 13 C, 14 N, 17 O, 29 Si), 3 and mass spectra. 1,3 Preparative Method : TMS‐NSO is prepared from the reaction of (SiMe 3 ) 3 N and SOCl 2 in anhydrous CH 2 Cl 2 at room temperature for 20 h, 4 or from PhSNSO by heating with Me 3 SiSPh at 100 °C for 1 h. 2 Distillation then affords TMS‐NSO. Purification : distillation. Handling, Storage, and Precautions : TMS‐NSO is sensitive to moisture and air, and its use after storage is challenging.

image [2762957‐87‐7] C 9 H 21 NOSSi (MW 219.4) InChI = 1S/C9H21NOSSi/c1‐7(2)13(8(3)4,9(5)6)10‐12‐11/h7‐9H,1‐6H3 InChIKey = ZJJCFIWQFNLRFK‐UHFFFAOYSA‐N (used as a sulfinamidation or a sulfinamidination reagent for the synthesis of aza‐sulfur compounds) Alternative Names : triisopropylsilyl sulfinamine, ((triisopropylsilyl)imino)‐λ 4 ‐sulfanone, TIPS ‐ NSO. Physical Data : unknown. Solubility : miscible with common organic solvents including THF, Et 2 O, CH 2 Cl 2 , CHCl 3 , MeCN, toluene, and benzene. Form Supplied in : light‐yellow liquid, commercially available. Analysis of Reagent Purity : spectroscopic data: IR, NMR ( 1 H, 13 C). 1 Preparative Method : TIPS ‐ NSO is prepared from dropwise addition of SOCl 2 to TIPS‐NH 2 in the presence of Et 3 N at 0 °C in anhydrous Et 2 O. After stirring the reaction for 2 h, the solid Et 3 N·HCl salt is removed by filtration through a pad of anhydrous Na 2 SO 4 and the removal of the solvent in vacuo affords TIPS‐NSO. 1 Purification : none required. Handling, Storage, and Precautions : TIPS ‐ NSO may be slightly volatile. For this reason, when removing solvent on a rotary evaporator, the bath temperature should be set to 30 °C or lower. For long‐term storage, it is kept at −20 °C in a freezer under an inert atmosphere. Hydrolysis of TIPS‐NSO can potentially result in the evolution of toxic SO 2 .

Sulfur-containing compounds are found in myriad applications. Sulfones and sulfonamides are the most common functional groups used in medicinal and agrochemical endeavours. Isosteres of these functional groups, for example, sulfoximines and sulfonimidamides, are emerging functionalities, and they are increasingly common in the relevant patent literature. However, in general, the associated synthetic routes still have limitations, including the use of harsh reaction conditions and highly reactive reagents. A variety of catalytic reactions that employ a diverse range of substrate classes have been developed to address these issues. This short review highlights recent catalytic syntheses of aza-sulfur compounds, which we hope will open new directions in discovery chemistry. 1 Introduction 2 Reactions of N -Sulfinylamines 3 Reactions with Sulfenamides 4 Reactions with Sulfinates 5 Reactions with Sulfinamides 6 Reactions with Other Aza-Sulfur Compounds 7 Conclusion

Combining simple amines with the bench-stable sulfinylamine Tr-NSO allows in situ preparation of reactive alkyl sulfinylamines, which when combined with alkyl radicals generated by photocatalytic decarboxylation, provides N-alkyl sulfinamides. The reactions are broad in scope and tolerate a wide variety of functional groups on both the acid and amine components. The sulfinamide products are used to prepare a selection of challenging S(VI) products. The method provides a convenient way to use reactive and unstable alkyl sulfinylamines.

A modular synthesis of sulfondiimidoyl fluorides-the double aza-analogues of sulfonyl fluorides-allowing variation of the carbon and both nitrogen-substituents is reported. The chemistry uses readily available organometallic reagents, commercial sulfinylamines, simple electrophiles, and N-fluorobenzenesulfonimide (NFSI), as the starting materials. The reactions are broad in scope, efficient, and scalable. We show that the sulfondiimidoyl fluoride products can be combined with amines to provide sulfondiimidamides, and with organolithium reagents to provide sulfondiimines, and that reactivity in these transformations can be modulated by variation of the N-substituents.

Sulfonyl chlorides not only play a crucial role in protecting group chemistry but also are important starting materials in the synthesis of sulfonamides, which are in-demand motifs in drug discovery chemistry. Despite their importance, the number of different synthetic approaches to sulfonyl chlorides is limited, and most of them rely on traditional oxidative chlorination chemistry from thiol precursors. In this report, we disclose a novel Sandmeyer-type sulfonyl chloride synthesis from feedstock anilines and DABSO, used as a stable SO2 surrogate, in the presence of HCl and a Cu catalyst. The method works on a wide range of anilines and allows for the isolation of the sulfonyl chloride after aqueous workup or its direct conversion into the sulfonamide by simple addition of an amine after the completion of the Sandmeyer reaction. The scalability of this method was demonstrated on a 20 g scale, and the corresponding heterocyclic sulfonyl chloride was isolated in 80% yield and excellent purity.

Sulfur functional groups are ubiquitous in molecules used in the pharmaceutical and agrochemical industries, and within these collections sulfones hold a prominent position. The double aza-analogues of sulfones, sulfondiimines, offer significant potential in discovery chemistry but to date their applications have been limited by the lack of convenient synthetic routes. The existing methods mainly rely on imination of low-valent-sulfur intermediates, or the combination of pre-formed organometallic reagents and electrophilic S(VI)-functionalities. Herein, we describe a Friedel-Crafts-type reaction of sulfondiimidoyl fluorides with (hetero)aryls. This new SuFEx reactivity benefits from broad functional group tolerance, mild reaction conditions, and does not require the use of pre-formed organometallic reagents. The efficient use of unprotected indoles and pyrroles, as well as furan, thiophene and carbocyclic aromatics, further demonstrates the advantages of these reactions. We show that the reactivity of the sulfondiimidoyl fluorides can be tuned by switching the N-substituents, allowing an expansion of the range of coupling partners. The utility of the transformation is exemplified by the synthesis of the sulfondiimine analogue of the HIV-I reverse transcriptase-inhibitor L-737,126.

Catalysis using substoichiometric copper facilitates the synthesis of masked (hetero)aryl sulfinates under mild, base-free conditions from aryl iodides and the commercial sulfonylation reagent sodium 1-methyl 3-sulfinopropanoate (SMOPS). The development of a tert-butyl ester variant of the SMOPS reagent allowed the use of aryl bromide substrates. The sulfones thus generated can be unmasked and functionalized in situ to form a variety of sulfonyl-containing functional groups.

Two synthetic routes to sulfondiimidamides have recently been reported. The ability to prepare and manipulate sulfondiimidamides, which are the double aza-analogs of sulfonamides, in an efficient and predictable way, opens new possibilities for exploring chemical space.

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

A new N-silyl sulfinylamine reagent allows the rapid preparation of a broad range of (hetero)aryl, alkenyl, and alkyl primary sulfinamides, using Grignard, organolithium, or organozinc reagents to introduce the carbon fragment. Treatment of these primary sulfinamides with an amine in the presence of a hypervalent iodine reagent leads directly to NH-sulfonimidamides. This two-step sequence is straightforward to perform and provides a modular approach to sulfonimidamides, allowing ready variation of both reaction components, including primary and secondary amines.

The advent of sulfur(VI)-fluoride exchange (SuFEx) processes as transformations with click-like reactivity has invigorated research into electrophilic species featuring a sulfur-fluorine bond. Among these, sulfonyl fluorides have emerged as the workhorse functional group, with diverse applications being reported. Sulfonyl fluorides are used as electrophilic warheads by both medicinal chemists and chemical biologists. The balance of reactivity and stability that is so attractive for these applications, particularly the resistance of sulfonyl fluorides to hydrolysis under physiological conditions, has provided opportunities for synthetic chemists. New synthetic approaches that start with sulfur-containing substrates include the activation of sulfonamides using pyrilium salts, the deoxygenation of sulfonic acids, and the electrochemical oxidation of thiols. Employing non-sulfur-containing substrates has led to the development of transition-metal-catalysed processes based on palladium, copper and nickel, as well as the use of SO2F2 gas as an electrophilic hub. Selectively manipulating molecules that already contain a sulfonyl fluoride group has also proved to be a popular tactic, with metal-catalysed processes again at the fore. Finally, coaxing sulfonyl fluorides to engage with nucleophiles, when required, and under suitable reaction conditions, has led to new activation methods. This Review provides an overview of the challenges in the efficient synthesis and manipulation of these intriguing functional groups.