Friedel-Crafts Reactivity with Sulfondiimidoyl Fluorides for the Synthesis of Heteroaryl Sulfondiimines.

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.

Palladium-Catalyzed Addition of Aryl Halides to -Sulfinylamines for the Synthesis of Sulfinamides.

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.

Sandmeyer Chlorosulfonylation of (Hetero)Aromatic Amines Using DABSO as an SO Surrogate.

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 SO surrogate, in the presence of HCl and a Cu catalyst.

Exploiting trans-Sulfinylation for the Synthesis of Diverse N-Alkyl Sulfinamides via Decarboxylative Sulfinamidation.

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 Modular Synthesis of Sulfondiimidoyl Fluorides and their Application to Sulfondiimidamide and Sulfondiimine Synthesis.

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.

Copper-Catalyzed Synthesis of Masked (Hetero)Aryl Sulfinates.

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 -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.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides.

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.

Modular Two-Step Route to Sulfondiimidamides.

Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature.

Photocatalytic Late-Stage Functionalization of Sulfonamides via Sulfonyl Radical Intermediates.

A plethora of drug molecules and agrochemicals contain the sulfonamide functional group. However, sulfonamides are seldom viewed as synthetically useful functional groups. To confront this limitation, a late-stage functionalization strategy is described, which allows sulfonamides to be converted to pivotal sulfonyl radical intermediates.

Reductant-Free Cross-Electrophile Synthesis of Di(hetero)arylmethanes by Palladium-Catalyzed Desulfinative C-C Coupling.

An efficient Pd-catalyzed one-pot desulfinative cross-coupling to access medicinally relevant di(hetero)arylmethanes is reported. The method is reductant-free, and involves a sulfinate transfer reagent and a Pd-catalyst mediating the union of two electrophilic coupling partners; a (hetero)aryl halide and a benzyl halide. We establish for the first time that benzyl sulfinates, generated in situ, undergo efficient Pd-catalyzed desulfinative cross-coupling with (hetero)aryl halides to generate di(hetero)arylmethanes.

Diverse saturated heterocycles from a hydroacylation/conjugate addition cascade.

Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,β-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity.

A Silyl Sulfinylamine Reagent Enables the Modular Synthesis of Sulfonimidamides via Primary Sulfinamides.

A new -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.

Sulfonyl fluorides as targets and substrates in the development of new synthetic methods.

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.

Azine-N-oxides as effective controlling groups for Rh-catalysed intermolecular alkyne hydroacylation.

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry. We show that by using azine N-oxide substituted aldehydes, good reactivity can be achieved, and that they are highly effective substrates for the intermolecular hydroacylation of alkynes. Employing a Rh(i)-catalyst, we achieve a mild and scalable aldehyde C-H activation, that permits the coupling with unactivated terminal alkynes, in good yields and with high regioselectivities (up to >20 : 1 l:b).

Sulfinates from Amines: A Radical Approach to Alkyl Sulfonyl Derivatives via Donor-Acceptor Activation of Pyridinium Salts.

Synthetically versatile alkyl sulfinates can be prepared from readily available amines, using Katritzky pyridinium salt intermediates. In a catalyst-free procedure, primary, secondary, and benzylic alkyl radicals are generated by photoinduced or thermally induced single-electron transfer (SET) from an electron donor-acceptor (EDA) complex, and trapped by SO to generate sulfonyl radicals. Hydrogen atom transfer (HAT) from Hantzsch ester gives alkyl sulfinate products, which are used to prepare a selection of medicinal chemistry relevant sulfonyl-containing motifs.

Exploiting Configurational Lability in Aza-Sulfur Compounds for the Organocatalytic Enantioselective Synthesis of Sulfonimidamides.

Methods for establishing the absolute configuration of sulfur-stereogenic aza-sulfur derivatives are scarce, often relying on cumbersome protocols and a limited pool of enantioenriched starting materials. We have addressed this by exploiting, for the first time, a feature of sulfonimidamides in which it is possible for tautomeric structures to also be enantiomeric. Such sulfonimidamides can readily generate prochiral ions, which we have exploited in an enantioselective alkylation process.

Nickel(II)-Catalyzed Addition of Aryl and Heteroaryl Boroxines to the Sulfinylamine Reagent TrNSO: The Catalytic Synthesis of Sulfinamides, Sulfonimidamides, and Primary Sulfonamides.

We report a redox-neutral Ni(II)-catalyzed addition of (hetero)aryl boroxines to -sulfinyltritylamine (TrNSO). The reactions use a catalyst generated from the combination of commercial, air-stable NiCl·(glyme) and a commercially available bipyridine ligand, and deliver sulfinamide products. The scope of the reaction is established using a sulfonimidamide synthesis, in which the initially formed sulfinamides undergo oxidative chlorination with the inexpensive and safe chlorinating agent, trichloroisocyanuric acid (TCCA), to produce sulfonimidoyl chlorides as key intermediates.

Base-Activated Latent Heteroaromatic Sulfinates as Nucleophilic Coupling Partners in Palladium-Catalyzed Cross-Coupling Reactions.

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd -catalyzed cross-coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi-step transformations. Here we introduce base-activated, latent sulfinate reagents: β-nitrile and β-ester sulfones.

Sequential Catalytic Functionalization of Aryltriazenyl Aldehydes for the Synthesis of Complex Benzenes.

We demonstrate that aryltriazenes can promote three distinctive types of C-H functionalization reactions, allowing the preparation of complex benzene molecules with diverse substitution patterns. 2-Triazenylbenzaldehydes are shown to be efficient substrates for Rh(I)-catalyzed intermolecular alkyne hydroacylation reactions. The resulting triazene-substituted ketone products can then undergo either a Rh(III)-catalyzed C-H activation, or an electrophilic aromatic substitution reaction, achieving multifunctionalization of the benzene core.

Rediscovering Sulfinylamines as Reagents for Organic Synthesis.

Sulfinylamines (R-N=S=O), monoaza analogues of sulfur dioxide, have been known for well over a century, and their reactivity as sulfur electrophiles and in Diels-Alder reactions is well-established. However, they have only rarely been used in organic synthesis in recent decades despite the increasing prominence of compounds containing N=S=O functionality, such as sulfoximines and sulfonimidamides. This Minireview aims to bring wider visibility to the unique chemistry enabled by this class of compounds.

Primary Sulfonamide Synthesis Using the Sulfinylamine Reagent -Sulfinyl--(-butyl)hydroxylamine, -BuONSO.

Sulfonamides have played a defining role in the history of drug development and continue to be prevalent today. In particular, primary sulfonamides are common in marketed drugs. Here we describe the direct synthesis of these valuable compounds from organometallic reagents and a novel sulfinylamine reagent, -BuONSO.

The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations.

Azine-containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition-metal-catalysed cross-coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds.

Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides.

Sulfoximines and sulfonimidamides are promising compounds for medicinal and agrochemistry. As monoaza analogues of sulfones and sulfonamides, respectively, they combine good physicochemical properties, high stability, and the ability to build complexity from a three-dimensional core. However, a lack of quick and efficient methods to prepare these compounds has hindered their uptake in molecule discovery programmes.

α-Amidoaldehydes as Substrates in Rhodium-Catalyzed Intermolecular Alkyne Hydroacylation: The Synthesis of α-Amidoketones.

We show that readily available α-amidoaldehydes are effective substrates for intermolecular Rh-catalyzed alkyne hydroacylation reactions. The catalyst [Rh(dppe)(C H F)][BAr ] provides good reactivity, and allows a broad range of aldehydes and alkynes to be used as substrates, delivering α-amidoketone products. High yields and high levels of regioselectivity are achieved.