Herein, we introduce a new synthetic protocol for azole alkylation. Our strategy first engages azoles using alkenylthianthrenium electrophiles to provide 1,2-azolothianthrenium salts, then selectively excises the sulfonium moiety via single electron transfer (SET). Given that alkenylthianthrenium salts can be readily accessed from alkenes, the net azole addition-hydrogenolysis sequence unlocks a versatile approach to formal Markovnikov alkene hydroazolation. Moreover, the key radical intermediate formed after reduction can be engaged in reactions beyond hydrogen atom transfer (HAT), providing access to carboazolation products that would be otherwise prohibitively difficult to prepare. Mechanistic studies into the reduction of the alkylthianthrenium electrophile implicate an unusual silyl radical attack on DMF that generates a strong SET reductant in situ under otherwise exceedingly mild conditions. Overall, this work introduces new approaches to transform alkylsulfonium building blocks and immediately expands the range of N-alkyl azole molecules that can be readily prepared and studied.

Single electron transfer (SET) reduction is among the most fundamental strategies for the activation of organic compounds. The design of selective reactions that leverage SET is grounded by the premise that differences in substrate redox potentials predict relative rates of SET, with more favourable reductions occurring faster1. However, across the diverse modes of redox catalysis2,3, devising reactions that require SET to the harder to reduce of two reactants remains challenging. This restriction all but precludes coupling reactions when targeting substrates that are thermodynamically difficult to reduce or oxidize4,5. Here we introduce an alternative selectivity manifold for outer-sphere SET that is divorced from substrate redox potentials. We show that super-potent photoreductants render substrate redox potentials irrelevant through diffusion-limited SET, allowing a new selectivity profile to emerge from competition between downstream chemical steps and back electron transfer (BET). We validate these principles in the context of radical annulation reactions between cyclopropyl ketones and easier-to-reduce alkenes. Although these mismatched redox potentials previously precluded these reactions, we promote selective radical annulation even as the requisite ketone reduction becomes disfavoured by a volt. More broadly, these studies offer a general blueprint for the design of SET reactions that require violation of redox potential control.

image [19767‐45‐4] C 2 H 5 NaO 3 S 2 (MW 164.17) InChI = 1S/C2H6O3S2.Na/c3‐7(4,5)2‐1‐6;/h6H,1‐2H2,(H,3,4,5);/q;+1/p‐1 InChIKey = XOGTZOOQQBDUSI‐UHFFFAOYSA‐M (reagent commonly used as a nucleophile, reductant, or hydrogen atom transfer catalyst) Physical Data : mp 250 °C. Solubility : H 2 O, MeOH, EtOH, DMSO. Form Supplied in : white solid; widely available. Analysis of Reagent Purity : NMR. Purification : recrystallize from water. 1 Handling, Storage, and Precautions : store under nitrogen atmosphere at 2–8 °C. Toxicity (oral) rat LD50: 4440 mg kg −1 . 2 Reactive toward electrophiles, oxidizing agents, strong bases.

Despite tremendous progress in alkene 1,2-difunctionalization, analogous methods to generate 1,3-patterns from alkenes remain limited. Recently, Silvi and co-workers reported a homologative strategy to transform alkenes into 1,3-dielectrophiles (DOI: https://doi.org/10.1002/anov.70005). They introduce a novel iodomethyl thianthrenium salt as a precursor to methyl thianthrenium radical, which adds across unactivated alkenes. Substitution of the 1,3-dielectrophiles delivers a general homologative alkene difunctionalization platform.

The stereoselective functionalization of C-H bonds represents a central challenge in modern organic synthesis. Despite decades of innovation in C-H activation chemistry, methods for Z-selective functionalization of alkenes have eluded synthetic practitioners. Terminal alkenes present the biggest challenge for Z-selectivity as they require selective cleavage of the more hindered of two otherwise virtually identical C-H bonds. Herein, we describe the transformation of alkenes into transient 1,2-bis-sulfonium intermediates found to undergo Z-selective elimination, overturning a textbook E2 stereoselectivity rule through stabilizing interactions. We identify paired electrolysis as an enabling strategy to both selectively generate the requisite bis-sulfonium intermediate and drive its rapid elimination in situ. The resultant Z-alkenyl sulfonium linchpins provide access to a wide array of Z-alkene targets from inexpensive feedstocks through robust cross-coupling reactions.

Azoles are important synthetic targets due to their diverse applications in areas ranging from human health to food security. Accordingly, access to N-functionalized azoles is an essential goal in modern synthetic chemistry. Surprisingly, however, the relied-upon azole N-alkylation strategies fundamentally limit the structural diversity of these important compounds that can be synthesized and studied. Here we introduce an approach to prepare a broad array of important but difficult-to-access N-alkyl azole compounds. We accomplish this through the introduction of a base-catalysed hydroazolation of readily accessible alkenylthianthrenium electrophiles. This strategy circumvents the classical challenge of azole alkylation regiocontrol through an unusual reversible C–N-bond-forming step that exploits the thermodynamic differences between azole N-alkylation isomers. This reaction furnishes a class of versatile azolothianthrenium building blocks that provides a general platform to investigate diverse N-alkyl azole molecules. More broadly, the distinctive approach outlined through this project is poised to impact the design and development of diverse regioselective alkylation reactions. Azoles are important synthetic targets due to their diverse applications in areas ranging from human health to food security. Now it has been shown that the hydroazolation of alkenylthianthrenium salts provides a modular platform to access diverse, densely functionalized N-alkyl azole compounds with high N-regioselectivity.

Herein, we introduce a new platform for alkene carboxy-alkylation. This reaction is designed around CO2 center dot- addition to alkenes followed by radical polar crossover, which enables alkylation through carbanion attack on carbonyl electrophiles. We discovered that CO2 center dot- adds to alkenes faster than it reduces carbonyl electrophiles and that this reactivity can be exploited by accessing CO2 center dot- via hydrogen atom transfer from formate. This photocatalytic system transforms vinylarenes and carbonyl compounds into a diverse array of substituted gamma-lactone products. Furthermore, indoles can be engaged through dearomative carboxy-alkylation, delivering medicinally relevant C(sp3)-rich heterocyclic scaffolds. Mechanistic studies reveal that the active photocatalyst is generated in situ through a photochemically induced reaction between the precatalyst and DMSO. Overall, we have developed a three-component alkene carboxy-alkylation reaction enabled by the use of formate as the CO2 center dot- precursor.

A detailed mechanistic study of the Z-selective allylic functionalization via thianthrenium salts is presented. Kinetic analyses, deuterium labeling experiments, and computational methods are used to rationalize the observed reactivity and selectivity. We find that the reaction proceeds via a rate-determining and stereodetermining allylic deprotonation of an alkenylthianthrenium species. The Z-configuration of the resultant allylic ylide is translated into the Z-allylic amine product through a sequence of subsequent fast and irreversible steps: protonation to form a Z-allylic thianthrenium electrophile and then regioselective substitution by the nucleophile. In the stereodetermining deprotonation step, computational studies identified a series of stabilizing nonbonding interactions in the Z-alkene-forming transition state that contribute to the stereoselectivity.

Oxidative alkene functionalization reactions are a fundamental class of complexity-building organic transformations. However, the majority of established approaches rely on electrophilic reagents that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene-derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene-derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible.

Modular strategies to rapidly increase molecular complexity have proven immensely synthetically valuable. In principle, transformation of an alkene into a dielectrophile presents an opportunity to deliver two unique nucleophiles across an alkene. Unfortunately, the selectivity profiles of known dielectrophiles have largely precluded this deceptively simple synthetic approach. Herein, we demonstrate that dicationic adducts generated through electrolysis of alkenes and thianthrene possess a unique selectivity profile relative to more conventional dielectrophiles. Specifically, these species undergo a single and perfectly regioselective substitution reaction with phthalimide salts. This observation unlocks an appealing new platform for aminofunctionalization reactions. As an illustrative example, we implement this new reactivity paradigm to address a longstanding synthetic challenge: alkene diamination with two distinct nitrogen nucleophiles. Studies into the mechanism of this process reveal a key alkenyl thianthrenium salt intermediate that controls the exquisite regioselectivity of the process and highlight the importance of proton sources in controlling the reactivity of alkenyl sulfonium salt electrophiles.

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate. This deoxygenation procedure is effective across structurally and electronically diverse alcohols and enables a variety of difficult net transformations. This protocol requires no precautions to exclude air or moisture and remains efficient on multigram scale. Finally, the system can be adapted to a one-pot benzoylation-deoxygenation sequence to enable direct alcohol deletion. Mechanistic studies validate that the role of acidic additives is to promote the key C(sp3 )-O bond fragmentation step.

Cyclopropanes are desirable structural motifs with valuable applications in drug discovery and beyond. Established alkene cyclopropanation methods give rise to cyclopropanes with a limited array of substituents, are difficult to scale, or both. Herein, we disclose a new cyclopropane synthesis through the formal coupling of abundant carbon pronucleophiles and unactivated alkenes. This strategy exploits dicationic adducts derived from electrolysis of thianthrene in the presence of alkene substrates. We find that these dielectrophiles undergo cyclopropanation with methylene pronucleophiles via alkenyl thianthrenium intermediates. This protocol is scalable, proceeds with high diastereoselectivity, and tolerates diverse functional groups on both the alkene and pronucleophile coupling partners. To validate the utility of this new procedure, we prepared an array of substituted analogs of an established cyclopropane that is en route to multiple pharmaceuticals.

In this issue of Chem, Sigman, Toste, and co-workers use data science tools to target the development of a novel family of chiral phosphoric acid scaffolds. These conformationally flexible catalysts were designed to induce enantioselectivity through predictable non-covalent interactions, offering an attractive alternative to state-of-the-art chiral catalyst scaffolds that rely on rigid chiral pockets. In this issue of Chem, Sigman, Toste, and co-workers use data science tools to target the development of a novel family of chiral phosphoric acid scaffolds. These conformationally flexible catalysts were designed to induce enantioselectivity through predictable non-covalent interactions, offering an attractive alternative to state-of-the-art chiral catalyst scaffolds that rely on rigid chiral pockets. Data science enables the development of a new class of chiral phosphoric acid catalystsLiles et al.ChemMarch 24, 2023In BriefAlthough catalyst design represents a fundamental challenge in asymmetric catalysis, data science can streamline the process of optimization by enabling the discovery of key catalyst structure-activity relationships. By carefully designing a training set and subsequent reactivity profiling, we herein demonstrate the successful application of data science tools for the design of a new class of adaptable phosphoric acids. These catalysts exhibit a single example of point chirality and can induce high levels of selectivity in a transfer hydrogenation reaction. Full-Text PDF

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Herein, we report a new class of electrophotocatalysts, polycyclic aromatic hydrocarbons, that promote the reduction of unactivated carbonyl compounds to generate versatile ketyl radical intermediates. This catalytic platform enables previously challenging intermolecular ketyl radical coupling reactions, including those that classic reductants (e.g., SmI2/HMPA) have failed to promote. More broadly, this study outlines an approach to fundamentally expand the array of reactive radical intermediates that can be generated via electrophotocatalysis by obviating the need for rapid mesolytic cleavage following substrate reduction.

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Despite the increased probability of clinical success for small molecule therapeutic candidates with increased 3D complexity, new drug targets remain dominated by flat molecules due to the abundance of coupling reactions available for their construction. In principle, heteroarene hydrofunctionalization reactions offer an opportunity to transform readily accessible planar molecules into more three-dimensionally complex analogs through the introduction of a single molecular vector. Unfortunately, dearomative hydrofunctionalization reactions remain limited. Herein, we report a new strategy to enable the dearomative hydrocarboxylation of indoles and related heterocycles. This reaction represents a rare example of a heteroarene hydrofunctionalization that meets the numerous requirements for broad implementation in drug discovery. The transformation is highly chemoselective, broad in scope, operationally simple, and readily amenable to high-throughput experimentation (HTE). Accordingly, this process will allow existing libraries of heteroaromatic compounds to be translated into diverse 3D analogs and enable exploration of new classes of medicinally relevant molecules.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Herein we disclose a strategy to promote the hydrocarboxylation of unactivated alkenes using photochemical activation of formate salts. We illustrate that an alternative initiation mechanism circumvents the limitations of prior approaches and enables hydrocarboxylation of this challenging substrate class. Specifically, we found that accessing the requisite thiyl radical initiator without an exogenous chromophore eliminates major byproducts that have plagued attempts to exploit similar reactivity for unactivated alkene substrates. This redox-neutral method is technically simple to execute and effective across a broad range of alkene substrates. Feedstock alkenes, such as ethylene, are hydrocarboxylated at ambient temperature and pressure. A series of radical cyclization experiments indicate how the reactivity described in this report can be diverted by more complex radical processes.

Isomerization reactions represent a powerful class of synthetic transformations. These processes allow chemists to assemble molecules with robust bond-forming reactions then fine-tune key structural features of the molecule including functional group position and stereochemistry. Accordingly, expanding the breadth of selective isomerization tools has the potential to substantially streamline chemical synthesis.

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Small molecule therapeutic candidates with increased 3D complexity, on average, possess a higher probability of clinical success. However, new drug targets remain dominated by flat molecules due the wealth of robust coupling reactions available for their construction. Heteroarene dearomatization reactions offer an ideal opportunity to transform readily accessible 2D structures into saturated analogs. Broadly employed heteroarene hydrogenation reactions rehybridize C(sp2) sites to C(sp3) without otherwise perturbing the molecular shape. In stark contrast, heteroarene difunctionalization strategies dramatically change the molecular structure. In principle, heteroarene hydrofunctionalization reactions constitute an elusive middle ground by disrupting aromaticity and introducing a single molecular vector. Unfortunately, dearomative hydrofunctionalization reactions remain limited. Herein, we report a new strategy to enable the dearomative hydrocarboxylation of indoles and related heterocycles. This reaction represents a rare example of a heteroarene hydrofunctionalization that meets the numerous requirements for broad implementation in drug discovery. The transformation is highly chemoselective, broad in scope, operationally simple, and readily amenable to high-throughput experimentation (HTE). Accordingly, this process will allow existing libraries of heteroaromatic compounds to be translated into diverse 3D analogs and enable exploration of new classes of medicinally relevant molecules.