Catalytic Olefin Transpositions Facilitated by Ruthenium N,N,N-Pincer Complexes.

In this report, we demonstrate olefin transposition/isomerization reactions catalyzed by a series of N,N,N-pincer (1,3-bis(2-pyridylimino)isoindoline) Ru-hydride complexes. The protocol proceeds at room temperature for most substrates, achieving excellent yields, regioselectivity, and diastereoselectivity in short reaction times. The air-stable Ru-chloride derivatives of these complexes exhibit comparable reactivity enabling benchtop setup and synthetic versatility. Furthermore, we demonstrate the potential for one-pot cascade sequences of the products derived from the transposition reactions.

Revisiting the Reactivity of the Dismissed Hydrogen Atom Transfer Catalyst Succinimide-N-oxyl.

Phthalimide-N-oxyl (PINO) and related radicals are promising catalysts for C-H functionalization reactions. To date, only a small number of N-oxyl derivatives have demonstrated improved activities over PINO. We postulate that the lack of success in identifying superior catalysts is associated not only with challenges in the design and synthesis of new structures, but also the way catalysts are evaluated and utilized. Catalyst evaluation typically relies on the use of chemical oxidants to generate N-oxyl radicals from their parent N-hydroxy compounds. Herein we provide an example where a potential-controlled electrochemical analysis reveals that succinimide-N-oxyl (SINO) compares favorably to PINO as a hydrogen atom transfer (HAT) catalyst-in contrast to previous claims based on other approaches. Our efforts to understand the basis for the greater reactivity of SINO relative to PINO have underscored that the HAT kinetics are significantly influenced by factors beyond changes in thermodynamics. This is perhaps best illustrated by the similar reactivity of tetrachloro-PINO and SINO despite the latter engaging in substantially more exergonic reactions. The key role of HAT transition state (TS) polarization prompted the design and initial characterization of a chlorinated SINO derivative, which we found to be the most reactive N-oxyl HAT catalyst reported to date.

Attenuating N-Oxyl Decomposition for Improved Hydrogen Atom Transfer Catalysts.

The design of N-oxyl hydrogen atom transfer catalysts has proven challenging to date. Previous efforts have focused on the functionalization of the archetype, phthalimide-N-oxyl. Driven in part by the limited options for modification of this structure, this strategy has provided only modest improvements in reactivity and/or solubility. Our previous mechanistic efforts suggested that while the electron-withdrawing carbonyls of the phthalimide are necessary to maximize the O-H bond dissociation enthalpy of the HAT product hydroxylamine and overall reaction thermodynamics, they undergo nucleophilic substitution leading to catalyst decomposition. In an attempt to minimize this vulnerability, we report the characterization of N-oxyl catalysts wherein the aryl ring in PINO is replaced with the combination of a substituted heteroatom and quaternary carbon. By rendering one carbonyl carbon less electrophilic and the other less sterically accessible, the corresponding N1-aryl-hydantoin-N3-oxyl radical showed significantly higher stability than PINO as well as a modest improvement in reactivity. This proof-of-principle in new scaffold design may accelerate future HAT catalyst discovery and development.

A general alkene aminoarylation enabled by N-centred radical reactivity of sulfinamides.

Arylethylamines are popular structural elements in bioactive molecules but are often made through a linear series of synthetic steps. A modular protocol to assemble arylethylamines from alkenes in one step would represent a useful advance in discovery chemistry, though current limitations preclude a generally applicable method. In this work we disclose an aminoarylation of alkenes using aryl sulfinamide reagents as bifunctional amine and arene donors. This reaction features excellent regioselectivity and diastereoselectivity on a variety of activated and unactivated substrates. Using a weakly oxidizing photocatalyst, a nitrogen radical is generated under mild conditions and adds to an alkene to form a new C-N bond. A desulfinylative aryl migration event known as a Smiles-Truce rearrangement follows to form a new C-C bond. In this manner, arylethylamines can be rapidly assembled from abundant alkene feedstocks. Moreover, chiral information from the sulfinamide can be transferred via rearrangement to a new carbon stereocentre in the product, thus advancing the development of traceless asymmetric alkene difunctionalization.

EDA Photochemistry: Mechanistic Investigations and Future Opportunities.

Recently, organic synthesis has seen a renaissance in radical chemistry due to the accessibility of mild methods for radical generation using visible light. While renewed interest in synthetic radical chemistry has been driven by the advent of photoredox catalysis, a resurgence of electron donor-acceptor (EDA) photochemistry has also led to many new radical transformations. Similar to photoredox catalysis, EDA photochemistry involves light-promoted single-electron transfer pathways. However, the mechanism of electron transfer in EDA systems is unique wherein the lifetimes of radical intermediates are often shorter due to competitive back-electron transfer. Distinguishing between EDA and photoredox mechanisms can be challenging since they can form identical products. In this perspective, we seek to provide insight on the mechanistic studies which can distinguish between EDA and photoredox manifolds. Additionally, we highlight some key challenges in EDA photochemistry and suggest future goals which could advance the synthetic potential of this field of research.

Exploring Cuneanes as Potential Benzene Isosteres and Energetic Materials: Scope and Mechanistic Investigations into Regioselective Rearrangements from Cubanes.

Cuneane is a strained hydrocarbon that can be accessed via metal-catalyzed isomerization of cubane. The carbon atoms of cuneane define a polyhedron of the C2v point group with six faces─two triangular, two quadrilateral, and two pentagonal. The rigidity, strain, and unique exit vectors of the cuneane skeleton make it a potential scaffold of interest for the synthesis of functional small molecules and materials. However, the limited previous synthetic efforts toward cuneanes have focused on monosubstituted or redundantly substituted systems such as permethylated, perfluorinated, and bis(hydroxymethylated) cuneanes. Such compounds, particularly rotationally symmetric redundantly substituted cuneanes, have limited potential as building blocks for the synthesis of complex molecules. Reliable, predictable, and selective syntheses of polysubstituted cuneanes bearing more complex substitution patterns would facilitate the study of this ring system in myriad applications. Herein, we report the regioselective, AgI-catalyzed isomerization of asymmetrically 1,4-disubstituted cubanes to cuneanes. In-depth DFT calculations provide a charge-controlled regioselectivity model, and direct dynamics simulations indicate that the nonclassical carbocation invoked is short-lived and dynamic effects augment the charge model.

The design of PINO-like hydrogen-atom-transfer catalysts.

Phthalimide-N-oxyl (PINO) is a valuable hydrogen-atom-transfer (HAT) catalyst for selective C-H functionalization. To advance and optimize PINO-catalysed HAT reactions, researchers have been focused on modifying the phthalimide core structure. Despite much effort and some notable advances, the modifications to date have centred on optimization of a single parameter of the catalyst, such as reactivity, solubility or stability. Unfortunately, the optimization with respect to one parameter is often associated with a worsening of the others. The derivation of a single catalyst structure with optimal performance across multiple parameters has therefore remained elusive. Here we present an analysis of the structure-activity relationships of PINO and its derivatives as HAT catalysts, which we hope will stimulate further development of PINO-catalysed HAT reactions and, ultimately, lead to much improved catalysts for real-world applications.

Leveraging the Persistent Radical Effect in the Synthesis of trans-2,3-Diaryl Dihydrobenzofurans.

A simple method for accessing trans-2,3-diaryl dihydrobenzofurans is reported. This approach leverages the equilibrium between quinone methide dimers and their persistent radicals. This equilibrium is disrupted by phenols that yield comparatively transient phenoxyl radicals, leading to cross-coupling between the persistent and transient radicals. The resultant quinone methides with pendant phenols rapidly cyclize to form dihydrobenzofurans (DHBs). This putative biomimetic access to dihydrobenzofurans provides superb functional group tolerance and a unified approach for the synthesis of resveratrol-based natural products.

High-Throughput Optimization of Photochemical Reactions using Segmented-Flow Nanoelectrospray-Ionization Mass Spectrometry.

Within the realm of drug discovery, high-throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry-based platform to enable the rapid exploration of photoredox reactions for early-stage drug discovery. Specifically, microwell plate-based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization-mass spectrometry analysis. This approach was demonstrated for the late-stage modification of complex drug scaffolds, as well as the subsequent structure-activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high-throughput library diversification.

Formal Cycloadditions Driven by the Homolytic Opening of Strained, Saturated Ring Systems.

The field of strain-driven, radical formal cycloadditions is experiencing a surge in activity motivated by a renaissance in free radical chemistry and growing demand for sp3 -rich ring systems. The former has been driven in large part by the rise of photoredox catalysis, and the latter by adoption of the "Escape from Flatland" concept in medicinal chemistry. In the years since these broader trends emerged, dozens of formal cycloadditions, including catalytic, asymmetric variants, have been developed that operate via radical mechanisms. While cyclopropanes have been studied most extensively, a variety of strained ring systems are amenable to the design of analogous reactions. Many of these processes generate lucrative, functionally decorated sp3 -rich ring systems that are difficult to access by other means. Herein, we summarize recent efforts in this area and analyze the state of the field.

Radical generation enabled by photoinduced N-O bond fragmentation.

Recent advances in synthetic chemistry have seen a resurgence in the development of methods for visible light-mediated radical generation. Herein, we report the development of a photoactive ester based on a quinoline N-oxide core structure, that provides a strong oxidant in its excited state. The heteroaromatic N-oxide provides access to primary, secondary, and tertiary radical intermediates, and its application toward the development of a photochemical Minisci alkylation is reported.

Mechanism of Visible Light-Mediated Alkene Aminoarylation with Arylsulfonylacetamides.

Alkene aminoarylation with arylsulfonylacetamides via a visible-light mediated radical Smiles-Truce rearrangement represents a convenient approach to the privileged arylethylamine pharmacaphore traditionally generated by circuitous, multi-step sequences. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies designed to interrogate the proposed mechanism, including the key aryl transfer event. The data are consistent with a rate-limiting 1,4-aryl migration occurring either via a stepwise process involving a radical Meisenheimer-like intermediate or in a concerted fashion dependent on both arene electronics and alkene sterics. Our efforts to probe the mechanism have significantly expanded the substrate scope of the transformation with respect to the migrating aryl group and provide further credence to the synthetic potential of radical aryl migrations.

Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides.

Arylethylamines are abundant motifs in myriad natural products and pharmaceuticals, so efficient methods to synthesize them are valuable in drug discovery. In this work, we disclose an intramolecular alkene aminoarylation cascade that exploits the electrophilicity of a nitrogen-centered radical to form a C-N bond, then repurposes the nitrogen atom's sulfonyl activating group as a traceless linker to form a subsequent C-C bond. This photoredox catalysis protocol enables the preparation of densely substituted arylethylamines from commercially abundant aryl sulfonamides and unactivated alkenes under mild conditions. Reaction optimization, scope, mechanism, and synthetic applications are discussed.

Development of an automated screen for Kv7.2 potassium channels and discovery of a new agonist chemotype.

To identify pore domain ligands on Kv7.2 potassium ion channels, we compared wild-type (WT) and W236L mutant Kv7.2 channels in a series of assays with previously validated and novel agonist chemotypes. Positive controls were retigabine, flupirtine, and RL-81; i.e. Kv7.2 channel activators that significantly shift voltage-dependent activation to more negative potentials (ΔV50) at 5 µM. We identified 6 new compounds that exhibited differential enhancing activity between WT and W236L mutant channels. Whole cell patch-clamp electrophysiology studies were conducted to identify Kv7.2. Kv7.2/3, Kv7.4, and Kv7.5 selectivity. Our results validate the SyncroPatch platform and establish new structure activity relationships (SAR). Specifically, in addition to selective Kv7.2, Kv7.2/3, Kv7.4. and Kv7.5 agonists, we identified a novel chemotype, ZK-21, a 4-aminotetrahydroquinoline that is distinct from any of the previously described Kv7 channel modifiers. Using flexible receptor docking, ZK-21 was predicted to be stabilized by W236 and bind perpendicular to retigabine, burying the benzyl carbamate group into a tunnel reaching the core of the pore domain.

A One-Pot Photochemical Method for the Generation of Functionalized Aminocyclopentanes.

Detailed herein is the development of a photochemical intermolecular formal [3+2] cycloaddition between cyclopropylimines and substituted alkenes to generate aminocyclopentane derivatives. The Schiff base of the cyclopropylimine was designed to enable a masked N-centered radical approach in which the requisite open-shell character was achieved upon excitation with visible light. The cycloaddition products were directly converted to N-functionalized aminocyclopentanes via solvolysis and N-acylation. The photochemical component of this reaction sequence was demonstrated to operate in continuous flow.

Aryl Transfer Strategies Mediated by Photoinduced Electron Transfer.

Radical aryl migrations are powerful techniques to forge new bonds in aromatic compounds. The growing popularity of photoredox catalysis has led to an influx of novel strategies to initiate and control aryl migration starting from widely available radical precursors. This review encapsulates progress in radical aryl migration enabled by photochemical methods─particularly photoredox catalysis─since 2015. Special attention is paid to descriptions of scope, mechanism, and synthetic applications of each method.

Photochemical Formal (4 + 2)-Cycloaddition of Imine-Substituted Bicyclo[1.1.1]pentanes and Alkenes.

Amines containing bridged bicyclic carbon skeletons are desirable building blocks for medicinal chemistry. Herein, we report the conversion of bicyclo[1.1.1]pentan-1-amines to a wide range of polysubstituted bicyclo[3.1.1]heptan-1-amines through a photochemical, formal (4 + 2)-cycloaddition of an intermediate imine diradical. To our knowledge, this is the first reported method to convert the bicyclo[1.1.1]pentane skeleton to the bicyclo[3.1.1]heptane skeleton. Hydrolysis of the imine products gives complex, sp3-rich primary amine building blocks.

Photochemically derived 1-aminonorbornanes provide structurally unique succinate dehydrogenase inhibitors with in vitro and in planta activity.

Agrochemical fungicidal leads have been prepared from photochemically derived 1-aminonorbornane building blocks. The unique 1-aminonorbornane core is generated via direct excitation of a Schiff base precursor, leveraging the N-centered radical character of the excited state species to facilitate a series of radical reactions that construct the norbornane core. This process requires no exogenous reagents, only solvent and photons; thus, it represents an exceptionally simple and efficient means of generating the key building blocks. These (hetero) arene-fused 1-aminonorbornanes are unprecedented in both the agrochemical and pharmaceutical discovery literature; therefore, photochemical advances have provided the unique opportunity to explore the functional utility of novel chemical space. Toward this end, the 1-aminonorbornanes were used to generate next-generation succinate dehydrogenase inhibitors. In vitro fungicidal activity is demonstrated against three fungal plant pathogens affecting field crops, specifically: Fusarium graminearum, Sclerotinia sclerotiorum, and Macrophomina phaseolina. The in vitro performance against F. graminearum was shown to translate into a greenhouse setting. The discovery of in planta fungicidal activity illustrates the interdisciplinary value available via photochemical innovation.

Evolution towards green radical generation in total synthesis.

The use of radicals as intermediates in total synthesis has evolved since their initial use in the latter half of the twentieth century. Radical generation from metal hydride methodologies has shifted to "greener" techniques including catalytic metal-mediated systems, electrochemical and photoredox-mediated processes. This review will focus on these classical and contemporary methods for radical generation and their applications in recent total syntheses.