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Pharmaceutical synthesis often requires the formation of adjacent carbon-carbon and carbon-nitrogen bonds. Monos et al. present a method that delivers the carbon and nitrogen components in a single reagent, specifically, an aryl ring tethered through sulfur dioxide to an amide. A light-activated catalyst primes an olefin to react with the nitrogen, which in turn leads to migration of the aryl ring and loss of the sulfur bridge. The efficient room-temperature process is applicable to a variety of different arenes, including heterocycles. Science , this issue p. 1369 Photoredox catalysis activates alkenes to form adjacent C–C and C–N bonds through coupling with a single reagent. Alkene aminoarylation with a single, bifunctional reagent is a concise synthetic strategy. We report a catalytic protocol for the addition of arylsulfonylacetamides across electron-rich alkenes with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity to provide 2,2-diarylethylamines. In this process, single-electron alkene oxidation enables carbon-nitrogen bond formation to provide a key benzylic radical poised for a Smiles-Truce 1,5-aryl shift. This reaction is redox-neutral, exhibits broad functional group compatibility, and occurs at room temperature with loss of sulfur dioxide. As this process is driven by visible light, uses readily available starting materials, and demonstrates convergent synthesis, it is well suited for use in a variety of synthetic endeavors.

The implementation of continuous flow technology is critical towards enhancing the application of photochemical reactions for industrial process development. However, there are significant time and resource constraints associated with translating discovery scale vial-based batch reactions to continuous flow scale-up conditions. Herein we report the development of a droplet microfluidic platform, which enables high-throughput reaction discovery in flow to generate pharmaceutically relevant compound libraries. This platform allows for enhanced material efficiency, as reactions can be performed on picomole scale. Furthermore, high-throughput data collection via on-line ESI mass spectrometry facilitates the rapid analysis of individual, nanoliter-sized reaction droplets at acquisition rates of 0.3 samples/s. We envision this high-throughput screening platform to expand upon the robust capabilities and impact of photochemical reactions in drug discovery and development. Translating discovery scale vial-based batch reactions to continuous flow scale-up conditions is limited by significant time and resource constraints. Here, the authors report a photochemical droplet microfluidic platform, which enables high throughput reaction discovery in flow to generate pharmaceutically relevant compound libraries.

Arene dearomatization reactions are an important class of synthetic technologies for the rapid assembly of unique chemical architectures. Herein, we report a catalytic protocol to initiate a carboamination/dearomatization cascade that proceeds through transient sulfonamidyl radical intermediates formed from native sulfonamide N–H bonds leading to 1,4-cyclohexadiene-fused sultams. Importantly, this work demonstrates a facile approach to employ two-dimensional aromatic compounds as modular building blocks to generate richly substituted, three-dimensional compounds. These reactions occur at room temperature under visible light irradiation and are catalyzed by the combination of an iridium(III) photocatalyst and a dialkyl phosphate base. Reaction optimization, substrate scope, mechanistic features, and synthetic applications of this transformation are presented. Arene dearomatization reactions allow chemists to rapidly build unique chemical architectures from largely available starting materials. Here, the authors show a photocatalytic carboamination/dearomatization cascade process leading to 1,4-cyclohexadiene-fused sultams via N-centered radicals.

Radical-chain processes can dominate the kinetics of photogenerated radical catalysis Free radicals are exploited in biology, often through highly controlled enzymatic reactions, to drive many reactions that would be difficult via nonradical routes that transfer two electrons ( 1 ). In synthetic chemistry, visible-light photoredox catalysis has emerged as an economical and environmentally benign route for promoting free radical transformations in the lab ( 2 – 4 ). Although the initial light-sensitization steps are well established ( 5 ), insufficient attention has been dedicated to essential mechanistic features of the closed catalytic cycle ( 6 ). Several reports have hypothesized that these photocatalyzed reactions are terminated through a closed catalytic cycle, which delivers the final product and regenerates the ground state of the photosensitizer (PS). However, Cismesia and Yoon ( 6 ) highlight that some of the mechanistic proposals may be incomplete and may involve radical chains.

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. Single-step addition of an aryl ring and a protected amine across an alkene is a succinct route to valuable phenethylamine products, but existing methods suffer from limited scope. Now a family of compounds containing a sulfinamide functional group have been developed to react via electrophilic radicals to yield phenethylamines through an aryl migration with precise stereochemical control.

Persistent free radicals have become indispensable in the synthesis of organic materials through living radical polymerization. However, examples of their use in the synthesis of small molecules are rare. Here, we report the application of persistent radical and quinone methide intermediates to the synthesis of the resveratrol tetramers nepalensinol B and vateriaphenol C. The spontaneous cleavage and reconstitution of exceptionally weak carbon-carbon bonds has enabled a stereoconvergent oxidative dimerization of racemic materials in a transformation that likely coincides with the biogenesis of these natural products. The efficient synthesis of higher-order oligomers of resveratrol will facilitate the biological studies necessary to elucidate their mechanism(s) of action.

The large number of reagents that have been developed for the synthesis of trifluoromethylated compounds is a testament to the importance of the CF 3 group as well as the associated synthetic challenge. Current state-of-the-art reagents for appending the CF 3 functionality directly are highly effective; however, their use on preparative scale has minimal precedent because they require multistep synthesis for their preparation, and/or are prohibitively expensive for large-scale application. For a scalable trifluoromethylation methodology, trifluoroacetic acid and its anhydride represent an attractive solution in terms of cost and availability; however, because of the exceedingly high oxidation potential of trifluoroacetate, previous endeavours to use this material as a CF 3 source have required the use of highly forcing conditions. Here we report a strategy for the use of trifluoroacetic anhydride for a scalable and operationally simple trifluoromethylation reaction using pyridine N -oxide and photoredox catalysis to affect a facile decarboxylation to the CF 3 radical. Trifluoromethylation is a key transformation, particularly for pharmaceuticals, but many reagents are expensive and difficult to scale up. Here, the authors show that trifluoroacetic anhydride can act as a CF 3 source, allowing the radical reactions to be easily and inexpensively carried out at scale.

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. Hydrogen atom transfer has an expanding role in synthesis, enabling direct C–H functionalization. This Review highlights the state-of-the-art design of phthalimide- N -oxyl catalysts, aiming to stimulate the development of the next generation of efficient and selective catalysts.

Radical reactions are a powerful class of chemical transformations. However, the formation of radical species to initiate these reactions has often required the use of stoichiometric amounts of toxic reagents, such as tributyltin hydride. Recently, the use of visible-light-mediated photoredox catalysis to generate radical species has become popular, but the scope of these radical precursors has been limited. Here, we describe the identification of reaction conditions under which photocatalysts such as fac -Ir(ppy) 3 can be utilized to form radicals from unactivated alkyl, alkenyl and aryl iodides. The generated radicals undergo reduction via hydrogen atom abstraction or reductive cyclization. The reaction protocol utilizes only inexpensive reagents, occurs under mild reaction conditions, and shows exceptional functional group tolerance. Reaction efficiency is maintained upon scale-up and decreased catalyst loading, and the reaction time can be significantly shortened when the reaction is performed in a flow reactor. Visible-light-mediated photocatalytic generation of carbon-centred radicals from alkyl, alkenyl and aryl iodides, which then undergo subsequent hydrogen-atom abstraction or reductive cyclizations, is reported. The protocol is characterized by the use of inexpensive reagents, mild conditions, exceptional functional group tolerance, and good to high yields.

N-oxyl species are promising hydrogen atom transfer (HAT) catalysts to advance C–H bond activation reactions. However, because of the complex structure–activity relationship within the N-oxyl structure, catalyst optimization is a key challenge, particularly for simultaneous improvement across multiple parameters. This paper describes a data-driven approach to optimize N-oxyl hydrogen atom transfer catalysts. A focused library of 50 N-hydroxy compounds was synthesized and characterized by three parametersoxidation peak potential, HAT reactivity, and stabilityto generate a database. Statistical modeling of these activities described by their intrinsic physical organic parameters was used to build predictive models for catalyst discovery and to understand their structure–activity relationships. Virtual screening of 102 synthesizable candidates allowed for rapid identification of several ideal catalyst candidates. These statistical models clearly suggest that N-oxyl substructures bearing an adjacent heteroatom are more optimal HAT catalysts compared to the historical focus, phthalimide-N-oxyl, by striking the best balance among all three target experimental properties.