Radical-polar Crossover Research Articles

Zinc Promoted Cross-Electrophile Sulfonylation to Access Alkyl-Alkyl Sulfones.

The transition metal-catalyzed multi-component cross-electrophile sulfonylation, which incorporates SO2 as a linker within organic frameworks, has proven to be a powerful, efficient, and cost-effective means of synthesizing challenging alkyl-alkyl sulfones. Transition metal catalysts play a crucial role in this method by transferring electrons from reductants to electrophilic organohalides, thereby causing undesirable side reactions such as homocoupling, protodehalogenation, β-hydride elimination, etc. It is worth noting that tertiary alkyl halides have rarely been demonstrated to be compatible with current methods owing to various undesired side reactions. In this work, a zinc-promoted cross-electrophile sulfonylation is developed through a radical-polar crossover pathway. This approach enables the synthesis of various alkyl-alkyl sulfones, including 1°-1°, 2°-1°, 3°-1°, 2°-2°, and 3°-2° types, from inexpensive and readily available alkyl halides. Various functional groups are well tolerated in the work, resulting in yields of up to 93%. Additionally, this protocol has been successfully applied to intramolecular sulfonylation and homo-sulfonylation reactions. The insights gained from this work shall be useful for the further development of cross-electrophile sulfonylation to access alkyl-alkyl sulfones.

Stereoselective polar radical crossover for the functionalization of strained-ring systems

Radical-polar crossover of organoborates is a poweful tool that enables the creation of two C-C bonds simultaneously. Small ring systems have become essential motifs in drug discovery and medicinal chemistry. However, step-economic methods for their selective functionalization remains scarce. Here we present a one-pot strategy that merges a simple preparation of strained organoboron species with the recently popularized polar radical crossover of borate derivatives to stereoselectively access tri-substituted azetidines, cyclobutanes and five-membered carbo- and heterocycles.

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation.

The radical hydroarylation of alkenes is an efficient strategy for accessing linear alkylarenes with high regioselectivity. Herein, we report the electroreductive hydroarylation of electron-deficient alkenes and styrene derivatives using (hetero)aryl halides under mild reaction conditions. Notably, the present hydroarylation proceeded with high efficiency under transition-metal-catalyst-free conditions. The key to success is the use of 1,3-dicyanobenzene as a redox mediator and visible-light irradiation, which effectively suppresses the formation of simple reduction, i.e., hydrodehalogenation, products to afford the desired products in good to high yields. Mechanistic investigations proposed that a reductive radical-polar crossover pathway is likely to be involved in this transformation.

Intermolecular Aza-Wacker Coupling of Alkenes with Azoles by Photo-Aerobic Selenium-π-Acid Multicatalysis.

Herein, the intermolecular, photoaerobic aza-Wacker coupling of azoles with alkenes by means of dual and ternary selenium-π-acid multicatalysis is presented. The title method permits an expedited avenue toward a broad scope of N-allylated azoles and representative azinones under mild conditions with broad functional group tolerance, as is showcased in more than 60 examples including late-stage drug derivatizations. From a regiochemical perspective, the protocol is complementary to cognate photoredox catalytic olefin aminations, as they typically proceed through either allylic hydrogen atom abstraction or single electron oxidation of the alkene substrate. These methods predominantly result in C-N bond formations at the allylic periphery of the alkene or the less substituted position of the former π-bond (i.e., anti-Markovnikov selectivity). The current process, however, operates through a radical-polar crossover mechanism, which solely affects the selenium catalyst, thus allowing the alkene to be converted strictly through an ionic two-electron transfer regime under Markovnikov control. In addition, it is shown that the corresponding N-vinyl azoles can also be accessed by sequential or one-pot treatment of the allylic azoles with base, thus emphasizing the exquisite utility of this method.

Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Hybrid Palladium-Catalyzed Intramolecular Carboamination of Conjugated Dienes: Synthesis of Functionalized Pyrrolidines via Selective Trifluoromethylarene Defluorination.

The incorporation of difluoromethylene groups into aza-heterocycles represents a compelling yet underexplored avenue in contemporary chemical research. In this study, we unveil a hybrid palladium-catalyzed intramolecular gem-difluoroalkylamination of conjugated dienes, providing a versatile approach to the synthesis of diverse functionalized pyrrolidines. Noteworthy features include mild reaction conditions and a remarkable tolerance toward various functional groups. Additionally, the use of alkyl iodides as electrophiles facilitates the generation of the corresponding alkylamination products. Control experiments support a proposed hybrid palladium-catalyzed radical-polar crossover pathway, offering insights into the underlying chemical processes governing this transformation.

Visible‐Light‐Induced Domino Cyclization to Access Pyrido[2,3‐d]pyrimidine‐2,4‐diones via a Radical‐Polar Crossover Reaction

Comprehensive SummaryCatalytic and green strategies for the synthesis of privileged scaffolds are synthetically appealing. We now report a radical‐polar crossover (RPC)‐enabled three‐component cyclization of bromodifluoroalkyls with enaminones and 6‐aminouraciles via a visible‐light‐induced domino cyclization. The reaction exhibited a broad substrate scope (> 40 examples) including complex molecules, which highlighted the utility of this strategy for the construction of a library of bioactive analogs.

Visible-Light-Induced Regioselective Radical-Polar Crossover 1,4-Hydrophosphinylation of 1,3-Enynes: Access to Trisubstituted Allenes Bearing a Phosphine Oxide Group.

The radical 1,4-functionalizations of 1,3-enynes have emerged as a powerful strategy for the synthesis of multisubstituted allenes. However, the phosphorus-centered radical-initiated transformations remain largely elusive. Herein, visible-light photoredox catalytic regioselective radical hydrophosphinylation of 1,3-enynes with diaryl phosphine oxides as phosphinoyl radical precursors has been realized. This protocol features mild conditions, a wide substrate scope, and good functional group tolerance, producing a diverse range of phosphinoyl-substituted allenes in moderate to good yields with high atom economy. Detailed mechanistic experiments revealed a radical-polar crossover process in the reaction.

Electroreductive Arylcarboxylation of Styrenes with CO2 and Aryl Halides via a Radical-Polar Crossover Mechanism.

2,3-Diaryl propanoic acids are important structures as a result of their widespread presence in numerous bioactive compounds. However, the limitations of existing synthetic techniques include the requirement for costly catalysts and limited substrates. Here, we developed a novel electroreductive arylcarboxylation of alkenes with CO2 based on a radical-polar crossover pathway assisted by easily accessible dimethyl terephthalate as a reductive mediator. This method will provide an efficient strategy for the synthesis of 2,3-diarylpropanoic acids.

Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis.

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, we report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines. This procedure exhibits a wide substrate scope that tolerates various functional groups. The utility of this method is demonstrated in the efficient synthesis of a TRPV6 inhibitor, CFTR modulator, and other bioactive molecules. Combined experimental and computational studies suggest that the hybrid palladium-catalyzed radical-polar crossover mechanism is crucial for achieving exceptional 1,4-syn-addition selectivity (dr > 20:1).

Alkoxy Diazomethylation of Alkenes by Photoredox-Catalyzed Oxidative Radical-Polar Crossover.

Herein, we present the discovery and development of the first photoredox-catalyzed alkoxy diazomethylation of alkenes with hypervalent iodine reagents and alcohols. This multicomponent process represents a new disconnection approach to diazo compounds and is featured by a broad scope, mild reaction conditions, and excellent selectivity. Key to the process was the generation of diazomethyl radicals, which engaged alkenes and alcohols in an inter- and intramolecular fashion by a photoredox-catalyzed oxidative radical-polar crossover leading to unexplored β-alkoxydiazo compounds. The synthetic utility of such diazo compounds was demonstrated with a series of transformations involving C-H, N-H, and O-H insertions as well as in the construction of complex sp3-rich heterocycles.

Visible-Light Activation of Diorganyl Bis(pyridylimino) Isoindolide Aluminum(III) Complexes and Their Organometallic Radical Reactivity.

We report on the synthesis and characterization of a series of (mostly) air-stable diorganyl bis(pyridylimino) isoindolide (BPI) aluminum complexes and their chemistry upon visible-light excitation. The redox non-innocent BPI pincer ligand allows for efficient charge transfer homolytic processes of the title compounds. This makes them a universal platform for the generation of carbon-centered radicals. The photo-induced homolytic cleavage of the Al-C bonds was investigated by means of stationary and transient UV/Vis spectroscopy, spin trapping experiments, as well as EPR and NMR spectroscopy. The experimental findings were supported by quantum chemical calculations. Reactivity studies enabled the utilization of the aluminum complexes as reactants in tin-free Giese-type reactions and carbonyl alkylations under ambient conditions, which both indicated radical-polar crossover behavior. A deeper understanding of the physical fundamentals and photochemical process was provided, furnishing in turn a new strategy to control the reactivity of bench-stable aluminum organometallics.

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes.

We report the detailed background for the discovery and development of the synthesis of homopropargylic azides by the azido-alkynylation of alkenes. Initially, a strategy involving SOMOphilic alkynes was adopted, but only resulted in a 29% yield of the desired product. By switching to a radical-polar crossover approach and after optimization, a high yield (72%) of the homopropargylic azide was reached. Full insights are given about the factors that were essential for the success of the optimization process.

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines.

Herein, we report a visible-light-mediated palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines, affording unsaturated γ- and ε-amino acid derivatives with diverse structures. In this methodology, the diazo compound readily transforms into a hybrid α-ester alkylpalladium radical with the release of dinitrogen. The radical intermediate selectively adds to the double bond of a 1,3-diene or allene, followed by the allylpalladium radical-polar crossover path and selective allylic substitution with the amine substrate, thereby leading to a single unsaturated γ- or ε-amino acid derivative. This approach proceeds under mild and simple reaction conditions and shows high functional group tolerance, especially in the incorporation of various bioactive molecules. The studies on scale-up reactions and diverse derivatizations highlight the practical utility of this multicomponent reaction protocol.

Photodriven Radical-Polar Crossover Cyclization Strategy: Synthesis of Pyrazolo[1,5-a]pyridines from Diazo Compounds.

This work demonstrates the synthesis of a variety of perfluoroalkyl heterocycles via a visible-light-driven radical-polar crossover cyclization strategy. In this process, single-electron reduction/SNV-type/cyclization sequences follow the radical addition reaction of a diazoester, which differs from the current role of diazoesters as radical precursors/acceptors. This transformation demonstrates excellent functional group compatibility and allows for the modification of many bioactive molecules with diazoesters. Such a reaction could represent a novel approach to the photochemical transformation of diazo compounds.

Cyclic Amine Synthesis via Catalytic Radical-Polar Crossover Cycloadditions.

The rapid assembly of valuable cyclic amine architectures in a single step from simple precursors has been recognized as an ideal platform in term of efficiency and sustainability. Although a vast number of studies regarding cyclic amine synthesis has been reported, new synthetic disconnection approaches are still high in demand. Herein, we report a catalytic radical-polar crossover cycloaddition to cyclic amine synthesis triggered from primary sulfonamide under photoredox condition. This newly developed disconnection, comparable to established synthetic approaches, will allow to construct β, β-disubstituted cyclic amine and β-monosubstituted cyclic amine derivatives efficiently. This study highlights the unique utility of primary sulfonamide as a bifunctional reagent, which acts as a radical precursor and a nucleophile. The open-shell methodology demonstrates broad tolerance to various functional groups, drug derivatives and natural products in an economically and sustainable fashion.

Reactivity of Superbasic Carbanions Generated via Reductive Radical-Polar Crossover in the Context of Photoredox Catalysis.

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

N-Heterocyclic nitrenium-catalyzed photoreductive radical-polar crossover for alkene dicarbofunctionalization

The photoredox radical-polar crossover paradigm is a valuable tool for 1,2-difunctionalization of alkenes. However, the use of unactivated alkyl halides as radical precursors remains far less developed. Here, we report a photoreductive N-heterocyclic nitrenium-catalyzed radical-polar crossover for the 1,2-dicarbofunctionalization of alkenes by using unactivated alkyl and aryl iodides. These reactions can be carried out under simple, transition-metal-free conditions with easily obtainable materials such as alkyl/aryl halides, alkenes, and aldehydes. The reactions exhibit a broad range of substrate compatibility and good tolerance towards functional groups. This approach offers a new tool to unlock the compatibility of carbon skeletons.

Cobalt-Catalyzed Carbon-Heteroatom Transfer Enables Regioselective Tricomponent 1,4-Carboamination.

Tricomponent cobalt(salen)-catalyzed carbofunctionalization of unsaturated substrates by radical-polar crossover has the potential to streamline access to broad classes of heteroatom-functionalized synthetic targets, yet the reaction platform has remained elusive, despite the well-developed analogous hydrofunctionalizations mediated by high-valent alkylcobalt intermediates. We report herein the development of a cobalt(salen) catalytic system that enables carbofunctionalization. The reaction entails a tricomponent decarboxylative 1,4-carboamination of dienes and provides a direct route to aromatic allylic amines by obviating preformed allylation reagents and protection of oxidation-sensitive aromatic amines. The catalytic system merges acridine photocatalysis with cobalt(salen)-catalyzed regioselective 1,4-carbofunctionalization that facilitates the crossover of the radical and polar phases of the tricomponent coupling process, revealing critical roles of the reactants, as well as ligand effects and the nature of the formal high-valent alkylcobalt species on the chemo- and regioselectivity.

E-Selective Radical Difunctionalization of Unactivated Alkynes: Preparation of Functionalized Allyl Alcohols from Aliphatic Alkynes.

Radical difunctionalization of aliphatic alkynes provides direct access to valuable multi-substituted alkenes, but achieving a high level of chemo- and stereo-control remains a formidable challenge. Herein a novel photoredox neutral alkyne di-functionalization is reported through functional group migration followed by a radical-polar crossover and energy transfer-enabled stereoconvergent isomerization of alkenes. In this sequence, a hydroxyalkyl and an aryl group are incorporated concomitantly into an alkyne, leading to diversely functionalized E-allyl alcohols. The scope of alkynes is noteworthy, and the reaction tolerates aliphatic alkynes containing hydrogen donating C─H bonds that are prone to intramolecular hydrogen atom transfer. The protocol features broad functional group compatibility, high product diversity, and exclusive chemo- and stereoselectivity, thus providing a practical strategy for the elusive radical di-functionalization of unactivated alkynes.