Radical Cascade Research Articles

Modular assembly of arenes, ethylene and heteroarenes for the synthesis of 1,2-arylheteroaryl ethanes.

The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, to address these limitations, we present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. We disclosed a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C-S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, our approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals. This study highlights the significance of radical polarity matching in designing selective multi-component couplings.

Photocatalyzed Acylmethylation/Cyclization of Unactivated Alkenes with Sulfoxonium Ylides towards Acylmethylated Polycyclic Quinazolinones

AbstractThe synthesis of acylmethylatated pyrrolo‐quinazolinones was developed via photo‐induced cascade radical addition/cyclization of N‐(but‐3‐enyl)quinazolin‐4(3H)‐ones with sulfoxonium ylides using 4CzIPN as the photocatalyst. This approach was also suitable for the construction of acylmethylatated piperidino‐quinazolinones. This protocol features with mild conditions, convenient operation, broad substrate scope and good functional group compatibility.

TBTH (Bu3SnH) catalyzed C-H and C-Cl functionalization: Radical cascade cyclization for the construction of tetracyclic benzimidazole derivatives

A radical cascade cyclization of cyanamides, catalyzed by Tributyltin hydride (Bu3SnH), has been successfully devised. Herein, we present a pioneering and uncomplicated methodology for the fabrication of tetracyclic 11H-benzo [4,5] imidazo[2,1-a] isoindole derivatives. This synthesis entails a sequence of inert Csp2-X/Csp2-H functionalization processes applied to N-cyano groups, followed by the radical cyclization of iminyl motifs. This study represents a significant advancement in the intramolecular radical cascade cyclization reaction of cyanamides, enabling the efficient synthesis of 1,2-disubstituted benzimidazole molecules, specifically the 11H-benzo [4,5] imidazo[2,1-a] isoindol and its analogues, achieved with yields ranging from 42% to 86%. Notably, this approach has been instrumental in the synthesis of a diverse array of compounds, establishing their efficacy as potent antibreast cancer agents. Furthermore, the proposed mechanism has been meticulously elucidated through a series of control experiments.

Visible Light-Induced Radical Cascade Difluoromethylation/Cyclization of Unactivated Alkenes: Access to CF2H-Substituted Polycyclic Imidazoles.

An efficient and mild protocol for the visible light-induced radical cascade difluoromethylation/cyclization of imidazoles with unactivated alkenes using easily accessible and bench-stable difluoromethyltriphenylphosphonium bromide as the precursor of the -CF2H group has been developed to afford CF2H-substituted polycyclic imidazoles in moderate to good yields. This strategy, along with the construction of Csp3-CF2H/C-C bonds, is distinguished by mild conditions, no requirement of additives, simple operation, and wide substrate scope. In addition, the mechanistic experiments have indicated that the difluoromethyl radical pathway is essential for the methodology.

Thermal and Photoinduced Radical Cascade Annulation using Aryl Isonitriles: An Approach to Quinoline-Derived Benzophosphole Oxides.

Herein, we present a radical cascade addition cyclization sequence to access quinoline-based benzophosphole oxides from ortho-alkynylated aromatic phosphine oxides using various aryl isonitriles as radical acceptors and inexpensive tert-butyl-hydroperoxide (TBHP) as a terminal oxidant in the presence of a catalytic amount of silver acetate. Alternatively, the same cascade can be realized through a sustainable photochemical approach utilizing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an organic photocatalyst at room temperature. The introduced modular approach shows broad functional group tolerance and offers straightforward access to complex P,N-containing polyheterocyclic arenes. These novel π-extended benzophosphole oxides exhibit interesting photophysical and electrochemical properties such as absorption in the visible region, emission and reversible reduction at low potentials, which makes them promising for potential materials science applications. The photophysical properties can further be tuned by the addition of external Lewis and Brønsted acids.

Thermische und photoinduzierte Anellierungen über radikalische Kaskaden mit Arylisonitrilen: Ein Zugang zu Chinolin‐abgeleiteten Benzophospholoxiden

AbstractIn diesem Artikel stellen wir eine Kaskade bestehend aus einer radikalischen Addition und Zyklisierung vor, um Chinolin‐basierte Benzophospholoxide aus ortho‐alkinylierten aromatischen Phosphanoxiden zu erhalten. Dabei werden verschiedene Arylisonitrile als Radikalakzeptoren und kostengünstiges tert‐Butylhydroperoxid (TBHP) als terminales Oxidationsmittel in Gegenwart einer katalytischen Menge Silberacetat verwendet. Alternativ kann die Kaskade auch über einen nachhaltigen photochemischen Ansatz unter Verwendung von 1,2,3,5‐Tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzol (4CzIPN) als organischem Photokatalysator bei Raumtemperatur realisiert werden. Der vorgestellte modulare Ansatz zeigt eine breite Toleranz gegenüber funktionellen Gruppen und bietet einen einfachen Zugang zu komplexen P,N‐haltigen polyheterozyklischen Arenen. Diese neuartigen π‐erweiterten Benzophospholoxide besitzen interessante photophysikalische und elektrochemische Eigenschaften wie Absorption im sichtbaren Bereich, Emission und eine reversible Reduktion bei niedrigen Potentialen, weswegen sie vielversprechend für potenzielle materialwissenschaftliche Anwendungen sind. Die photophysikalischen Eigenschaften können weiterhin durch Zugabe externer Lewis‐ und Brønsted‐Säuren beeinflusst werden.

Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions

AbstractDue to the innate highly reactive properties and short life‐time, organic free radicals can often serve as promoters or intermediates to engage in various radical transformations, which are often otherwise difficult to access by ionic pathway‐based mechanisms. With the evolvement of radical chemistry, chiral radical catalyzed‐transformations have recently emerged as an attractive and robust platform for synthesis of chiral molecules of interest. Herein, we highlight several creative and strategic advances in chiral radical catalyst design, cyclization reaction achievements, and future challenges. Key ScientistsIn the 1980s, some pioneering studies by Feldman and Oshima revealed that the thiyl radical could catalyze cyclization of vinylcyclopropane with alkenes, providing access to racemic cyclopentanes. In 1996, Brian P. Roberts reported an interesting enantioselective hydrosilylation of prochiral alkenes by using thioglucose‐derived chiral thiyl radical catalysts. Since then, chiral radical catalysis has become an emerging and promising catalytic strategy in organic synthesis. However, this field has not been extensively explored further until the Maruoka group in 2014 achieved the asymmetric C—C bond formation by employing a newly designed indanol core‐based chiral thiyl radical catalyst. In this protocol, an enantioselective radical cyclization of vinylcyclopropanes with electron‐rich alkenes was developed. In 2020, Chen and Xiao disclosed a nitrogen radical‐catalyzed version of this reaction. Later, this strategy was further expanded to metalloradical catalyzed asymmetric radical cascade cyclization reactions by Zhang in 2021. Later on, Wang, Fu and Zhang et al. described a novel class of boryl radical‐catalyzed asymmetric radical cycloisomerization reactions, further showcasing enormous synthetic potential of chiral radical catalysis. This Emerging Topic has focused on asymmetric radical cyclization reactions involving diverse chiral radical catalysts.

A Photoinduced Radical Cascade Cyclization for the Synthesis of Angularly Fused Tricyclic Compounds.

A photoinduced electron transfer (PET)-triggered cascade reaction has been devised for the conversion of second-generation enol silyl ethers into angularly fused tricyclic scaffolds. Utilizing readily available and cost-effective DCA and phenanthrene as the catalytic systems, this cascade transformation is achieved with high efficiency. The reaction demonstrates a good substrate scope and excellent stereoselectivity, thereby enriching the realm of PET-induced cascade reactions. Additionally, the radical adducts generated through this process can serve as valuable subunits for the synthesis of complex molecules.

Photoinduced Perfluoroalkyloximation of Alkenes with Simple Perfluoroalkyl Halides

Comprehensive SummaryIn this paper, the difunctionalizative perfluoroalkyloximation of alkenes has been developed for the first time. This photochemical method allows for the synthesis of various perfluoroalkyl ethanone oximes with excellent regioselectivity and good functional group tolerance. Our method employs the most common perfluoroalkyl source, perfluoroalkyl iodides, as Rf reagents. Besides long‐chain perfluoroalkyl groups, this approach could be extended to incorporating additional groups, including trifluoromethyl, difluoromethyl, sulfonyl, and malonate, selectively into olefins, resulting in a range of β‐substituted ethanone oximes. Notably, the potential of this method in the Fukuyama indole synthesis, generating novel 2‐perfluoroalkylated 3‐(α‐oximidobenzyl)indoles via a radical cascade mechanism with 2‐vinylphenylacryloyl isocyanate as the radical acceptor, presents a compelling avenue for drug synthesis. The protocol is efficient, scalable, and useful for late‐stage modification of bioactive molecules.

Phosphomethylpyrimidine Synthase (ThiC): Trapping of Five Intermediates Provides Mechanistic Insights on a Complex Radical Cascade Reaction in Thiamin Biosynthesis

Phosphomethylpyrimidine Synthase (ThiC): Trapping of Five Intermediates Provides Mechanistic Insights on a Complex Radical Cascade Reaction in Thiamin Biosynthesis

Visible-Light-Promoted Radical Cascade Cyclization of 2-Vinyl Benzimidazoles: Access to Benzo[4,5]imidazo[1,2-b]isoquinolin- 11(6H)-ones.

A visible-light-enabled photoredox radical cascade cyclization of 2-vinyl benzimidazole derivatives is developed. This chemistry is applicable to a wide range of N-aroyl 2-vinyl benzimidazoles as acceptors, and halo compounds, including alkyl halides, acyl chlorides and sulfonyl chlorides, as radical precursors. The Langlois reagent also serves as an effective partner in this photocatalytic oxidative cascade process. This protocol provides a robust alternative for rendering highly functionalized benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-ones.

Visible-light-induced cascade radical cyclization for the synthesis of amide-functionalized fused quinazolinones

A light-induced non-activated olefin cascade radical addition/cyclization reaction was proposed, leading to the successful synthesis of 39 quinazolinone derivatives containing amide moieties, with yields up to 88 %. The reaction mechanism was studied by radical strapping test and DFT methods, verifying an oxidative-triggered cascade process promoted by the acylamino radicals. This strategy features mild conditions and broad substrate compatibility, providing a high atom-economical synthesis method for diverse quinazolinone.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Boryl Radical as a Catalyst in Enabling Intra- and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules.

Cascade radical cyclization constitutes an atom- and step-economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox-active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium-based N-heterocyclic carbene (NHC)-boryl radical is capable of catalyzing cascade cyclization reactions in both intra- and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo- and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β-elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Boryl Radical as a Catalyst in Enabling Intra‐ and Intermolecular Cascade Radical Cyclization Reactions: Construction of Polycyclic Molecules

AbstractCascade radical cyclization constitutes an atom‐ and step‐economic route for rapid assembly of polycyclic molecular skeletons. Although an array of redox‐active metal catalysts has recently shown robust applications in enabling various catalytic cascade radical processes, the use of free organic radical as the catalyst, which is capable of triggering strategically distinct cascades, has rarely been developed. Here, we disclosed that the benzimidazolium‐based N‐heterocyclic carbene (NHC)‐boryl radical is capable of catalyzing cascade cyclization reactions in both intra‐ and intermolecular pathways, assembling [5,5] fused bicyclic and [6,6,6] fused tricyclic molecules, respectively. The catalytic reactions start with the chemo‐ and regioselective addition of the boryl radical catalyst to a tethered alkene or alkyne moiety, followed by either an intramolecular formal [3+2] or an intermolecular [2+2+2] cycloaddition process to construct bicyclo[3.3.0]octane or tetrahydrophenanthridine skeletons, respectively. Eventually, a β‐elimination occurs to release the boryl radical catalyst, completing a catalytic cycle. High to excellent diastereoselectivity is achieved in both catalytic reactions under substrate control.

Access to N-Fused Quinazolinones by Radical-Promoted Cascade Annulations of Alkenyl N-Cyanamides with Aromatic Aldehydes.

A cascade radical cyclization of alkenyl N-cyanamides with aromatic aldehydes has been achieved for an expeditious synthesis of keto-methylated dihydropyrrolo-quinazolinones. Benzoyl radicals, generated from aryl aldehydes in the presence of di-tert-butyl peroxide (DTBP), promoted the domino annulations leading to distinctive functionalized quinazolinones in good yields. In addition, the robustness of the present protocol is validated by employing heterocyclic and natural product-based aldehydes.

Ir-catalyzed photoredox cascade radical annulation reactions toward phosphinimides bearing quaternary carbon center at room temperature

Organophosphorus aza-heterocycles are widely found in the framework of numerous bioactive molecules, functional materials, and commercially available drugs. We report herein a photoredox-catalyzed radical addition cascade annulation sequence of acyclic phosphinimides with a variety of organohalides under mild and external oxidant-free reaction conditions. A wide range of functionalized phosphinimides bearing a quaternary carbon center could be efficiently and selectively produced by employing diverse radical precursors, including sulfonyl, perfluoroalkyl, trichloromethyl, and carbonyl halides, under mild reaction conditions.

Red-Light-Promoted Radical Cascade Reaction to Access Tetralins and Dialins Enabled by Zinc(II)porphyrin, A Light-Flexible Catalyst.

[5,15-Bis(pentafluorophenyl)-10,20-diphenylporphinato]zinc(II) (1), a metalloporphyrin derivative that was recently reported as an efficient photocatalyst driven by blue LEDs by our group, was found to catalyze a red-light-promoted (630 nm LEDs) radical cascade reaction of N-3-arylpropionyloxyphthalimides with radicophiles including electron-deficient alkenes and alkynes, providing access to a range of functionalized tetralin and dialin derivatives. The radical cascade reaction catalyzed by 1 took place via an oxidative quenching cycle in DMSO, where no sacrificial electron donor was required, uncovering a unique solvent effect capable of promoting the porphyrin catalysis.

Efficient Functionalization of Organosulfones via Photoredox Catalysis: Direct Incorporation of α-Carbonyl Alkyl Side Chains into α-Allyl-β-Ketosulfones.

A novel and efficient method for functionalizing organosulfones has been established, utilizing a visible-light-driven intermolecular radical cascade cyclization of α-allyl-β-ketosulfones. This process employs fac-Ir(ppy)3 as the photoredox catalyst and α-carbonyl alkyl bromide as the oxidizing agent. Via this approach, the substrates experience intermolecular addition of α-carbonyl alkyl radicals to the alkene bonds, initiating a sequence of C-C bond formations that culminate in the production of organosulfone derivatives. Notably, this technique features gentle reaction conditions and an exceptional compatibility with a wide array of functional groups, making it a versatile and valuable addition to the field of organic synthesis.

Chemoselective Synthesis of 3-Bromomethyloxindoles via Visible-Light-Induced Radical Cascade Bromocyclization of Alkenes.

A novel visible-light-induced radical cascade bromocyclization of N-arylacrylamides has been accomplished. This reaction overcomes the overbromination at the benzene rings suffered in traditional electrophilic reactions, thus enabling the first highly chemoselective synthesis of valuable 3-bromomethyloxindoles. The combination of pyridine and anhydrous medium is identified as the key factor for the high chemoselectivity in the current photoreaction system, which might work by suppressing the in situ generation of low-concentration Br2 from N-bromosuccinimide. Moreover, the mild reaction conditions ensure the generation of a wide range of the new desired products with excellent functional group tolerance.