Radical Cascade Process Research Articles

Pyridine‐Boryl Radical‐Catalyzed [3 + 2] Cycloadditions of Alkyne‐Tethered Cyclopropyl Ketones

AbstractBicyclo[3.3.0]octanes represent crucial structural motifs found in various bioactive natural compounds. In this study, we present the first metal‐free formal [3 + 2] cycloadditions of alkyne‐tethered cyclopropyl ketones via pyridine‐boryl radical catalysis, affording bicyclo[3.3.0]octanes with high efficiency and broad substrate scope. This reaction features the generation of ketyl radical by pyridine‐boryl radical and a consecutive 5‐exo‐dig and 5‐exo‐trig radical cascade process.

Photo‐catalyzed Stereospecific Synthesis of Trisubstituted Alkenes Incorporating 3,3‐Difluoro‐γ‐Lactams from Morita‐Baylis‐Hillman Acetates and N‐Allylbromodifluoroacetamides

A photocatalytic methodology has been devised for the stereoselective construction of trisubstituted alkenes incorporating 3,3‐difluoro‐γ‐lactams in 17‐93% yields via a radical cascade process utilizing MBH acetates and N‐allylbromodifluoroacetamides as starting materials. The reaction mechanism involves single‐electron transfer, 5‐exo‐trig cyclization, radical addition, and elimination in a cascade fashion.

Photoredox/HAT-Catalyzed Intramolecular Hydrocyclization of Alkenes toward 2,3-Fused Quinazolinones and Dihydroquinazolinones.

New photochemical approaches to 2,3-fused quinazolinones and dihydroquinazolinones are disclosed. The intramolecular hydrocyclization proceeds in moderate to excellent yields across diverse alkenes with high regioselectivity and diastereocontrol. Mechanistic studies indicated that the radical cascade processes involve thiophenol acting as single-electron transfer and hydrogen atom transfer reagents. The success of the gram-scale synthesis proves the strategy can be used for practical applications.

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.

Atom Transfer Radical Addition Reactions of Quinoxalin-2(1H)-ones with CBr4 and Styrenes Using Mes-Acr-MeClO4 Photocatalyst.

The atom transfer radical addition (ATRA) reaction is defined as a method for introducing halogenated compounds into alkenes via a radical mechanism. In this study, we present an ATRA approach for achieving regioselective functionalization of quinoxalin-2(1H)-ones by activating C-Br bonds of CBr4 and subsequent trihaloalkyl-carbofunctionalization of styrenes employing the 9-mesityl-10-methylacridinium perchlorate (Fukuzumi) photocatalyst under 3W blue LED (450-470 nm) irradiation. This three-component radical cascade process demonstrates remarkable efficiency in the synthesis of 1-methyl-3-(3,3,3-tribromo-1-(4-chlorophenyl)propyl)quinoxalin-2(1H)-one derivatives.

Visible light-induced cascade sulfonylation/annulation of ortho-allyloxy chalcones with sodium sulfinates for the synthesis of sulfonated chromane derivatives.

A visible-light-induced radical cascade reaction for the synthesis of structurally diverse sulfonated chromanes is described. The protocol involves the addition of sulfonyl radicals to ortho-allyloxy chalcones and intramolecular Michael addition reactions in the presence of eosin Y as a photocatalyst. Additionally, this protocol shows that it is also an effective method to construct seven-membered oxygen-containing heterocycles. The method features a wide substrate scope, the use of easily accessible materials and excellent functional group tolerance with high to excellent yields. Control experiments and mechanistic studies indicate that a visible light-induced radical cascade process is involved in the transformation.

NHC-Catalyzed Tandem Reaction: A Strategy for the Synthesis of 2-Pyrrolidinone-Functionalized Phenanthridines.

Herein, an N-heterocyclic carbene (NHC)-catalyzed tandem cyclization/addition/cyclization reaction of 2-isocyanobiaryls and α-bromo-N-cinnamylamides for the synthesis of 2-pyrrolidinone-functionalized phenanthridines is developed. This protocol features a radical cascade process, broad substrate scope, and good functional group compatibility under metal- and oxidant-free reaction conditions.

Enantioselective radical cascade cyclization via Ti-catalyzed redox relay

Radical cascade cyclization reactions provide an efficient method for the construction of polycyclic architectures with multiple stereogenic centers. However, achieving enantioselectivity control of this type of reaction is a challenging task. Here, we report an enantioselective cyclization of polyfunctional aryl cyclopropyl ketone and alkyne units, wherein the stereochemical outcome is directed by a chiral Ti(salen) catalyst. This transformation was proposed to proceed via a radical cascade process involving the reductive ring-opening of the cyclopropyl ketone followed by two annulation events entailing cyclization of the ensuing alkyl radical onto the alkyne and subsequent addition of the incipient vinyl radical to the Ti(IV)-enolate.

Radical Cascade Reaction in Heterocyclic Synthesis: Formation of Bicyclic 2,3‐dihydrostannoles and Other Heterocyclic Compounds from Amide‐type 1,6‐Enyne Compounds

AbstractAmide‐type 1,6‐enyne compounds, readily available from unsaturated N‐Boc acyl amide and propargylic mesylate, underwent a radical cascade reaction upon treatment with Bu3SnH, giving bicyclic 2,3‐dihydrostannole lactams in good yields. Regioselectivity of the reaction depended on the presence or absence of alkyne substituents; alkyl‐substituted internal alkynes selectively gave 2,3‐dihydrostannoles in good yields, while terminal alkynes gave a mixture of piperidine and 2,3‐dihydrostannole. The reaction promoted the radical cascade process starting from the addition of tin radical to the alkenyl terminal followed by 5‐exo‐dig radical cyclization. The resulting vinyl radical attack the tin atom, and direct radical substitution progressed, giving bicyclic 2,3‐dihydrostannoles in good yields.

Visible-Light-Induced Radical Cascade Cross-Coupling via C(sp3)-H Activation and C-N/N-O Cleavage: Feasible Access to Methylenebisamide Derivatives.

Here we report facile and manipulable access to methylenebisamide derivatives via visible-light-driven radical cascade processes incorporating C(sp3)-H activation and C-N/N-O cleavage. Mechanistic studies reveal that a traditional Ir-catalyzed photoredox pathway and a novel copper-induced complex-photolysis pathway are both involved, contributing to activating the inert N-methoxyamides and rendering the valuable bisamides. This approach exhibits many advantages, including mild reaction conditions, broad scope and functional group tolerance, and competitive step economy. Given the mechanistic plenitude and operational simplicity, we believe this package deal paves a promising way for the synthesis of valuable nitrogen-containing molecules.

Ag(i)-catalyzed three-component radical cascade synthesis of 3-organoselenyl chromones from 2-methoxyaryl alkynones, Se powder and organic boronic acids

A new three-component radical cascade process has been proposed for the synthesis of 3-organoselenyl chromones from 2-methoxyaryl alkynones, Se powder and organic boronic acids.

Total Synthesis of Puberuline C.

Puberuline C (1) is an architecturally complex C19-diterpenoid alkaloid with a unique ring fusion pattern. The 6/7/5/6/6/6-membered rings (ABCDEF-rings) contain one tertiary amine and six oxygen functionalities, and possess 12 contiguously aligned stereocenters, three of which are quaternary. These structural features of 1 make its chemical construction exceptionally challenging. Here, we disclose the first total synthesis of 1. The synthesis was accomplished from 2-cyclohexenone (9) by integrating radical cascade and Mukaiyama aldol reactions as the key transformations. A double Mannich reaction fused the A- and E-rings, and Sonogashira coupling attached the C-ring, efficiently leading to ACE-rings with the requisite 19 carbons of 1. The chemically stable tertiary chloride of the ACE-ring structure was then transformed to the corresponding bridgehead radical, which participated in the simultaneous cyclization of the B- and F-rings via a highly organized radical cascade process. This unusual step installed five contiguous stereocenters, including two quaternary carbons, without damaging the preexisting multiple polar functionalities. Subsequently, the intramolecular Mukaiyama aldol reaction between silyl enol ether and acetal was realized by applying a combination of SnCl4 and ZnCl2, forging the last remaining D-ring of the hexacycle. Finally, 3 was elaborated into 1 through regio- and stereoselective functionalizations of the BCD-rings. Our novel radical-based strategy achieved the total synthesis of 1 in 32 total steps from simple 9, demonstrating the power of the radical cascade reaction to streamline the assembly of highly complex molecules.

Visible light-initiated radical 1,3-difunctionalization of β,γ-unsaturated ketones.

Radical-mediated 1,2-difunctionalization of olefins is a well-established synthetic technique widely used in the rapid construction of structurally diverse molecular entities. However, radical-mediated 1,3-difunctionalization reactions are rare, and the substrates are generally limited to strained skeletons. Here, we report a practical approach for 1,3-difunctionalization of available β,γ-unsaturated ketones via a radical cascade process including visible light-irradiated radical addition, thermodynamic stability-driven 1,2-carbonyl migration from unactivated all-carbon quaternary center, and terminal C-radical varied transformations. Various highly functionalized alkyl skeletons with different valuable functional groups at positions 1 and 3 and the carbonyl group at position 2 have been synthesized through a radical chain pathway or Cu-catalyzed Ritter-type reaction. Moreover, this protocol provides a real case of diversity-oriented radical rearrangement for drug discovery. We identified a previously unknown chemotype of dual inhibitors for hypoxia-inducible factor (HIF) and WNT signaling pathways from products. These small-molecule inhibitors could suppress HIF and WNT signaling-dependent HCT116 cell growth in 2D and 3D culture systems.

Copper‐Catalyzed 1,2‐Dicarbonylative Cyclization of Alkenes with Alkyl Bromides via Radical Cascade Process

AbstractHerein, we developed a new procedure on 1,2‐dicarbonylative cyclization of 4‐aryl‐1‐butenes with alkyl bromides. Using simple copper catalyst, two molecules of carbon monoxide were introduced into the double bond with the formation of four new C−C bonds and a new ring. Various α‐tetralones and 2,3‐dihydroquinolin‐4‐ones were formed in moderate to good yields.

Copper-Catalyzed 1,2-Dicarbonylative Cyclization of Alkenes with Alkyl Bromides via Radical Cascade Process.

Herein, we developed a new procedure on 1,2-dicarbonylative cyclization of 4-aryl-1-butenes with alkyl bromides. Using simple copper catalyst, two molecules of carbon monoxide were introduced into the double bond with the formation of four new C-C bonds and a new ring. Various α-tetralones and 2,3-dihydroquinolin-4-ones were formed in moderate to good yields.

Metal‐Free Arylsulfonyl Radical Triggered Cascade Cyclization of Phenyl‐Linked 1,6‐Enynes: Synthesis of 2,3‐Dihydro‐1H‐indenes and 10a,11‐Dihydro‐10H‐benzo[b]fluorines

Comprehensive SummaryAryl sulfonyl radical triggered cascade cyclization of phenyl‐linked 1,6‐enynes for the synthesis of biologically important indenes containing alkenyl C—X bonds and 10a,11‐dihydro‐10H‐benzo[b]fluorines is presented. In these radical cascade processes, three new chemical bonds, including C—S, C—C, and C—X bonds, and three C—C bonds are formed in one step. The method is attractive and valuable due to its metal‐free, mild reaction conditions, broad substrate scope and good functional group tolerance.

Front Cover: Synthesis of Tetrahydro‐4H‐pyrido[1,2‐b]isoquinolin‐4‐ones from Ugi 4‐CR‐Derived Dihydroisoquinoline‐Xanthates (Eur. J. Org. Chem. 22/2022)

The Front Cover illustrates an efficient protocol for synthesizing polyfunctionalized tetrahydro-4H-pyrido[1,2-b]isoquinolinones. The methodology highlights the power of combining the four-component Ugi reaction with a xanthate-based radical cascade process to achieve molecular complexity in a few steps. The cover art features the beautiful library building of the authors’ University in Mexico City and the waterfall in the Basaltic Prisms, Huasca de Ocampo, Hidalgo, Mexico. More information can be found in the Research Article by L. D. Miranda et al.

Iron‐Catalyzed Silylation and Spirocyclization of Biaryl‐Ynones: A Radical Cascade Process toward Silylated Spiro[5.5]trienones

AbstractIron‐catalyzed cascade silyl radical addition/6‐exo‐trig cyclization/dearomatization of biaryl ynones has been developed. This approach uses silane as the precursor of silyl radical as well as silylation reagent, 1,10‐phenanthroline as the ligand, andtert‐butyl hydroperoxide (TBHP) as the oxidant. By employing this tandem process, a series of silylated spiro[5.5]trienones were prepared.magnified image

Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures.

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, β-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Photoredox Catalysis toward 2-Sulfenylindole Synthesis through a Radical Cascade Process.

A radical cascade process initiated through visible-light induced thiyl radical coupling with ortho-substituted arylisocianides followed by an intramolecular cyclization and subsequent aromatization to access 2-sulfenylindoles is described. The key thiyl radicals are promptly generated via a hydrogen atom transfer event. The redox-neutral protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions. Furthermore, the implementation of a continuous flow variant allows smooth scalability with a short residence time through process intensification.