Radical Cascade Reaction Research Articles

Highly Regioselective Modular Assembly of 3-Phosphonyl Polysubstituted Pyridines through Radical Cascade Cyclization of 1,5-Enynes with Phosphine Oxide by Photoinitiation.

A series of 3-phosphonyl polysubstituted pyridine were first synthesized by photocatalysis, combining a phosphonyl radical cascade reaction, Boc deprotection, and aromatization. This strategy can avoid the difficulties of activating the C3-H bond on pyridine to synthesize 3-phosphonylpyridine under mild conditions. Furthermore, by constructing different enynes, we can achieve the metal-free modular synthesis of 3-phosphonyl polysubstituted pyridine, which will be transferred into a new type of phosphine ligand. This is of significance for organometallic catalysis. The regioselective control and detailed reaction mechanism of the cascade reaction are explained by DFT calculations.

A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C─C and C─N bonds

P450 peroxidase activities are valued for their ability to catalyze complex chemical transformations using economical H2O2; however, they have been largely underexplored compared to their monooxygenase and peroxygenase activities. In this study, we identified an unconventional P450 enzyme, PtmB, which catalyzes the dimerization of purine nucleobases and tryptophan-containing diketopiperazines (TDKPs), yielding C3-nucleobase pyrroloindolines and nucleobase-TDKP dimers. Unlike typical TDKP P450 enzymes reliant on NAD(P)H cofactors and electron transfer systems, PtmB, and its analogs exhibit remarkable peroxidase activity in synthesizing adenine and other modified 6-aminopurine nucleobase-TDKP dimers. Structural analysis of the PtmB-substrate complex, mutation assays, and computational investigations reveal adenine's dual role as both substrate and acid-base catalyst in activating H2O2 to generate Compound I (Cpd I). This initiates a specific radical cascade reaction, facilitating the formation of precise C─C and C─N bonds. Biochemical assays and molecular dynamics simulations demonstrate that adenine's 6-NH2 hydrogen-bonding networks induce necessary conformational changes for H2O2 activation, thereby driving peroxidase activity. This study unveils an unusual catalytic mechanism for the P450 peroxidase system and underscores the pivotal role of nucleobases in enzyme-mediated reactions, which offers different prospects for developing P450 peroxidases and nucleobase-based biocatalysts.

Recent Advances in Radical Reactions of 1,n‐Enynes with Phosphorus‐Centered Radicals

AbstractOrganophosphorus compounds have been widely used as achiral and chiral ligands in organic synthesis (PPh3, BINAP, dppe, Duphos, Xantphos, PPFA, Chiraphos, SEGPHOS), flame retardants, functional materials (LED, PV), as well as agrochemicals and medicines due to their broad biological activities. As the privileged versatile building blocks, 1,n‐enynes have been successfully applied in the synthesis of various functionalized cyclic compounds based on their two active unsaturated chemical bonds (C═C double and C≡C triple bonds). With the development of highly selective and efficient methods in organic chemistry, various organophosphorus cyclic compounds synthesis through radical cascade strategy has attracted considerable attention in recent years. In here, we have summarized the recent main achievements in the radical cascade reactions of 1,n‐enynes with phosphorus‐centered radicals. Furthermore, we also displayed the detailed reaction mechanisms in this review.

Asymmetric Three-Component Radical Cascade Reactions Enabled by Synergistic Photoredox/Brønsted Acid Catalysis: Access to α-Amino Acid Derivatives

Asymmetric Three-Component Radical Cascade Reactions Enabled by Synergistic Photoredox/Brønsted Acid Catalysis: Access to α-Amino Acid Derivatives

Visible-Light-Induced Dearomative Annulation of Indoles toward Stereoselective Formation of Fused- and Spiro Indolines.

Dearomatization approaches are attractive for their abilities to transform simple, planar arenes into complex, three-dimensional architectures. In particular, visible-light driven dearomatization strategies are significant because of their mild, green, and sustainable nature, enabling the fabrication of new chemical bonds via an electron transfer or energy transfer process. Indole compounds, being potentially bioactive and readily accessible, can be employed efficiently as building blocks for constructing diverse annulated frameworks under photocatalysis. Highly stereoselective radical cascade reactions of appropriate indole systems can provide complex cyclic scaffolds bearing multiple stereocenters. In fact, the past few years have witnessed the renaissance of dearomative cycloadditions of indoles via visible-light-induced photocatalysis. The present review highlights recent advances (2019-mid 2024) in visible-light-driven dearomative annulation of indoles leading to formation of polycyclic indolines, including angularly fused and spiro indolines. Most of the reactions described in this review are simple, providing quick access to the desired products. Additionally, characteristic reaction mechanisms are offered to provide an understand of how indole scaffolds show distinctive reactivity under photocatalytic conditions.

Superoxide Ion-Assisted Radical Cascade Reaction: Synthesis of 3-nitro-4-aryl-2H-chromen-2-ones from Aryl Alkynoate Esters under Methylene Blue Visible Light Photocatalysis

Background: From an industries and academic perspective, there is a need for a method for producing 3-nitro-4-aryl-2H-chromen-2-ones from aryl alkynoate esters that is both economic and environmental benign. In this context, superoxide ion-assisted radical cascade reaction can be an efficient and greener protocol. Objective: Herein, we have demonstrated an unprecedented methylene blue (MB) visible light photocatalysis for the production of a series of 3-nitro-4-aryl-2H-chromen-2-ones from readily available aryl alkynoate esters and a nitrating agent in solution. Methods: Synthesis of 3-nitro-4-aryl-2H-chromen-2-ones has been performed in the presence of aryl alkynoate ester, TBAN, DIPEA, solvent, catalyst and molecular oxygen under visible light irradiation at room temperature. The products were purified by column chromatography using silica gel, and the mixture of ethyl acetate/petroleum ether as an eluting solvent and characterized by IR, NMR and mass spectroscopic analysis. Results: A series of aryl alkynoate esters were successfully nitrated into corresponding 3-nitro-4- aryl-2H-chromen-2-ones with good isolated yields by this protocol, in which the key NO2-radicals formed by the action of superoxide ion (O2−·). Conclusion: In contrast to the literature-reported methods of synthesis of 3-nitro-4-aryl-2Hchromen- 2-ones, the process described here for making 3-nitro-4-aryl-2H-chromen-2-ones uses methylene blue visible light photocatalysis, is inexpensive, mild, does not require a metal precursor or high temperatures, and is successful when using the direct sunlight.

Radical Cascade Annulation of Biphenyl Acrylamides to Dibenzo‐azepinones: Experimental and DFT Studies

AbstractAn efficient method for the conversion of biphenyl acrylamides to dibenzoazepinones with −SCF3 incorporation is described. This operationally simple radical cascade reaction employs CAN as an oxidant and exhibits good functional group tolerance. Substrates featuring −OCH3, −CH3, −Br or −Cl at the para‐position of the aromatic ring exhibits a preference for an ipso‐cyclization due to the intervention of DMSO in the reaction. Density functional theory (DFT) calculations provide valuable insights into the reaction's energetics and product selectivity.

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

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.

Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of β-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of β-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of β-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral β-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Self-photocatalyzed three-component radical cascade reaction of quinoxalinones, simple alkenes and zhdankin reagent

A photoinduced, self-catalyzed three-component reaction of quinoxalinones with unactivated alkenes and IBA-N3 was developed. Quinoxalin-2(1H)-ones act as both reagent and photocatalyst in this reaction system. This methodology provides a simple, practical and sustainable method to access diverse azidoalkylated quinoxalinones with potential use in medical and pharmaceutical.

Synthesis of bridged bicyclic thiazine-2-thione and thiazole-2-thiones through DBU-promoted regioselective annulation of quinone monoacetals under mild conditions

The first regioselective [4 ​+ ​2] annulation reactions of quinone monoacetals with isothiocyanates and Na2S have been accomplished. This convenient and novel protocol involves the synthesis of valuable bridged thiazine-2-thione and thiazole-2-thiones through DBU-promoted at room temperature. Mechanism study reveals the dearomative transformation possibly undergoes a radical cascade reaction on the structure of quinone monoacetals to an efficient synthesis of a broad range of thione-containing heterocyclic compounds with broad tolerance in moderate to excellent yields. Moreover, the reported procedure can be easily applied to a 1g scale.

Recent Advances in the Construction of Coumarin or Quinolin-2-ones Compounds via Radical Cascade Reactions

Abstract: Free radical reactions occupy an important position in synthetic organic chemistry as well as medicinal chemistry, significantly complementing and extending the synthesis of coumarin or quinolin-2-one compounds. Moreover, the use of constructing coumarin or quinolin-2-one compounds functionalized at the C3 position has certain advantages over traditional noble metalcatalyzed or high-temperature cyclization, which is more in line with the advocates of green chemistry. The design of alkenes or alkynes as radical acceptors for cascade reactions presents a novel and robust approach to obtaining coumarin or quinolin-2-one molecules. These radical cascade cyclization reactions have been well explored and studied over the past decade. As a result, we have compiled a review of the rapidly developing cutting-edge research in this field, featuring typical examples and in-depth exploration of the underlying mechanisms.

Synthesis of 1,1-Diarylvinylsulfides via Visible-Light-Promoted Cascade Reaction of Alkynoates with Phenyl Disulfides.

Without any additives and photocatalysts, the visible-light-promoted radical cascade reaction between alkynoates and phenyl disulfides has been developed at room temperature. Through S-S bond photolysis and homolytic cleavage, addition of a sulfur radical, aryl migration, decarboxylation, and H atom abstraction, the cascade reaction provides an efficient and practical route to trisubstituted 1,1-diarylvinylsulfides with a wide scope of substrates and good to excellent yields.

Recent advances in the radical cascade reaction for constructing nitrogen heterocycles using azides as radical acceptors.

Due to the high conversion properties, azide compounds are widely utilized in organic synthesis. For instance, azide compounds readily release nitrogen to form a new N-C bond when they function as radical acceptors for the active intermediates in the reaction. Over the past decade, strategies employing azides as radical acceptors to construct nitrogen heterocycles have been extensively developed. This approach has emerged as a crucial method for synthesizing nitrogen heterocycles. Therefore, this paper provides a review of the research advancements in tandem cyclization reactions using azides as radical acceptors, summarizing the process of reaction design, exploration, reasoning of the mechanism, and prospects for further research of these reactions.

Efficient synthesis of SCF3-containing 3-alkenylquinoxalinones via three-component radical cascade reaction.

An efficient and practical method for the synthesis of 3-alkenylquinoxalinones containing the SCF3 group has been readily developed through a three-component radical cascade reaction involving quinoxalinones, alkynes and AgSCF3. The reaction was found to be compatible with a variety of substrates and exhibited a high functional group tolerance and complete E-selectivity. The preliminary study suggests the involvement of a SCF3 radical in the transformation.

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.

Photocatalytic Radical Cascade Dehalogenation/Carbo-cyclization/Sulfonylation Leading to Indole- and Benzofuran-Based Benzylic Sulfones.

This study presents a convenient approach to the synthesis of indole- and benzofuran-based benzylic sulfones using unactivated alkynes containing aryl iodides and sodium sulfinates under visible light irradiation. The procedure involves a sequential series of dehalogenation, carbo-cyclization, and radical sulfonylation. Plausible insights into the reaction mechanism are derived from control experiments, leading to the proposal of a radical cascade reaction pathway.

Radical Dearomatising Spirocyclisation of Benzisoxazole‐Tethered Ynones

AbstractThe dearomative spirocyclisation of benzisoxazoles through a radical chain mechanism is described. Densely functionalised spirocycles were prepared in high yields by reacting benzisoxazole‐tethered ynones with aryl thiols in 1,2‐dichloroethane (DCE) at 60 °C. The identification of stabilising three‐electron interactions was key to the development of this new radical cascade reaction. The obtained spirocyclic products were converted into other spirocyclic scaffolds through a two‐step hydrogenolysis‐cyclisation sequence.

New synthesis of β-aryl-GABA drugs

A new synthetic method for the preparation of β-aryl-GABA drugs is reported. The key step for the construction of α,β-unsaturated-β-aryl-γ-lactam derivatives relies on a novel cascade radical reaction. An N-propargyl aryl amide was rapidly constructed starting from an aryl carboxylic acid and propargyl amine. Protection of the amide N–H with a Boc group, followed by a cascade radical aryl migration reaction, produced the key intermediate, an unsaturated β-aryl-γ-lactam. Further catalytic hydrogenation and deprotection gave rolipram. Meanwhile, coupling of the glycine methyl ester and propargyl bromide, followed by benzoylation gave the radical precursor. The radical reaction resulted in the production of the unsaturated β-aryl-γ-lactam with the glycine moiety. After aminolysis reactions, phenylpiracetam and phenylpiracetam hydrazide were produced, respectively. This synthetic protocol provides a general and simple approach for preparing racemates or chiral forms of β-aryl-GABA drugs and analogues.