Generation Of Alkyl Radicals Research Articles

Photocatalyst‐Free Synthesis of Oxindoles and Isoquinolinediones via the Radical Reaction of N‐Arylacrylamides with Monoalkyl Cesium Oxalate Salts by Visible Light Catalysis

AbstractA photocatalyst‐free cascade reaction of N‐alkyl‐N‐arylmethacrylamides with monoalkyl cesium oxalate salts is described. In the presence of visible light and (NH4)2S2O8, monoalkyl cesium oxalate salts undergo single‐electron oxidation/CO2 extrusion to generate alkyl radicals, followed by the addition and subsequent cyclization to give alkylated oxindoles. In addition, N‐alkyl‐N‐methacryloylbenzamides could be applied for the cascade reaction, providing a series of alkylated isoquinolinediones, which are completely different from the products obtained with monoalkyl oxalates as substrates.

Recent Advances in Methodologies for Radical‐Mechanistic Borylation†

Comprehensive SummaryWe reviewed works on radical borylation reactions since 2020 from two aspects. 1. Borylation from alkyl or aryl radicals: This approach involves the generation of alkyl or aryl radicals from various precursors such as halides and carboxylic acids, followed by their reaction with diboron reagents to form boron esters. 2. Borylation from boron‐centered radicals: This approach involves generating boron‐centered radicals, which then react with substrates to achieve borylation. Key Scientists

Intracellular Generation of Alkyl Radicals Enabled by a Self-Catalytic ATRP Nanoinitiator.

Oxygen-independent alkyl radicals (R•) have demonstrated great promise in combating tumor hypoxia. Currently, Azo compounds have been the primary source of R•, suffering from external stimuli and decomposition during circulation. Herein, we developed a self-catalytic ATRP nanoinitiator that could generate R• via glutathione (GSH) reduction and thus selectively induce apoptosis of tumor cells. Specifically, a conjugation of laccase (possessing a copper(II) complex) and polymeric alkyl bromide, poly(iBBr), was fabricated to yield an ATRP nanoinitiator (Lac-P(iBBr)). After internalization by cells featured with overexpressed GSH, copper(II) in Lac-P(iBBr) was reduced to copper(I) by GSH, which abstracted the Br atom in poly(iBBr) to yield toxic R•. Moreover, GSH-depletion intensified the oxidative damage caused by R•. Efficient generation of R• by Lac-P(iBBr) could happen in lab flasks, living cells, and tumor-bearing mice without any external stimuli, as demonstrated by the radical product, as well as the consumption of GSH. Moreover, the self-catalytic ATRP nanoinitiator significantly induced cell apoptosis and suppressed tumor growth. Our study expands the chemical toolbox to manipulate cell fates.

Photoinduced generation of alkyl and phthalimide nitrogen radicals from N-hydroxyphthalimide esters for the synthesis of benzophenone-type bioisosteres

Photoinduced generation of alkyl and phthalimide nitrogen radicals from N-hydroxyphthalimide esters for the synthesis of benzophenone-type bioisosteres

Photoinduced Multicomponent Heteroarylation of [1.1.1]Propellane with Katritzky Pyridinium Salts.

(Hetero)arylated bicyclo[1.1.1]pentanes (BCPs) are important for the construction of complex druglike target molecules. Herein, we developed a method for light-induced, Cs2CO3-promoted homolytic cleavage of pyridinium C-N bonds for generating alkyl radicals from amino acid-derived Katritzky salts and use of the radicals for functionalization of [1.1.1]propellane to rapidly generate (hetero)arylated BCPs. The method features excellent functional group tolerance and a broad substrate scope and can be used to functionalize structurally complex natural products.

Homologation of Ketones: Direct Transformation of Alkyl Ketones to Aryl Ketones via Photoredox Catalyzed Deacylation-Aroylation Sequence.

Ketones, as essential functional group skeletons, have garnered significant interest due to their diverse transformations. Herein, we describe a versatile photoredox catalyzed deacylation-aroylation strategy that enables the direct transformation of alkyl ketones to aryl ketones. This process involves photoredox deacylation of dihydroquinazolinones derived from alkyl ketones to generate alkyl radicals, followed by subsequent NHC-catalyzed or NHC-mediated radical aroylation.

Direct Excitation Strategy for Deacylative Couplings of Ketones.

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research.

Direct excitation strategy for deacylative couplings of ketones

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical‐generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon‐centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C–C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible‐light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni‐metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non‐catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst‐free approaches in cutting‐edge research.

Theoretical Study on Photo‐Induced Copper Autoredox Construction of Chiral Amines

AbstractDensity functional theory (DFT) calculations were conducted to investigate the photo‐induced copper‐catalyzed C−N coupling reaction for the synthesis of chiral tertiary amines. The ligands′ effects on the metal center and the factors determining regioselectivity in chiral tertiary amine formation were examined. The computational results revealed that the oxidative quenching process involved in the photocatalytic redox cycle via CuI‐CuI*‐CuII‐CuIII transitions. Throughout the reaction, four key processes occurred: C−Br bond activation, ligand exchange, amide ion/Br ion exchange, and C−N coupling. Among these steps, alkyl radical generation through single electron transfer was identified as the rate‐determining step with an energy barrier of 13.9 kcal/mol. The chelating diphosphine ligand improved copper‘s reducibility and its capacity to activate the C−Br bond by charge transfer when exposed to visible light (CT). Copper's own redox process was facilitated by interactions between diphosphine and diamine ligands. Finally, when combined with oxygen, this catalyst system formed a chiral plane CuII‐O1‐N1‐N2‐N3 essential for enantioselective product formation.

In situ copper photocatalysts triggering halide atom transfer of unactivated alkyl halides for general C(sp3)-N couplings

Direct reduction of unactivated alkyl halides for C(sp3)-N couplings under mild conditions presents a significant challenge in organic synthesis due to their low reduction potential. Herein, we introduce an in situ formed pyridyl-carbene-ligated copper (I) catalyst that is capable of abstracting halide atom and generating alkyl radicals for general C(sp3)-N couplings under visible light. Control experiments confirmed that the mono-pyridyl-carbene-ligated copper complex is the active species responsible for catalysis. Mechanistic investigations using transient absorption spectroscopy across multiple decades of timescales revealed ultrafast intersystem crossing (260 ps) of the photoexcited copper (I) complexes into their long-lived triplet excited states (>2 μs). The non-Stern-Volmer quenching dynamics of the triplets by unactivated alkyl halides suggests an association between copper (I) complexes and alkyl halides, thereby facilitating the abstraction of halide atoms via inner-sphere single electron transfer (SET), rather than outer-sphere SET, for the formation of alkyl radicals for subsequent cross couplings.

Sulfonamide-directed site-selective functionalization of unactivated C(sp3)−H enabled by photocatalytic sequential electron/proton transfer

The generation of alkyl radical from C(sp3)−H substrates via hydrogen atom abstraction represents a desirable yet underexplored strategy in alkylation reaction since involving common concerns remain adequately unaddressed, such as the harsh reaction conditions, limited substrate scope, and the employment of noble metal- or photo-catalysts and stoichiometric oxidants. Here, we utilize the synergistic strategy of photoredox and hydrogen atom transfer (HAT) catalysis to accomplish a general and practical functionalization of unactived C(sp3)−H centers with broad reaction scope, high functional group compatibility, and operational simplicity. A combination of validation experiments and density functional theory reveals that the N-centered radicals, generated from free N − H bond in a stepwise electron/proton transfer event, are the key intermediates that enable an intramolecular 1,5-HAT or intermolecular HAT process for nucleophilic carbon-centered radicals formation to achieve heteroarylation, alkylation, amination, cyanation, azidation, trifluoromethylthiolation, halogenation and deuteration. The practical value of this protocol is further demonstrated by the gram-scale synthesis and the late-stage functionalization of natural products and drug derivatives.

Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: "Digging Their Graves with Their Forks".

The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm's digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals-which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.

Iron-Catalyzed Photochemical Synthesis of Sulfinamides from Aliphatic Hydrocarbons and Sulfinylamines.

An iron-catalyzed photochemical sulfinamidation of hydrocarbons with N-sulfinylamines has been developed. The merger of ligand-to-metal charge transfer (LMCT) of FeCl3 with hydrogen atom transfer (HAT) process is the key for the generation of alkyl radicals from hydrocarbons, and the resultant alkyl radicals were readily trapped by N-sulfinylamines to produce structurally diverse sulfinamides. Contrary to traditional methods that inevitably use sensitive organometallic reagents and prefunctionalized substrates, our approach features simple operation and the wide availability of starting materials. Gratifyingly, the reaction is scalable, and the obtained sulfinamides can be conveniently converted to highly functionalized sulfur(VI) derivatives.

Visible-Light-Induced PhI(OAc)2-Mediated Alkylation of Heteroarenes with Simple Alkanes and Ethers.

The direct alkylation of heteroarenes with alkanes has been successfully achieved through visible-light-induced hypervalent iodine-mediated C-H functionalization of both coupling partners at ambient temperatures. This reaction proceeds via the in situ generation of nucleophilic alkyl radicals from alkanes through hydrogen atom transfer (HAT), followed by a Minisci-type reaction with heteroarenes. These mild reaction conditions have demonstrated their suitability for the alkylation of a wide range of heterocycles, including azoles, pyridines, quinolines, isoquinolines, and quinoxalinones.

Metal-Organic Layers with Photosensitizer and Pyridine Pairs Activate Alkyl Halides for Photocatalytic Heck-Type Coupling with Olefins.

Photochemical generation of alkyl radicals from haloalkanes often requires strong energy input from ultraviolet light or a strong photoreductant. Haloalkanes can alternatively be activated with nitrogen-based nucleophiles through a sequential SN2 reaction and single-electron reduction to access alkyl radicals, but these two reaction steps have opposite steric requirements on the nucleophiles. Herein, we report the design of Hf12 metal-organic layers (MOLs) with iridium-based photosensitizer bridging ligands and secondary-building-unit-supported pyridines for photocatalytic alkyl radical generation from haloalkanes. By bringing the photosensitizer and pyridine pairs in proximity, the MOL catalysts allowed facile access to the pyridinium salts from SN2 reactions between haloalkanes and pyridines and at the same time enhanced electron transfer from excited photosensitizers to pyridinium salts to facilitate alkyl radical generation. Consequentially, the MOLs efficiently catalyzed Heck-type cross-coupling reactions between haloalkanes and olefinic substrates to generate functionalized alkenes. The MOLs showed 4.6 times higher catalytic efficiency than the homogeneous counterparts and were recycled and reused without a loss of catalytic activity.

Green Molecular Transformation in Dual Catalysis: Photoredox Activation of Vitamin B12 Using Heterogeneous Photocatalyst.

This concept focuses on dual-catalysis using metal complexes and heterogeneous photocatalysts. Vitamin B12 derivatives are sophisticated metal complexes that facilitate enzymatic reactions in the biological systems. The B12 enzymes inspired reactions catalytically proceed in dual-catalyst systems of B12 derivatives and heterogeneous photocatalysts, such as titanium oxide (TiO2) and metal-organic frameworks (MOFs), under light irradiation. The cobalt ions in B12 derivatives are effectively reduced by photoexcited photocatalysts, producing low-valent Co(I) species. The photoinduced nucleophilic Co(I) species react with an alkyl halide to form an organometallic complex with a Co-C bond. The Co-C bond dissociates during photolysis to generate alkyl radicals. Based on this mechanism, dual-catalysis effectively promotes various light-driven organic syntheses and light-driven dehalogenation reactions of toxic alkyl halides. The trends of the dual-catalyst system and recent progress in this field are discussed in this concept.

Organophotoredox Catalysis: Switchable Radical Generation from Alkyl Sodium Sulfinates for Sulfonylation and Alkylative Activation of C-C Bonds of Cyclopropenes.

Generating alkyl radicals from the sulfonyl radicals remains challenging in synthetic chemistry. Here, we report an efficient photocatalyzed strategy using alkyl sodium sulfinates as both sulfonylating and alkylating reagents by controlling the reaction temperature. This methodology provides a versatile protocol for synthesizing diastereoselective sulfonylated cyclopropanes and poly-substituted styrene derivatives. This methodology is successfully demonstrated with a wide variety of cyclopropenes and alkyl sulfinates, showcasing its broad substrate scope, high diastereo- and E/Z selectivity, and yielding good to excellent yields.

Enantioenriched Allylesters via a Copper-Catalyzed Diene Carboesterification with Alkyltrifluoroborates and Carboxylic Acids.

The rapid synthesis of a range of enantioenriched allylic esters is enabled by a new 3-component catalytic enantioselective 1,2-carboesterification of readily available dienes with carboxylic acids and potassium alkyltrifluoroborates. The chiral copper catalyst, formed in situ from Cu(OTf)2 and (4S,4'S)-2,2'-(cyclopentane-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole), is implicated in both the generation of alkyl radicals from the alkyltrifluoroborates as well as the enantioselective formation of C-O bonds. Potassium salts of primary and secondary alkyltrifluoroborates as well as several benzylic trifluoroborates, tert-butyltrifluoroborate, and phenyltrifluoroborate participate in the reaction. The regioselectivity and enantioselectivity are strongly impacted by variations in all of the reaction components, which in turn are thought to impact the C-O bond-forming reductive elimination from a [Cu(III)] intermediate.

Multifunctional nanoparticles for enhanced sonodynamic-chemodynamic immunotherapy with glutathione depletion.

Aim: This study aimed to develop a sonodynamic-chemodynamic nanoparticle functioning on glutathione depletion in tumor immunotherapy. Materials & methods: The liposome-encapsulated 2,2-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and copper-cysteine nanoparticles, AIPH/Cu-Cys@Lipo, were synthesized with a one-pot method. 4T1 cells were injected into female BALB/c mice for modeling. Results: AIPH/Cu-Cys@Lipo was well synthesized. It generatedalkyl radicals upon ultrasound stimulation. AIPH/Cu-Cys@Lipo promoted the generation of -OH via a Fenton-like reaction. Both in vitro and in vivo experiments verified that AIPH/Cu-Cys@Lipo significantly inhibited tumor development by decreasing mitochondrial membrane potential, activating CD4+ and CD8+ T cells and promoting the expression of IL-2 and TNF-α. Conclusion: AIPH/Cu-Cys@Lipo provides high-quality strategies for safe and effective tumor immunotherapy.

Photoredox catalyzed release of carbon-based radicals from 2-substituted-1,3-imidazolidines

We describe herein easily oxidizable 2-substituted-1,3-imidazolidines for the photocatalyzed generation of (substituted) alkyl radicals for the forging of C(sp3)–C(sp3) bonds under metal-free conditions.