Atom Transfer Radical Addition Research Articles

Synthesis of Vinyl Sulfones from Substituted Alkenes via Molybdooxaziridine Catalysis

Herein we report the MoO2Dipic promoted sulfonation of alkenes using N‐Ts‐hydroxylamine as the quantitative source of Ts. The reaction works with high yields and stereoselectivities for styrenes with a wide variety of substitution patterns. A novel atom transfer radical addition mechanism involving the formation of molybdooxaziridine complex 1 as the active catalyst, difunctionalization with Ts‐NO, followed by oxidation, and then elimination as the rate‐determining‐step for the formation of vinylsulfone 3 has been proposed. Initial kinetic and mechanistic data indicates the formation of Ts‐NO and provides evidence for the proposed mechanism.

A General Platform for Copper-Catalyzed Atom Transfer Radical Addition with Electron-Deficient Olefins.

We disclose a broad platform for copper-catalyzed atom transfer radical addition (ATRA) of electron-deficient olefins. Catalytic Cu(dtbbpy)2(OTf)2 enables radical addition of electron-deficient alkyl halides to acrylates, acrylamides, and vinyl sulfones in fair to excellent yields. The resultant ATRA products can be used in a variety of telescoped reactions, including substitution with basic amine nucleophiles to afford α-amino esters. The synthetic utility of the products is further demonstrated through derivatization to give substituted cyclopropanes and a γ,δ-unsaturated ester.

Steric and Distance Effect on Electron Transfer in Dibenzo-Fused BODIPY-Based Photoredox Catalysts.

π-Extended BODIPY compounds are a compelling class of fluorophores known for their red or near-infrared (NIR) emission and high quantum yields, which are crucial for applications in materials science, solar cells, and biomedical imaging. Our recent study shows that we can use a dibenzo-fused BODIPY as a singlet-driven red photoredox catalyst by installing a simple electron donor group. Despite their potential in these applications, knowledge of electron transfer reactions involving dibenzo-fused BODIPY is still scarce. This paper presents the synthesis and systematic photophysical investigations of donor-acceptor (D-A) and donor-bridge-acceptor (D-bridge-A) series of dibenzo-fused BODIPY with N,N'-diethylaniline fragments serving as an electron donor. We examined the effects of methyl substituents and bridge length on the rates of photoinduced electron transfer (PeT). Through steady-state and time-resolved optical spectroscopy, electrochemistry, and density functional theory calculations, we elucidated how these simple structural modifications controlled the PeT rates and examined their impacts on catalytic activities in atom transfer radical addition (ATRA) reactions. Our results support previous studies on the (D-A) design of red heavy atom-free photocatalysts.

Singlets-Driven Photoredox Catalysts: Transforming Noncatalytic Red Fluorophores to Efficient Catalysts.

Red-light absorbing photoredox catalysts offer potential advantages for large-scale reactions, expanding the range of usable substrates and facilitating bio-orthogonal applications. While many red-light absorbing/emitting fluorophores have been developed recently, functional red-light absorbing photoredox catalysts are scarce. Many photoredox catalysts rely on long-lived triplet excited states (triplets), which can efficiently engage in single electron transfer (SET) reactions with substrates. However, triplets of π-conjugated molecules are often significantly lower in energy than photogenerated singlet excited states (singlets). Combined with the inherent low energy of red light, this could limit the reductive/oxidative powers. Here, we introduce a series of sustainable heavy atom-free photoredox catalysts based on red-light absorbing dibenzo-fused BODIPY. The catalysts consist of two covalently linked units: a dibenzo-fused BODIPY fluorophore and an electron donor, arranged orthogonally. Excitation of the dibenzoBODIPY unit induces charge separation (CS) from the donor to the dibenzoBODIPY unit, forming a radical pair (RP) state. Unlike the regular BODIPY counterparts, these catalysts do not form triplets. Instead, SET occurs from the high-energy singlet-born RP states, preventing energy loss and effectively utilizing the low-energy red light. The proximity of donor molecules allows efficient charge separation despite the CS being uphill in energy. The molecules demonstrate efficient catalysis of Atom Transfer Radical Addition (ATRA) reaction, yielding products with high yields ranging from 70 to 90%, while the molecule without a donor group does not exhibit catalytic activity. The mechanistic studies by transient absorption and electron paramagnetic resonance (EPR) spectroscopy methods support the proposed mechanism. The study presents a new molecular design strategy for converting noncatalytic fluorophores to efficient photoredox catalysts operating in the red spectral region.

Investigating Competing Inner‐ and Outer‐Sphere Electron‐Transfer Pathways in Copper Photoredox‐Catalyzed Atom‐Transfer Radical Additions: Closing the Cycle

AbstractThis integrated computational and experimental study comprehensively examines the viability of competing inner‐sphere electron transfer (ISET) and outer‐sphere electron transfer (OSET) processes in [Cu(dap)2]+‐mediated atom‐transfer radical additions (ATRA) of olefins and CF3SO2Cl that can deliver both R−SO2Cl and R−Cl products. Five sterically‐ and electronically‐varied representative alkenes were selected from which to explore and reconcile a range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap)2]+ initiating photoelectron transfer via ISET and the subsequent regeneration of the oxidized catalyst via ISET in the ground state to close the catalytic cycle and liberate products. R−SO2Cl/R−Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap)2SO2Cl]⋅++R⋅} and ligand exchange {i.e., [Cu(dap)2SO2Cl]⋅++Cl− }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts.

Investigating Competing Inner- and Outer-Sphere Electron-Transfer Pathways in Copper Photoredox-Catalyzed Atom-Transfer Radical Additions: Closing the Cycle.

This integrated computational and experimental study comprehensively examines the viability of competing inner-sphere electron transfer (ISET) and outer-sphere electron transfer (OSET) processes in [Cu(dap)2]+-mediated atom-transfer radical additions (ATRA) of olefins and CF3SO2Cl that can deliver both R-SO2Cl and R-Cl products. Five sterically- and electronically-varied representative alkenes were selected from which to explore and reconcile a range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap)2]+ initiating photoelectron transfer via ISET and the subsequent regeneration of the oxidized catalyst via ISET in the ground state to close the catalytic cycle and liberate products. R-SO2Cl/R-Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap)2SO2Cl]⋅++R⋅} and ligand exchange {i.e., [Cu(dap)2SO2Cl]⋅++Cl- }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts.

Tuning Co-Operative Energy Transfer in Copper(I) Complexes Using Two-Photon Absorbing Diimine-Based Ligand Sensitizers.

Photocatalysis mediated by low energy light wavelengths has potential to enable safer, sustainable synthetic methods. A phenanthroline-derived ligand bathocupSani, with a large two-photon absorption (TPA) cross section was used to construct a heteroleptic complex [Cu(bathocupSani)(DPEPhos)]BF4 and a homoleptic complex [Cu(bathocupSani)2]BF4. The ligand and the respective homoleptic complex with copper exhibit two-photon upconversion with an anti-Stokes shift of 1.2 eV using red light. The complex [Cu(bathocupSani)2]BF4 promoted energy transfer photocatalysis enabling oxidative dimerization of benzylic amines, sulfide oxidation, phosphine oxidation, boronic acid oxidation and atom-transfer radical addition.

Divalent Organocopper Complexes: Masked Radicals for Effective Electrochemically Driven Atom Transfer Radical Addition

Divalent Organocopper Complexes: Masked Radicals for Effective Electrochemically Driven Atom Transfer Radical Addition

A Metal‐Free Photochemical Atom Transfer Radical Addition of CBr4 onto Alkenes as a Key Step for Their Conversion to Propargylamines

AbstractΑ green and sustainable metal‐free photochemical protocol for the atom transfer radical addition (ATRA) of carbon tetrabromide onto alkenes was developed. Phenylglyoxylic acid was employed as the photoinitiator to promote the water‐mediated anti‐Markovnikov photochemical addition. A vast variety of alkenes was employed successfully, providing the corresponding products in good to high yields with excellent regioselectivity. The photochemical protocol found an application towards the three‐step synthesis of secondary or tertiary propargylamines starting from alkenes.

Regiodivergent Radical-Relay Alkene Dicarbofunctionalization.

Herein, we report a regiodivergent 1,n-dicarbofunctionalization of unactivated olefins enabled by a Ni-catalyzed radical relay that forges both C(sp3)-C(sp3) and C(sp2)-C(sp3) linkages, even at long-range. Initial studies support an intertwined scenario resulting from the merger of an atom-transfer radical addition (ATRA) and a chain-walking event, with site-selectivity being dictated by a judicious choice of the ligand backbone.

New functionally substitutes cyclopropanecarboxylic acids as ethylene biosynthesis innovative regulators

Background: Derivatives of small carbocycles (cyclobutanes and cyclopropanes) are known as bioactive molecules. Both their natural and synthetic representatives have multiple applications. Particularly, 1-aminocyclopropane-1-carboxylic acid (ACC) serves as the well-studied ethylene biosynthesis precursor. The development of new functionally substituted cyclopropane carboxylic acids, which show promise as effective inhibitors of ethylene biosynthesis, is crucial for regulating the plant cycle and preserving the quality of fruits and vegetables. Objectives: This research focused on the in-silico studies aimed at developing a universal and affordable methodology for synthesizing new analogs of ACC and assessing their modulating activity on ethylene biosynthesis in plants. The findings from this in silico research provide a foundation for the upcoming in vitro studies. Results: The elaborated efficient catalytic system [Cu(I) salt/amine/DMSO] enabled the synthesis of model compounds under mild conditions, resulting in increasing yields up to quantitative levels. For bioactivity preliminary assessment we performed in silico research of newly synthesized (E)-2-phenyl-1-chlorocyclopropane-1-carboxylic acid and drug-design an appropriate 1-amino-derivative as the inhibitor of 1-aminocyclopropane-1-carboxylate oxidase 2 (ACO2) of Arabidopsis thaliana. Docking results showed certain advantages of the newly synthesized compound in comparison to well-known inhibitors of ethylene biosynthesis. Conclusions: The recommended synthetic technology has increased efficiency in yield quantification. In silico studies, a high affinity for ACO2 has been demonstrated. The synthesized compounds exhibit superior characteristics compared to widely used market preparations for regulating ethylene biosynthesis. More detailed comparative in vitro studies are planned. Keywords: plant growth regulation, cyclopropane carboxylic acids, ethylene biosynthesis inhibitors, molecular docking, atom transfer radical addition (ATRA), Cu(I) Complex catalyst.

DNA-Compatible Photoredox Atom Transfer Radical Addition to Alkynes with Thiosulfonates

DNA-Compatible Photoredox Atom Transfer Radical Addition to Alkynes with Thiosulfonates

Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic Insights and Rational Design to Overcome Limitations.

Herein, we report mechanistic investigations into the Cu-catalyzed three-component carboamination of alkenes with α-halo carbonyls and aryl amines via an oxocarbenium intermediate. Monitoring the reaction reveals the formation of transient atom transfer radical addition (ATRA) intermediates with both electron-neutral and deficient vinyl arenes as well as unactivated alkenes. Based on our experimental studies and density functional theory calculations, the oxocarbenium is generated through atom transfer and subsequent intramolecular substitution. Further, mechanistic factors that dictate the regioselectivity of the nucleophilic attack onto the oxocarbenium to afford the γ-amino ester, γ-iminolactone, or γ-lactone are discussed. A strategy to overcome scope limitation with respect to unactivated alkenes is developed using the mechanistic insights gained herein. Finally, we demonstrate that under modified conditions, our Cu catalyst enables the ATRA reaction between a variety of alkyl halides and vinyl arenes/α-olefins, and we present a one-pot, two-step carbofunctionalization with an array of nucleophiles through ATRA/SN2.

Visible Light‐Induced Cyanomethyl Radical Triggered Cascade Cyclization of Phenyl‐Linked 1,6‐Enynes with a‐Halogenated Acetonitriles

Photo‐promoted cyanomethyl radical procedures for the preparation of 2,3‐dihydro‐1H‐indenes and 2,8‐dihydrocyclopenta[a]indenes from phenyl‐linked 1,6‐enynes with α‐halogenated acetonitriles are reported. The iodocyanomethylation/cyclization is performed via an atom‐transfer radical addition (ATRA) strategy under photocatalyst‐ and oxidant‐free conditions. In particular, the photoinduced cyanomethylative cascade bicyclization is carried out under the fac‐Ir(ppy)3/Na2CO3 catalystic symtem and visible light irradiation. These methods offer a one‐step and atom‐economical access to diverse cyano‐group containing five‐membered rings with broad substrate scope and high selectivity. A plausible reaction mechanism is also proposed.

Photocatalyzed atom transfer radical addition: Halo-difluoroalkylation of N-allylamides

A method for the halo-difluoroalkylation of N-allylamides using XCF2CO2Et as the halo-difluoroalkylation reagent is disclosed. This strategy combines single electron transfer with atom transfer radical addition, using 1 mol% of the photocatalyst fac-Ir(ppy)3 without any additives to achieve conversions with high atom economy. The reaction proceeds smoothly in the presence of different active functional groups and is obtained in moderate to good yields.

Access to β‐Lactam Sulfonamides from Sulfamoyl Chlorides via Photoredox Catalyzed C−S Bond Formation

AbstractSulfonyl chlorides are a synthetically attractive source of sulfonyl radicals in photoredox catalysis and are useful precursors in the synthesis of sulfones. Sulfamoyl chlorides, on the other hand, remain poorly represented despite their similar potential. In this study, N‐chlorosulfonylated β‐lactams were prepared from readily available precursors and utilized in an atom transfer radical addition (ATRA) reaction with a variety of olefins, producing β‐lactam sulfonamides in 49–95% yields. β‐Lactams fused to a dihydro‐1,2‐thiazine ring which closely resemble carbacephems, a widely used class of antibiotics, were also synthesized by an intra‐molecular ATRA reaction. This methodology enables the preparation of β‐lactam sulfonamides, a class of compounds that are of great interest in pharmacology.

Synthesis of 2,3-Dihydrobenzofurans via a Photochemical Gold-Mediated Atom Transfer Radical Addition Reaction.

A light-mediated cyclization reaction initiated by an atom transfer radical addition (ATRA) of haloalkanes onto alkenes was exploited for the synthesis of functionalized dihydrobenzofurans. Initial investigation indicated that the dimeric gold catalyst [Au2(μ-dppm)2Cl2] can effectively be used for intermolecular ATRA reactions. Further, the reactivity was applied in a cascade-like cyclization for the preparation of dihydrobenzofuran derivatives. With the presented photochemical approach, the functionalization can be achieved directly from ortho-allylphenols in yields of up to 96% under mild conditions.

Ketyl Radical Enabled Synthesis of Oxetanes

AbstractOxetanes, 4-membered oxygen-containing heterocycles, were identified to have pharmaceutical applications after the discovery of the chemotherapeutic drug taxol (Paclitaxel) and its analogues. Furthermore, oxetanes have been identified as bioisosteres for several common functional groups and are present in a number of natural products. However, oxetanes are one of the least common oxygen-containing heterocycles in active pharmaceutical ingredients on the market, which can be attributed, in part, due to challenges with their synthesis. Previous strategies rely on nucleophilic substitutions or [2+2]-cycloadditions, but are limited by the stepwise buildup of starting material and limitations in scope resulting from requirements for activated substrates. To address these limitations, we envisioned activating simple carbonyls to their corresponding α-oxy iodides to promote ketyl radical formation. These radicals can then undergo atom-transfer radical addition with alkenes followed by one-pot nucleophilic substitution to produce oxetanes. Herein, we present a proof-of-principle of this strategy in which fluoroalkyl carbonyls are successfully converted into the corresponding fluoroalkyl oxetanes.

Halogen-Bonding-Enabled Photoinduced Atom Transfer Radical Addition/Cyclization Reaction Leading to Tricyclic Heterocycles.

Atom transfer radical addition (ATRA) reactions are crucial for the dual functionalization of unsaturated hydrocarbons. Radical generation, pivotal in ATRA, has seen advancements from thermal to photochemical methods. Recent focus on halogen-bonding-based radical generation, including our group's innovative photochemical approach, offers cost-effective alternatives to transition-metal-dependent photocatalysts. This eliminates the need for high-energy UV light, enhancing the efficiency with noncovalent interactions.

Macrocyclic Copper(II) Complexes as Catalysts for Electrochemically Mediated Atom Transfer.

Copper-catalyzed electrochemical atom transfer radical addition (eATRA) is a new method for the creation of new C-C bonds under mild conditions. In this work, we have explored the reactivity of an analogous series of N4 macrocyclic CuII complexes as eATRA precatalysts, which are primed by reduction to their monovalent oxidation state. These complexes were fully characterized structurally, spectroscopically, and electrochemically. A spectrum of radical activation reactivity was found across the series [CuI(Me4cyclen)(NCMe)]+ (Me4cyclen = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane), [CuI(Me4cyclam)(NCMe)]+ (Me4cyclam = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), and [CuI(Me2py2clen)(NCMe)]+ (Me2py2clen = 3,7-dimethyl-3,7-diaza-1,5(2,6)-dipyridinacyclo-octaphane). The rate of radical production by [Cu(Me2py2clen)(NCMe)]+ was modest, but rapid radical capture to form the organocopper complex [CuI(Me2py2clen)(CH2CN)] led to a dramatic acceleration in catalysis, greater than seen in any comparable Cu complex, but this led to rapid radical self-termination instead of radical addition.