Stoichiometric Oxidant Research Articles

Copper‐Catalyzed Dearomative Cyclization of Indolyl Ynamides for Synthesis of Pentacyclic Spiroindolines

The dearomatization of indoles with ynamides is a convenient access towards polycyclic spiroindolines, which can be initiated by α‐ and β‐additions of ynamides. Currently, the related β‐addition initiated dearomative cyclization requires noble‐metal catalyst or stoichiometric oxidant. Herein, we report a copper‐catalyzed dearomative cyclization of aryl‐substituted indolyl ynamides through regioselective β‐addition onto ynamides, providing pentacyclic spiroindolines in 81–97% yields with >25:1 diastereoselectivities. Moreover, preliminary success has been obtained for the catalytic enantioselective dearomative cyclization.

Electrochemical Gold Redox Catalysis

AbstractThe high oxidation potential of Au(I)/Au(III) redox couple renders the development of gold‐catalyzed cross‐coupling reactions highly challenging. In the pursuit of Au(I)/Au(III) redox catalysis, various strategies, such as the use of stoichiometric oxidants, merged gold/photoredox systems, or ligand‐enabled approaches, have been adopted to achieve the oxidation of Au(I) to Au(III) complexes. Recently, electrochemical anodic oxidation‐based gold redox catalysis has emerged as a new technique to facilitate gold‐catalyzed cross‐coupling reactions. This concept article provides a succinct overview of electrochemical gold redox catalysis, highlighting the challenges and potential future developments.

Access to Diverse Carbonyl Compounds by Catalyst-Free and Photoinduced Aerobic Cleavage of C=N Bonds.

Functional group interconversion is of great significance in organic synthesis. However, aerobic cleavage of C=N bonds to access carbonyl compounds still suffered from some limitations such as harsh reaction conditions, stoichiometric oxidants, poor substrate scope and use of toxic reagents. Herein, we report a catalyst-free and photo-induced aerobic cleavage of C=N bonds to afford diverse carbonyl compounds using oxygen from air as green oxidant. This mild methodology permits N-tosylhydrazones converted into the corresponding carbonyl compounds including ketones, aldehydes and carboxylic acids, showing broad functional group tolerance and compatibility. Moreover, the gram-scale reaction and post-modification of complicated molecules proved the applicability and efficiency of this strategy. Finally, a plausible mechanism was proposed based on spectroscopic investigations and detailed mechanistic studies.

Photoredox Catalyzed Tandem Denitrogenative [4 + 2] Annulation of 1,2,3-Benzotriazin-4(3H)-ones with Terminal Olefins.

The dihydroisoquinolones skeleton is ubiquitous in natural products and biological molecules. Reported strategies for constructing dihydroisoquinolones usually require noble metal catalysts or stoichiometric oxidants, which limit their wide applications. Herein, we developed a photoredox catalyzed tandem denitrogenative [4 + 2] annulation reaction of 1,2,3-benzotriazin-4(3H)-ones with terminal olefins. A variety of dihydroisoquinolones can be accessed in moderate to excellent yield. This protocol features high atom-economy, mild reaction conditions, and is external oxidant-free, enabling the synthesis of various substituted dihydroisoquinolones.

An Electrosynthesis of 1,3,4-Oxadiazoles from N-Acyl Hydrazones.

The 1,3,4-oxadiazole is a widely encountered motif in the areas of pharmaceuticals, materials, and agrochemicals. This work has established a mild, mediated electrochemical synthesis of 2,5-disubstituted 1,3,4-oxadiazoles from N-acyl hydrazones. Using DABCO as the optimal redox mediator has enabled a mild oxidative cyclisation, without recourse to stoichiometric oxidants. In contrast to previous methods, this indirect electrochemical oxidation has enabled a broad range of substrates to be accessed, with yields of up to 83%, and on gram scale. The simplicity of the method has been further demonstrated by the development of a one-pot procedure, directly transforming readily available aldehydes and hydrazides into valuable heterocycles.

A facile access to aliphatic trifluoromethyl ketones via photocatalyzed cross-coupling of bromotrifluoroacetone and alkenes.

Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation (λ > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern-Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.

Light‐Induced Direct Decarboxylative Functionalization of Aromatic Carboxylic Acids

Aryl radicals are important intermediates in organic synthesis. The generation of these reactive species via direct decarboxylation of inexpensive and readily available aromatic carboxylic acids is an attractive goal. However, such a process intrinsically exhibits high energy barriers to overcome, which in consequence usually require precious metal catalysis, stoichiometric oxidants and harsh conditions, suffering from limitations such as poor functional group tolerance and low atom economy. In recent years, visible‐light‐induced photochemical reactions have provided new approaches to address this challenge. Three major strategies have been introduced in this emerging field: 1) one‐pot in‐situ activation of benzoic acids to generate intermediates such as benzoyl hypobromites or hypoiodites; 2) the use of specialized photocatalysts like biphenyl/1,4‐dicyanobenzene to promote decarboxylation through photo‐induced electron transfer or charge transfer processes; 3) photo‐induced LMCT (Ligand‐to‐Metal Charge Transfer) strategy where copper or iron salts coordinate to the carboxylate anion and generate aromatic radicals upon visible light excitation. On the basis of these three strategies, this review will systematically summarize the development of visible‐light‐induced direct decarboxylative functionalization of aromatic carboxylic acids, focusing on the reaction mechanism and substrate scope, and discuss their prospects in organic synthesis.

Electrochemical Dehydrogenative [3 + 2]/[5 + 2] Annulation of N-Arylacrylamides with γ,σ-Unsaturated Malonates via Direct C(sp3)-H/C(sp2)-H Functionalization.

Herein, we introduce an electrochemical dehydrogenative [3 + 2]/[5 + 2] annulation of easily available N-arylacrylamides with γ,σ-unsaturated malonates through C(sp3)-H/C(sp2)-H functionalization. The employment of inexpensive ferrocene as the redox catalyst allows access to diverse benzo[b]azepin-2-ones in moderate to excellent yields without stoichiometric oxidants. This protocol features broad substrate scope and excellent selectivity, and mechanistic studies indicated that the reaction proceeded through the oxidation of a C(sp3)-H bond to generate an alkyl radical, radical addition across the C═C bond, [3 + 2]/[5 + 2] annulations, and C(sp2)-H functionalization cascades.

DDQ catalyzed oxidative lactonization of indole-3-butyric acids.

Benzylic C-H bonds next to electron rich aromatic rings are susceptible to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) promoted functionalization. In this work benzylic carbocations formed in this manner are trapped by a pendant carboxylic acid to form a lactone. Indole-3-butyric acids are especially good substrates for the reaction. The lactonization functions well with catalytic amounts of DDQ combined with MnO2 as the stoichiometric oxidant. This cyclization proceeds with a number of indole-3-butyric acids, and yields were generally good as long as the indole was electron rich and free of bulky substituents near the reacting benzylic carbon. Indole-3-butyric acids functionalized with electron withdrawing groups tend to give more moderate yields. Other aromatic substrates also participate as long as the aromatic ring is functionalized with electron donating groups.

A Mechanistic Study on Iron-Based Styrene Aziridination: Understanding Epoxidation via Nitrene Hydrolysis.

Transition-metal-catalyzed nitrene transfer reactions are typically performed in organic solvents under inert and anhydrous conditions due to the involved air and water-sensitive nature of reactive intermediates. Overall, this study provides insights into the iron-based ([FeII(PBI)3](CF3SO3)2 (1), where PBI = 2-(2-pyridyl)benzimidazole), catalytic and stoichiometric aziridination of styrenes using PhINTs ([(N-tosylimino)iodo]benzene), highlighting the importance of reaction conditions including the effects of the solvent, co-ligands (para-substituted pyridines), and substrate substituents on the product yields, selectivity, and reaction kinetics. The aziridination reactions with 1/PhINTs showed higher conversion than epoxidation with 1/PhIO (iodosobenzene). However, the reaction with PhINTs was less selective and yielded more products, including styrene oxide, benzaldehyde, and 2-phenyl-1-tosylaziridine. Therefore, the main aim of this study was to investigate the potential role of water in the formation of oxygen-containing by-products during radical-type nitrene transfer catalysis. During the catalytic tests, a lower yield was obtained in a protic solvent (trifluoroethanol) than in acetonitrile. In the case of the catalytic oxidation of para-substituted styrenes containing electron-donating groups, higher yield, TON, and TOF were achieved than those with electron-withdrawing groups. Pseudo-first-order kinetics were observed for the stoichiometric oxidation, and the second-order rate constants (k2 = 7.16 × 10-3 M-1 s-1 in MeCN, 2.58 × 10-3 M-1 s-1 in CF3CH2OH) of the reaction were determined. The linear free energy relationships between the relative reaction rates (logkrel) and the total substituent effect (TE, 4R-PhCHCH2) parameters with slopes of 1.48 (MeCN) and 1.89 (CF3CH2OH) suggest that the stoichiometric aziridination of styrenes can be described through the formation of a radical intermediate in the rate-determining step. Styrene oxide formation during aqueous styrene aziridination most likely results from oxygen atom transfer via in situ iron oxo/oxyl radical complexes, which are formed through the hydrolysis of [FeIII(N•Ts)] under experimental conditions.

Palladium‐Catalyzed Aerobic γ‐C(sp3)−H Lactamization Using a NOx‐based Redox Mediator

AbstractHerein, we report a Pd‐catalyzed aerobic lactamization of unactivated γ‐C(sp3)−H bonds of aliphatic carboxylic acids and amino acids derivatives. The utilization of Pd(OAc)2 as a catalyst, along with catalytic AgNO2 as an electron transfer mediator, circumvents the need for stoichiometric oxidants and demonstrates significant practicality.

TBN as Organic Redox Cocatalyst for Oxidative Tiffeneau-Demjanov-Type Rearrangement Using O2 as Sole Oxidant.

The Tiffeneau-Demjanov-type rearrangement is a ring-expansion reaction involving the cationic rearrangement of cyclic alcohols. The carbocation intermediates can be generated in situ via various means, including Wacker oxidation. In near recent reports on the reinvestiagtions by Wahl et al. (Sietmann, J.; Tenberge, M.; Wahl, J. M. Wacker Oxidation of Methylenecyclobutanes: Scope and Selectivity in an Unusual Setting. Angew. Chem., Int. Ed. 2023, 62, e202215381) and Zhu et al. (Feng, Q.; Wang, Q.; Zhu, J.-P. Oxidative Rearrangement of 1,1-Disubstituted Alkenes to Ketones. Science 2023, 379, 1363-1368), stoichiometric oxidants were involved. In this work, we report the Tiffeneau-Demjanov-type rearrangement can be smoothly promoted by the Pd-TBN cocatalyzed aerobic Wacker oxidation using molecular oxygen as the sole oxidant. tert-Butanol is essential for achieving high yields. Since the first report by Grigg et al. in 1977 (Boontanonda, P.; Grigg, R. J. Palladium (II)-Catalysed Ring Expansion of Methylenecyclobutanes and Related Systems. J. Chem. Soc. Chem. Commun. 1977, 17, 583-584), the five-decade journey of Pd-catalyzed Tiffeneau-Demjanov-type rearrangement returns to the aerobic again.

Electrochemical Oxidation Enables Radical Dearomative Spiroannulation to 2H-Spiro[benzofuran-3,9'-fluoren]-2-one.

Developing pragmatic strategies for accessing functional benzofuran-2-ones from 3-([1,1'-biphenyl]-2-yl)benzofuran remains an enduring challenge. Herein, we have achieved a highly discriminating electrochemical oxidative dearomative spiroannulation of 3-([1,1'-biphenyl]-2-yl)benzofuran, culminating in the synthesis of 2H-spiro[benzofuran-3,9'-fluoren]-2-one derivatives. By harnessing the electrophilic intermediates of benzofuryl radical cations supported by DFT calculations, we attain exceptional regioselectivity while eliminating the need for stoichiometric oxidants. Mechanistic investigations reveal a sequence of events involving the benzofuran radical cation, encompassing the capture of H2O, nucleophilic arene attack, and subsequent deprotonation, ultimately yielding the final benzofuran-2-ones.

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis

AbstractAryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C−P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition‐metal catalyzed cross‐coupling reactions. Furthermore, we extended this methodology to form aryl C−Se, C−Te, and C−S bonds, showcasing its versatility and potential in bond formation processes.

Electrochemical Generation of Aryl Radicals from Organoboron Reagents Enabled by Pulsed Electrosynthesis.

Aryl radicals play a pivotal role as reactive intermediates in chemical synthesis, commonly arising from aryl halides and aryl diazo compounds. Expanding the repertoire of sources for aryl radical generation to include abundant and stable organoboron reagents would significantly advance radical chemistry and broaden their reactivity profile. While traditional approaches utilize stoichiometric oxidants or photocatalysis to generate aryl radicals from these reagents, electrochemical conditions have been largely underexplored. Through rigorous mechanistic investigations, we identified fundamental challenges hindering aryl radical generation. In addition to the high oxidation potentials of aromatic organoboron compounds, electrode passivation through radical grafting, homocoupling of aryl radicals, and decomposition issues were identified. We demonstrate that pulsed electrosynthesis enables selective and efficient aryl radical generation by mitigating the fundamental challenges. Our discoveries facilitated the development of the first electrochemical conversion of aryl potassium trifluoroborate salts into aryl C-P bonds. This sustainable and straightforward oxidative electrochemical approach exhibited a broad substrate scope, accommodating various heterocycles and aryl chlorides, typical substrates in transition-metal catalyzed cross-coupling reactions. Furthermore, we extended this methodology to form aryl C-Se, C-Te, and C-S bonds, showcasing its versatility and potential in bond formation processes.

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.

Pyrazine-Coordinated Dinuclear and Mononuclear Ruthenium Complexes Formed via the Conversion of the Triply Chlorido-Bridged Diruthenium(II) Complex.

The pyrazine-coordinated dinuclear and mononuclear ruthenium complexes were synthesized through the framework conversion reactions of the triply chlorido-bridged diruthenium(II) complex [{RuII,II(bbpma)}2(μ-Cl)3]+ (bbpma; benzylbis(2-pyridylmethyl)amine, [1]+) in the presence of pyrazine, which could function as the simple molecular multinucleation ligand of metal compounds. A reduction reaction of fac-[RuIIICl3(bbpma)] with zinc in the presence of hydrochloric acid afforded [1]+ in solution, and the following addition of pyrazine (1 equiv) in the solution led to the formation of a singly pyrazine (pz)-bridged diruthenium complex, [{RuII,II(μ-Cl2ZnCl2)(bbpma)}2(μ-pz)] ([2(II,II)(ZnCl2)2]). The stoichiometric two-electron oxidation of [2(II,II)(ZnCl2)2] was successfully proceeded, and a Ru(III)-Ru(III) species, [{RuIII,IIICl2(bbpma)}2(μ-pz)](PF6)2 ([III,III](PF6)2), was isolated. The reaction of [1]+ with excess amounts of pyrazine without hydrochloric acid afforded mononuclear Ru(III) and Ru(II) complexes containing one or two pyrazine, fac-[RuClm(pz)3-m(bbpma)]+ (m = 2; [3]+; m = 1; [4]+). The details of the electrochemical and spectroscopic properties of [1]+-[4]+ in organic and aqueous solutions were discussed.

Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Iron-Catalyzed Oxidative Rearrangement of Cyclopropanone Hemiaminals: General Access to Pyrroloindolones from Indoles.

A concise synthetic approach to medicinally relevant pyrroloindolones and related fused heterocycles is reported via the diastereoselective N-addition of unprotected indoles to readily accessible cyclopropanone equivalents. The resulting stable hemiaminals are shown to smoothly rearrange to pyrroloindolones in mild conditions using Fe(III) catalysis in the presence of inexpensive ammonium persulfate as a stoichiometric oxidant. Experimental evidence points toward the formation of a β-carboxylic radical intermediate prone to cyclization and oxidative rearomatization as the operative mechanistic pathway.

Electrochemical Oxidative 1,2-Dithiocyanation: Access to Functionalized Alkenes and Alkynes.

Reported herein is the 1,2-dithiocyanation of alkenes and alkynes via an efficient and facile electrochemical method. This approach not only showed a broad substrate scope and good functional-group compatibility but also avoided stoichiometric oxidants. Different from previous reports, various internal alkynes could be tolerated to provide tetra-substituted alkenes. Further gram-scale-up experiments and synthetic transformation demonstrated a potential application in organic synthesis. This process underwent a radical pathway, as evidenced by our mechanistic studies.