N-centered Radicals Research Articles

Photoredox-Catalyzed Tandem Cyclization of Enaminones with N-Sulfonylaminopyridinium Salts toward the Synthesis of 3-Sulfonaminated Chromones.

A photoredox-catalyzed intermolecular tandem sulfonamination/cyclization of enaminones was realized by using N-aminopyridinium salts as the sulfonaminated reagents without transition-metal catalysts or bases. The reaction exhibits a broad scope and good functional group tolerance, good yields, and regioselectivity. Preliminary mechanistic studies support the radical property of the reaction and the involvement of N-centered radical intermediates.

Copper-Catalyzed Radical Allene C(sp2 )-H Cyanation.

While the hydrogen atom abstraction (HAA) from C(sp3 )-H bond has been well explored, the radical-mediated chemo- and regio-selective functionalization of allenic C(sp2 )-H bond via direct HAA from C(sp2 )-H bond of allene remains an unsolved challenge in synthetic chemistry. This is primarily due to inherent challenges with addition of radical intermediates to allenes, regioselectivity of HAA process, instability of allenyl radical toward propargyl radical et al. Herein, we report a copper catalyzed allenic C(sp2 )-H cyanation of an array of tri- and di-substituted allenes with exceptional site-selectivity, while mono-substituted allene was successfully cyanated, albeit with a low yield. In the developed strategy, steric N-fluoro-N-alkylsulfonamide, serving as precursor of hydrogen atom abstractor, plays a crucial role in achieving the desired regioselectivity and avoiding addition of N-centered radical to allene.

Regioselective Synthesis of Unsymmetrical Vicinal Diamines via Azidoimination of Alkenes with TMSN3 and Ketimines.

2-Azidoimines are versatile precursors to value-added vicinal unsymmetrical diamines, which are among the most common motifs in biologically active compounds. Herein, we report their operationally simple synthesis through a highly regioselective intermolecular azidoamination of olefins under metal-free conditions. The approach proceeded through azide and iminyl, two differentiated N-centered radicals. The synthetic potential of the protocols was further established via the condensation/amination sequential cascade and chemoselective, orthogonal transformations to access vicinal primary diamines.

Competition between C-C and C-H Bond Fluorination: A Continuum of Electron Transfer and Hydrogen Atom Transfer Mechanisms.

In 2015, we reported a photochemical method for directed C-C bond cleavage/radical fluorination of relatively unstrained cyclic acetals using Selectfluor and catalytic 9-fluorenone. Herein, we provide a detailed mechanistic study of this reaction, during which it was discovered that the key electron transfer step proceeds through substrate oxidation from a Selectfluor-derived N-centered radical intermediate (rather than through initially suspected photoinduced electron transfer). This finding led to proof of concept for two new methodologies, demonstrating that unstrained C-C bond fluorination can also be achieved under chemical and electrochemical conditions. Moreover, as C-C and C-H bond fluorination reactions are both theoretically possible on 2-aryl-cycloalkanone acetals and would involve the same reactive intermediate, we studied the competition between single-electron transfer (SET) and apparent hydrogen-atom transfer (HAT) pathways in acetal fluorination reactions using density functional theory. Finally, these analyses were applied more broadly to other classes of C-H and C-C bond fluorination reactions developed over the past decade, addressing the feasibility of SET processes masquerading as HAT in C-H fluorination literature.

Elucidation of Underlying Reactivities of Alternating Current Electrosynthesis by Time-resolved Mapping of Short-lived Reactive Intermediates.

Alternating current (AC) electrolysis is an emerging field in synthetic chemistry, while its mechanistic studies are challenged by the effective characterization of the elusive intermediate processes. Herein, we develop an operando electrochemical mass spectrometry platform that allows time-resolved mapping of stepwise electrosynthetic reactive intermediates in both direct current and alternating current modes. By dissecting the key intermediate processes of electrochemical functionalization of arylamines, the unique reactivities of AC electrosynthesis, including minimizing the over-oxidation/reduction through the inverse process, and enabling effective reaction of short-lived intermediates generated by oxidation and reduction in paired electrolysis, were evidenced and verified. Notably, the controlled kinetics of reactive N-centered radical intermediates in multi-step sequential AC electrosynthesis to minimize the competing reactions was discovered. Overall, this work provides direct evidence for the mechanism of AC electrolysis, and clarifies the underlying reasons for its high efficiency, which will benefit the rational design of AC electrosynthetic reactions.

Copper-Catalyzed Reaction of N-Monosubstituted Hydrazones with CBr4: Unexpected Fragmentation and Mechanistic Study

The copper catalyzed reaction of N-monosubstituted hydrazones with carbon tetrabromide leads to formation of expected dibromodiazadienes and unexpected dibromostyrenes. The experimental and theoretical study of the reaction revealed a key role of N-centered radicals, which can eliminate aryl radicals to form the corresponding dibromostyrenes. Alternatively, the oxidation of intermediate N-centered radicals by Cu(II) results in the corresponding diazadienes. These two reaction pathways are competitive directions of the reaction. Consequently, the reaction can be useful for the synthesis of both dibromostyrenes and rare dibromodiazadienes.

Molecular mechanism for the activation of the potent hepatotoxin acetylhydrazine: Identification of the initial N-centered radical and the secondary C-centered radical intermediates.

Acetylhydrazine (AcHZ), a major human metabolite of the widely-used anti-tuberculosis drug isoniazid (INH), was considered to be responsible for its serious hepatotoxicity and potentially fatal liver injury. It has been proposed that reactive radical species produced from further metabolic activation of AcHZ might be responsible for its hepatotoxicity. However, the exact nature of such radical species remains not clear. Through complementary applications of ESR spin-trapping and HPLC/MS methods, here we show that the initial N-centered radical intermediate can be detected and identified from AcHZ activated by transition metal ions (Mn(III)Acetate and Mn(III) pyrophosphate) and myeloperoxidase. The exact location of the radical was found to be at the distal-nitrogen of the hydrazine group by 15N-isotope-labeling techniques via using 15N-labeled AcHZ we synthesized. Additionally, the secondary C-centered radical was identified unequivocally as the reactive acetyl radical by complementary applications of ESR spin-trapping and persistent radical TEMPO trapping coupled with HPLC/MS analysis. This study represents the first detection and unequivocal identification of the initial N-centered radical and its exact location, as well as the reactive secondary acetyl radical. These findings should provide new perspectives on the molecular mechanism of AcHZ activation, which may have potential biomedical and toxicological significance for future research on the mechanism of INH-induced hepatotoxicity.

Efficient and Selective Photogeneration of Stable N-Centered Radicals via Controllable Charge Carrier Imbalance in Cesium Lead Halide Nanocrystals.

Despite the versatility of semiconductor nanocrystals (NCs) in photoinduced chemical processes, the generation of stable radicals has been more challenging due to reverse charge transfer or charge recombination even in the presence of sacrificial charge acceptors. Here, we show that cesium lead halide (CsPbX3) NCs can selectively photogenerate either aminium or aminyl radicals from amines, taking advantage of the controllable imbalance of the electron and hole populations achieved by varying the solvent composition. Using dihalomethane as the solvent, irreversible removal of the electrons from CsPbX3 NCs enabled by the photoinduced halide exchange between the NCs and the dihalomethane resulted in efficient oxidative generation of the aminium radical. In the absence of dihalomethane in solvent, the availability of both electrons and holes resulted in the production of an aminyl radical via sequential hole transfer and reductive N-H bond dissociation. The negative charge of the halide ions on the NC's lattice surface appears to facilitate the aminyl radical production, competing favorably with the reversible charge transfer reverting to the reactant.

EnT-Mediated Amino-Sulfonylation of Alkenes with Bifunctional Sulfonamides: Access to β-Amino Sulfone Derivatives.

β-Amino sulfones are commonly found structural motifs in biologically active compounds. Herein, we report a direct photocatalyzed amino-sulfonylation reaction of alkenes for the efficicient production of important compounds by simple hydrolysis without the need for additional oxidants and reductants. In this transformation, the sulfonamides worked as bifunctional reagents, simultaneously generating sulfonyl radicals and N-centered radicals which were added to alkene in a highly atom-economical fashion with high regioselectivity and diastereoselectivity. This approach showed high functional group tolerance and compatibility, facilitating the late-stage modification of some bioactive alkenes and sulfonamide molecules, thereby expanding the biologically relevant chemical space. Scaling up this reaction led to an efficient green synthesis of apremilast, one of the best-selling pharmceuticals, demonstrating the synthetic utility of the applied method. Moreover, mechanistic investigations suggest that an energy transfer (EnT) process was in operation.

Evaluating the Effectiveness of Tethered Bis(urazolyl) Diradicals as Molecular Building Blocks for Dynamic Covalent Chemistry.

Dynamic covalent chemistry (DCvC) is a powerful means by which to rapidly prepare complex structures from simple molecular building blocks. Effective DCvC behavior is contingent upon the reversibility of covalent bond formation. Stabilized radical species, therefore, have been effectively used for these applications. In earlier work we demonstrated that properly substituted 1-arylurazolyl radicals showed promise as oxygen-insensitive heterocyclic N-centered radicals with a propensity for reversible bond formation. In this work we have synthesized several tethered bis(urazolyl) diradicals, varying by the type and length of connectivity between the urazole rings, and tested them for DCvC behavior. We have found that when the two aryl rings to which the urazolyl radical sites are attached are tethered by a chain of five or more carbons, equilibrium mixtures of monomeric and dimeric species are formed by N-N bond formation between two radical sites. DCvC behavior is observed that is sensitive to changes in temperature, concentration, and (to a lesser extent) solvent. In general, the dimer species is favored at lower temperatures and higher concentrations.

Fluoroamide-Directed Regiodivergent C-Alkylation of Nitroalkanes.

Herein, by exploiting different activation modes of fluoroamides, we achieved α- and δ-C(sp3)-H alkylation of nitroalkanes with switchable regioselectivity. Cu catalysis enabled the interception of a distal C-centered radical by a N-centered radical to couple nitroalkanes and unactivated δ-C-H bonds. In addition, imines generated in situ by fluoroamides were trapped by nitroalkanes to realize the α-C-H alkylation of amides. Both of those scalable protocols have broad substrate scopes and good functional group tolerance.

Dual-Role Disulfide-Catalyzed Intramolecular Hydroamination through N–H Activation

Key words N-centered radicals - disulfide catalysis - pyrrolidines - hydroamination

Photoinduced Disulfide-Catalyzed Intramolecular Anti-Markovnikov Hydroamination through in Situ N-S Species.

The photoinduced anti-Markovnikov hydroamination of olefins typically required photocatalysts with a high oxidative ability to initiate the single-electron process. Herein, we alternatively utilize bis(2,4,6-triisopropylphenyl) disulfide, an inexpensive reagent with relatively low oxidative ability, as a photo and hydrogen atom transfer catalyst to achieve intramolecular hydroamination. The mechanistic studies as well as the DFT calculations are consistent with a novel process involving N-centered radical generation through the homolysis of the in situ formed N-S species and subsequent cyclization. An array of diverse nitrogen-containing cycles could be obtained.

Photoinduced Copper-Catalyzed C(sp3)-P Bond Formation by Coupling of Secondary Phosphines with N-(Acyloxy)phthalimides and N-Fluorocarboxamides.

A photoinduced copper-catalyzed C(sp3)-P bond formation has been developed by using N-(acyloxy)phthalimides as radical precursors and secondary phosphine boranes as coupling partners. A variety of alkyl carboxylic acid derivatives can be readily transformed into the corresponding phosphines with high reaction efficiency and structural diversity. Besides, utilizing the 1,5-HAT of the N-centered radical process, the δ C(sp3)-H bond can be coupled with secondary phosphines, which provides a novel method for the regioselective formation of C(sp3)-P bonds.

1-[2,6-Dimethyl-4-(pent-4-yn-1-yloxy)phenyl]-4-phenyl-1,2,4-triazolidine-3,5-dione

Urazolyl radicals are a class of persistent nitrogen-centered radicals. In a previous work, we successfully formed self-assembled monolayers of substituted urazolyl radicals on gold surfaces. To extend the scope of these investigations, we sought to form a self-assembled monolayer using a urazolyl radical species that we knew existed predominantly in the dimerized N-N form instead of existing predominantly as free N-centered radical species, as had previously been investigated. We successfully synthesized the precursor urazole compound needed to generate the desired urazolyl radical, and completely characterized its structure. Most importantly, it was determined that the alkyne functional group that is needed to adhere to the gold surface remained intact. Unfortunately, however, we only obtained ambiguous results from attempts at forming self-assembled monolayers of this species on gold.

Regioselective C(sp2)-H imidation of arenes by redox neutral visible-light photocatalysis.

We report herein a redox neutral visible light-induced regioselective C(sp2)-H imidation of electron-rich arenes and heteroarenes using conceptually designed redox-active 1 as a source of the N-centered imidyl radical. Structurally diverse aromatic imides were obtained in moderate to good yields. This methodology has been successfully employed for the late stage imidation of complex molecules and has also been applied towards the formal total synthesis of the marine natural products carpatamides A, B and D. It has further been shown that the generated imides can easily be converted to the corresponding anilines in situ directly.

1-(4-{[3,5-bis({[3,5-Dimethyl-4-(4-methyl-3,5-dioxo-1,2,4-triazolidin-1-yl)-phenoxy]methyl})phenyl]methoxy}-2,6-dimethyl-phenyl)-4-methyl-1,2,4-triazolidine-3,5-dione

Appropriately substituted N-centered urazolyl radicals are capable of generating interesting cage-like structures upon forming N-N bonds. The radicals are generated by the oxidation of the corresponding NH urazole precursors. We synthesized a triurazole precursor that we hoped would dimerize through the formation of three N-N bonds to afford a large molecular cage. Unfortunately, the attempts at the oxidation of the urazoles to form urazolyl radicals instead only lead to random oligomerization, forming plastic-like materials rather than the desired cages.

Theoretical Study of the Atmospheric Chemistry of Methane Sulfonamide Initiated by OH Radicals and the CH3S(O)2N•H + 3O2 Reaction

In the present work, we have revisited the reaction mechanism of the atmospheric oxidation of methane sulfonamide (CH3S(═O)2NH2; MSAM) initiated by hydroxyl (OH) radicals in the gas phase. The present reaction has been studied for the first time using quantum calculations combined with chemical kinetic modeling. The abstraction of an H-atom from the -NH2 group of MSAM by OH radical to form the products CH3S(═O)2N•H + H2O was found to be a major path with a barrier height of ∼2.3 kcal mol-1 relative to the energy of the separated MSAM + •OH starting reactants. This study is the first to identify the reaction of MSAM with •OH as exclusively generating N-centered MSAM radicals. The chemical kinetic calculations for various paths associated with the MSAM + •OH reaction were performed under pre-equilibrium approximation conditions using canonical variational transition state theory, employing the small curvature tunneling method in the temperature range of 200-400 K. A recent experimental study reported that OH radical-mediated degradation of MSAM proceeds via the formation of the C-centered MSAM radical (•CH2S(═O)2NH2) product. However, the energetics and rate coefficient calculations in the present work suggest that the formation of the N-centered MSAM radical is a major path compared to that which proceeds via the C-centered MSAM radical. The overall rate coefficient for the MSAM + •OH reaction was calculated in the 200-400 K temperature range. The overall rate coefficient for the MSAM + •OH reaction was estimated to be k = 1.2 × 10-13 cm3 molecule-1 s-1 at 298 K. This rate coefficient at 298 K agrees well with the reported experimental value (1.4 × 10-13 cm3 molecule-1 s-1) at the same temperature. We also provide branching ratios for each path associated with the MSAM + •OH reaction. In addition, the atmospheric implications for the title reactions are discussed. The oxidation mechanism of the MSAM + •OH reaction suggests that the formed CH3S(═O)2N•H further reacts with atmospheric oxygen (3O2) to form the corresponding RO2 radical adduct. The downstream products of the CH3S(═O)2N•H + 3O2 reaction in the present work indicate that sulfur dioxide (SO2), carbon monoxide (CO), carbon dioxide (CO2), nitric acid (HNO3), nitrous oxide (N2O), and formic acid [HC(O)OH] are formed as final products.

Electrochemically Enabled Sulfoximido-Oxygenation of Alkenes with NH-Sulfoximines and Alcohols.

An electrochemical oxidative sulfoximido-oxygenation of alkenes has been developed by using NH-sulfoximines and alcohols directly. This method proceeds regioselectively without metal catalysts and external chemical oxidants and shows broad substrate scope and diverse functional group compatibility. Based upon the preliminary mechanism studies, N-centered sulfoximidoyl radicals were involved in this electrochemical process.

Site-Selective, Photocatalytic Vinylogous Amidation of Enones.

Despite the broad interest in organic compounds possessing a γ-aminocarbonyl motif, limited strategies for their synthesis have been reported. Herein, we describe a mild and efficient method for the site-selective amidation of unsaturated enones with electrophilic N-centered radicals as a key intermediate. The photocatalytic vinylogous reaction of dienolates with N-amino pyridinium salts affords γ-amido carbonyl compounds. This process is high-yielding, scalable, and tolerates a broad range of unsaturated α,β-unsaturated carbonyls, including biologically relevant compounds, as starting materials.