N-centered Radicals Research Articles

The emerging role of radical chemistry in the amination transformation of highly strained [1.1.1]propellane: Bicyclo[1.1.1]pentylamine as bioisosteres of anilines.

Bicyclo[1.1.1]pentylamines (BPCAs), emerging as sp3-rich surrogates for aniline and its derivatives, demonstrate unique structural features and physicochemical profiles in medicinal and synthetic chemistry. In recent years, compared with conventional synthetic approaches, the rapid development of radical chemistry enables the assembly of valuable bicyclo[1.1.1]pentylamines scaffold directly through the amination transformation of highly strained [1.1.1]propellane. In this review, we concisely summarize the emerging role of radical chemistry in the construction of BCPAs motif, highlighting two different and powerful radical-involved strategies including C-centered and N-centered radical pathways under appropriate conditions. The future direction concerning BCPAs is also discussed at the end of this review, which aims to provide some inspiration for the research of this promising project.

Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides.

Noncovalent interactions (NCIs) are critical elements of molecular recognition in a wide variety of chemical contexts. While NCIs have been studied extensively for closed-shell molecules and ions, very little is understood about the structures and properties of NCIs involving free radical intermediates. In this report, we describe a detailed mechanistic study of the enantioselective radical hydroamination of alkenes with sulfonamides and present evidence suggesting that the basis for asymmetric induction in this process arises from attractive NCIs between a neutral sulfonamidyl radical intermediate and a chiral phosphoric acid (CPA). We describe experimental, computational, and data science-based evidence that identifies the specific radical NCIs that form the basis for the enantioselectivity. Kinetic studies support that C-N bond formation determines the enantioselectivity. Density functional theory investigations revealed the importance of both strong H-bonding between the CPA and the N-centered radical and a network of aryl-based NCIs that serve to stabilize the favored diastereomeric transition state. The contributions of these specific aryl-based NCIs to the selectivity were further confirmed through multivariate linear regression analysis by comparing the measured enantioselectivity to computed descriptors. These results highlight the power of NCIs to enable high levels of enantioselectivity in reactions involving uncharged open-shell intermediates and expand our understanding of radical-molecule interactions.

Selective Three-Component 1,2-Aminoalkoxylation of 1-Aryl-1,3-dienes by Dual Photoredox and Copper Catalysis.

A three-component 1,2-aminooxygenation reaction of 1,3-dienes by dual photoredox and copper catalysis is described. This protocol uses N-aminopyridinium salts as N-centered radical precursors and nucleophilic alcohols as oxygen sources, providing modular and practical access to 1,2-aminoalkoxylation products with good yields and regioselectivity. Preliminary mechanistic studies support the radical property of the reaction and the involvement of N-centered radical intermediates.

Atmospheric Oxidation of Imine Derivative of Piperazine Initiated by OH Radical

The cyclic imine 1,2,3,6-tetrahydropyrazine (THPyz) has been observed to be the major atmospheric photo-oxidation product of piperazine, a widely used solvent in carbon-capture technology, yet little is known about its own fate. Very few studies have focused on the atmospheric chemistry of imines in general, despite consistently appearing as major products of amine oxidation. In this work, we explore the reaction mechanism of THPyz oxidation initiated by OH radicals, as well as the fate of the first-generation C-centered (alkyl) and N-centered (aminyl) radical products, with quantum chemistry and theoretical kinetics methods. We predict that the major initial reaction steps involve H-abstraction from a carbon adjacent to the amine nitrogen, leading to subsequent formation of a second imine function via the O2-addition/HO2-elimination pathway. Calculated yields of potentially hazardous products are low but non-negligible. Typically carcinogenic compounds, nitrosamines and nitramines, are expected to have a maximum yield of ∼7% and ∼11%, respectively, under high NOx regimes, considering the uncertainties in the obtained rates. Low yield (1–14%) of an isocyanate is also predicted, formed in a channel following initial H-abstraction from the imine carbon. The aminyl radical formed from OH radical addition to the imine carbon undergoes fast C–C bond scission, leading to an imidic acid. These pathways are minor for OH radical oxidation of THPyz but could be more competitive for other Schiff bases.

Regioselective Access to Vicinal Diamines by Metal-Free Photosensitized Amidylimination of Alkenes with Oxime Esters.

A metal-free photosensitized protocol for regioselective diamination of alkene feedstocks over a single step was developed based on the rationally designed bifunctional diamination reagent, thus affording a range of differentially protected 1,2-diamines in moderate to high yields. Mechanistic studies reveal that the reaction is initiated with a triplet-triplet energy transfer between thioxanthone catalyst and diamination reagent, followed by fragmentation to simultaneously generate long-lived iminyl radical and transient amidyl radical. The excellent regioselectivity presumably stems from the large reactivity difference between two different N-centered radical species. This protocol is characterized by excellent regioselectivity, broad functional group tolerance, and mild reaction conditions, which would enrich the diversity and versatility of facilitate the diversity-oriented synthesis of 1,2-diamine-containing complex molecule scaffolds.

Multicomponent Direct Assembly of N-Heterospirocycles Facilitated by Visible-Light-Driven Photocatalysis.

N-heterospirocycles are interesting structural units found in both natural products and medicinal compounds but have relatively few reliable methods for their synthesis. Here, we enlist the photocatalytic generation of N-centered radicals to construct β-spirocyclic pyrrolidines from N-allylsulfonamides and alkenes. A variety of β-spirocyclic pyrrolidines have been constructed, including drug derivatives, in moderate to very good yields. Further derivatization of the products has also been demonstrated as has a viable scale-up procedure, making use of flow chemistry techniques.

Effects of nitrite on the degradation of carbamazepine by sulfate radical oxidation

Activated persulfate oxidation has been demonstrated to be a viable approach to degrade carbamazepine (CBZ). However, the influence of nitrite (NO2−) commonly found in wastewaters and groundwaters on the degradation remains unclear. Herein, we found that the presence of NO2− not only reduced the rate but substantially changed the pathway of CBZ degradation in a heat activated peroxydisulfate (heat/PDS) oxidation process. This was because of the scavenging of sulfate radical (SO4−) by NO2− and the formation of nitrogen dioxide radical (NO2). Acridine was identified as a key intermediate during CBZ degradation. In the presence of NO2−, acridine could be further transformed to nitrated derivatives. During this process, an N-centered acridine radical is the key intermediate which coupled with the NO2 originated from the oxidation of NO2−. Besides nitroacridines, several nitrophenols were identified as well. In contrast to the nitroacridines, the nitro group in these nitrophenols was derived from oxidation of the amine in the parent CBZ. Increasing the NO2− concentration increased the formation of nitroacridines but inhibited the formation of nitrophenols. Since nitroaromatic compounds are usually toxic and persistent, this study highlights the potential environmental risks when SO4− is applied to degrade CBZ in the presence of NO2−.

Electrochemical Amidation: Benzoyl Hydrazine/Carbazate and Amine as Coupling Partners.

An electrochemical amidation of benzoyl hydrazine/carbazate and primary/secondary amine as coupling partners via concomitant cleavage and formation of C(sp2)-N bonds has been achieved. This methodology proceeds under metal-free and exogenous oxidant-free conditions producing N2 and H2 as byproducts. Mechanistic studies reveal the in situ generations of both acyl and N-centered radicals from benzoyl hydrazines and amines. The utility of this protocol is demonstrated through a large-scale, and synthesis of bezafibrate, a hyperlipidemic drug.

1,2-Amino oxygenation of alkenes with hydrogen evolution reaction

1,2-Amino oxygenation of alkenes has emerged as one of the most straightforward synthetic methods to produce β-amino alcohols, which are important organic building blocks. Thus, a practical synthetic strategy for 1,2-amino oxygenation is highly desirable. Here, we reported an electro-oxidative intermolecular 1,2-amino oxygenation of alkenes with hydrogen evolution, removing the requirement of extra-oxidant. Using commercial oxygen and nitrogen sources as starting materials, this method provides a cheap, scalable, and efficient route to a set of valuable β-amino alcohol derivatives. Moreover, the merit of this protocol has been exhibited by its broad substrate scope and good application in continuous-flow reactors. Furthermore, this method can be extended to other amino-functionalization of alkenes, thereby showing the potential to inspire advances in applications of electro-induced N-centered radicals (NCRs).

Bifunctional sulfilimines enable synthesis of multiple N-heterocycles from alkenes

Intramolecular cyclization of nitrogen-containing molecules onto pendant alkenes is an efficient strategy for the construction of N-heterocycles, which are of paramount importance in, for example, pharmaceuticals and materials. Similar intermolecular cyclization reactions, however, are scarcer for nitrogen building blocks, including N-centred radicals, and divergent and modular versions are not established. Here we report the use of sulfilimines as bifunctional N-radical precursors for cyclization reactions with alkenes to produce N-unprotected heterocycles in a single step through photoredox catalysis. Structurally diverse sulfilimines can be synthesized in a single step, and subsequently engage with alkenes to afford synthetically valuable five-, six- and seven-membered heterocycles. The broad and diverse scope is achievable by a radical-polar crossover annulation enabled by the bifunctional character of the reagents, which distinguishes itself from all other N-centred-radical-based reactions. The modular synthesis of the sulfilimines allows for larger structural diversity of N-heterocycle products than is currently achievable with other single cyclization methods.

Visible-light-driven intramolecular xanthylation of remote unactivated C(sp3)-H bonds

Visible light-mediated site-specific C(sp3)-H xanthylation of amides has been accomplished using N-xanthylamides. The N-centered radicals generated by light initiation of N-xanthylamide substrates undergo 1,5-hydrogen atom transfer to form benzylic or alkyl radical intermediates under metal- and catalyst-free conditions. This method exhibits a broad substrate scope, high functional group tolerance, and high regioselectivity. Furthermore, this strategy provides straightforward access to a range of derivatives through the subsequent elaboration of the xanthate group.

A One-Pot Photochemical Method for the Generation of Functionalized Aminocyclopentanes.

Detailed herein is the development of a photochemical intermolecular formal [3+2] cycloaddition between cyclopropylimines and substituted alkenes to generate aminocyclopentane derivatives. The Schiff base of the cyclopropylimine was designed to enable a masked N-centered radical approach in which the requisite open-shell character was achieved upon excitation with visible light. The cycloaddition products were directly converted to N-functionalized aminocyclopentanes via solvolysis and N-acylation. The photochemical component of this reaction sequence was demonstrated to operate in continuous flow.

Controlled Photochemical Synthesis of Substituted Isoquinoline-1,3,4(2H)-triones, 3-Hydroxyisoindolin-1-ones, and Phthalimides via Amidyl Radical Cyclization Cascade.

We report a controlled radical cyclization cascade of isoquinoline-1,3,4(2H)-triones, 3-hydroxyisoindolin-1-ones, and phthalimides from o-alkynylated benzamides by metal-free photoredox catalyzed amidyl N-centered radical addition to the C-C triple bond using the proton-coupled electron transfer (PCET) process under mild reaction conditions. A time tunable synthesis of 3-hydroxyisoindolin-1-ones and phthalimides via β-carbonyl-C(sp3) bond cleavage was also achieved under visible light irradiation. A mechanistic rationale for the radical cyclization cascade is supported by various control and quenching experiments as well as EPR studies.

Visible-Light-Accelerated Copper-Catalyzed [3 + 2] Cycloaddition of N-Tosylcyclopropylamines with Alkynes/Alkenes.

Copper-catalyzed [3 + 2] cycloadditions of N-tosylcyclopropylamine with alkynes and alkenes have been accomplished under visible light irradiation. The developed approach is compatible with a range of functionalities and allows the synthesis of diversified aminated cyclopentene and cyclopentane derivatives being relevant for drug synthesis. The protocol is operationally simple and economically affordable as it does not require any ligand, base, or additives. As the key step, the one-electron oxidation of the N-tosyl moiety by visible light-induced homolysis of a transient Cu(II)-tosylamide complex is proposed, providing a facile entry for N-centered radicals.

Diversification of Amidyl Radical Intermediates Derived from C-H Aminopyridylation.

The N-activating substituents typically encountered in C-H amination chemistry are challenging to remove and have limited scope for synthetic elaboration. Here, we demonstrate that N-benzylaminopyridinium species provide a platform for synthetic elaboration via reductive N-N bond activation to unveil electrophilic N-centered radicals. These reactive intermediates can be trapped either via anti-Markovnikov olefin carboamination to provide access to tetrahydroisoquinolines or via aza-Rubottom chemistry with silyl enol ethers to provide α-amino ketones.

Energy Transfer Photocatalytic Radical Rearrangement in N-Indolyl Carbonates.

A new type of sp3-like N-centered radical has been generated by selective energy transfer catalysis. Upon photoexcitation, homolytic N-O bond cleavage of N-indolyl carbonate in the presence of an Ir complex produced N- and O-centered radicals. The high spin density at the C3 position of indole led to radical recombination with the O-centered radical, affording valuable 3-oxyindole derivatives without decarboxylation. Transformations of the desired products into various molecules were also demonstrated.

Visible‐Light‐Driven Isocyanide Insertion to o‐Alkenylanilines: A Route to Isoindolinone Synthesis

AbstractA visible‐light‐mediated intermolecular radical insertion of isocyanides to electron‐deficient o‐alkenylanilines leading to isoindolinone is reported. Deuterium (D2O) and H2O18 labelling experiments suggest H and O incorporation in the product. The formation of an N‐centered radical (NCR) via stepwise PT/ET process was confirmed by radical trapping experiments, photoluminescence, cyclic voltammetry and DFT studies. This photo cascade methodology is overall a redox neutral process featuring metal‐free condition and broad substrate scope (32 examples). The synthesis of analogue of GABA receptor antagonist shows the practical utility of this method.magnified image

Photoredox synthesis of 6- and 7-membered ring scaffolds via N-centered radicals.

N-Containing heterocycles are important scaffolds due to their ubiquitous presence in bioactive compounds. Their synthesis has been considered as an important research field. In this work we report the access to 6- and 7-membered rings via a photoinduced strategy. To our knowledge, this work represents the first exemple of photo-induced 7-endo-trig cyclization with N-centered radicals.

Electricity mediated [3+2]-cycloaddition of N-sulfonylcyclopropanes with olefins via N-centered radical intermediates: access to cyclopentane analogs.

An external oxidant free electrochemical strategy is designed towards the β-scission of strained C-C bonds in cyclopropylamine. Moreover, the mechanistic studies ascertained that the methodology encompasses the N-center radical (NCRs) route and provides access to di- or tri-substituted cyclopentane analogs.

Chemical versatility of azide radical: journey from a transient species to synthetic accessibility in organic transformations.

The generation of azide radical (N3˙) occurs from its precursors primarily via a single electron transfer (SET) process or homolytic cleavage by chemical methods or advanced photoredox/electrochemical methods. This in situ generated transient open-shell species has unique characteristic features that set its reactivity. In the past, the azide radical was widely used for various studies in radiation chemistry as a 1e- oxidant of biologically important molecules, but now it is being exploited for synthetic applications based on its addition and intermolecular hydrogen atom transfer (HAT) abilities. Due to the significant role of nitrogen-containing molecules in synthesis, drug discovery, biological, and material sciences, the direct addition onto unsaturated bonds for the simultaneous construction of C-N bond with other (C-X) bonds are indeed worth highlighting. Moreover, the ability to generate O- or C-centered radicals by N3˙ via electron transfer (ET) and intermolecular HAT processes is also well documented. The purpose of controlling the reactivity of this short-lived intermediate in organic transformations drives us to survey: (i) the history of azide radical and its structural properties (thermodynamic, spectroscopic, etc.), (ii) chemical reactivities and kinetics, (iii) methods to produce N3˙ from various precursors, (iv) several significant azide radical-mediated transformations in the field of functionalization with unsaturated bonds, C-H functionalization via HAT, tandem, and multicomponent reaction with a critical analysis of underlying mechanistic approaches and outcomes, (v) concept of taming the reactivity of azide radicals for potential opportunities, in this review.