Iminyl Radicals Research Articles

Redox-Neutral Generation of Iminyl Radicals by N-Heterocyclic Carbene Catalysis: Rapid Access to Phenanthridines from Vinyl Azides.

An N-heterocyclic carbene-catalyzed oxidant-, metal- and light-free iminyl radical generation pathway stemming from the reaction of vinyl azide and α-bromo ester is uncovered. This newly developed methodology is successfully applied to the redox-neutral construction of a number of diversified phenanthridine derivatives with nice functional group compatibility. Insights from the mechanism study reveal that this NHC-catalyzed transformation potentially proceeds through an alkyl radical addition-initiated HAS process, with the iminyl radical as an active intermediate.

Photochemical single-step synthesis of β-amino acid derivatives from alkenes and (hetero)arenes

β-Amino acids are frequently found as important components in numerous biologically active molecules, drugs and natural products. In particular, they are broadly utilized in the construction of bioactive peptides and peptidomimetics, thanks to their increased metabolic stability. Despite the number of methodologies established for the preparation of β-amino acid derivatives, the majority of these methods require metal-mediated multistep manipulations of prefunctionalized substrates. Here we disclose a metal-free, energy-transfer enabled highly regioselective intermolecular aminocarboxylation reaction for the single-step installation of both amine and ester functionalities into alkenes or (hetero)arenes. A bifunctional oxime oxalate ester was developed to simultaneously generate C-centred ester and N-centred iminyl radicals. This mild method features a remarkably broad substrate scope (up to 140 examples) and excellent tolerance of sensitive functional groups, and substrates that range from the simplest ethylene to complex (hetero)arenes can participate in the reaction, thus offering a general and practical access to β-amino acid derivatives.

Persistent Radicals Derived from N-Heterocyclic Carbenes for Material Applications.

Persistent radicals are potential building blocks of novel materials in many fields. Recently, highly stable persistent radicals are considered to be within reach, thanks to several radical stabilization strategies such as spin delocalization and steric protection. N-Heterocyclic carbene (NHC)-derived substituents can be attached to a radical center for these purposes, as illustrated by numerous NHC-stabilized radicals reported in the last two decades.This Account describes our recent work on developing NHC-derived persistent radicals, as well as their prospective applications. Considering that NHCs not only stabilize radicals but also reversibly interact with gas molecules, in 2015 our group reported NHC-nitric oxide (NHC-NO) radicals produced by reversibly trapping nitric oxide (NO) radical gas in NHCs. The resultant compounds were loaded into biocompatible poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL) micelles and injected into tumor-bearing mice. Then, NO release was triggered by high-intensity focused ultrasound irradiation of the tumor tissue. Furthermore, the NHC-NO radicals could also serve as a platform to generate other organic radicals such as oxime ether or iminyl radicals. Apart from medicine-related applications, radicals stabilized by NHCs can be used as energy storage materials. In this context, the triazenyl radical containing two NHC units reported by our laboratory could be a cathode active material in batteries, as an organic alternative to LiCoO2. The subsequently prepared unsymmetrical triazenyl radical derivatives were applied as anolytes in nonaqueous all-organic redox flow batteries. In addition, a ferrocene-based redox flow battery anolyte was obtained by introducing NHC-derived substituents that effectively stabilize the ferrocenate derivatives previously reported only at low temperatures. The batteries containing NHC-supported radicals exhibited high energy efficiency and insignificant radical decomposition over multiple cycles. Finally, toward developing air-persistent organic radicals for flexible devices and MRI contrasting agents, we also highlight our recent air- and physiologically stable organic radicals derived from NHCs. Coordination of tris(pentafluorophenyl)borane to the NHC-NO radical produced a new radical cation that is stable in an organic solvent under air for several months. The readily accessible 1,2-dicarbonyl radical cations generated by the reaction of NHCs with oxalyl chloride are remarkably persistent even in an aqueous solution for several months. They are also highly stable even under physiological conditions, making them particularly attractive potential candidates for organic MRI contrast agents. We hope that this Account will serve as a guide for the future development of stable NHC-derived organic radicals and draw the attention of the synthetic community to their potential applications in material science.

Photocatalytic fluoroalkylations of (hetero)arenes enabled by the acid-triggered reactivity umpolung of acetoxime esters

The importance of trifluoromethyl (CF 3 ) group-containing compounds in pharmaceuticals, agrochemicals, and materials has spurred tremendous efforts devoted to the development of methods for incorporation of the trifluoromethyl group into molecular frameworks and discoveries of trifluoromethylating reagents. In this paper, we report a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a photocatalytic C–H fluoroalkylation method is attributed to discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond. Such a new reactivity mode of oxime esters will stimulate efforts to expand the synthetic applications of readily available oxime esters. • The unprecedented acid-triggered reactivity umpolung of acetoxime ester • Photocatalytic method for C–H fluoroalkylation of (hetero)arenes and olefines • Inexpensive and easily available fluoroalkyl carboxylic anhydrides • Simple acetoxime as an efficient activator to fluoroalkyl carboxylic anhydrides Over the past decades, considerable efforts have been devoted toward exploring readily available trifluoroacetic acid or its anhydride as a CF 3 source for trifluoromethylation reactions. Herein, a general photocatalytic method was developed for fluoroalkylation of arenes and aromatic heterocycles with fluoroalkyl carboxylic anhydrides using simple acetoxime as the activator. The established conditions were also applicable to oxytrifluoromethylation and intramolecular carbotrifluoromethylation of alkenes, and the modification of biologically active molecules and gram-scale synthesis further highlighted its potential utility. Compared with the fact that single-electron transfer (SET) reduction of oxime trifluoroacetate esters generates preferentially iminyl radical and stable trifluoroacetate anions, our work discovered the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward delivering a CF 3 radical. An ongoing challenge in trifluoromethylation reaction is the use of less expensive and more practical trifluoromethyl sources. We describe herein a general photocatalytic method for regioselective C–H fluoroalkylation of (hetero)arenes and olefines that uses readily available fluoroalkyl carboxylic anhydrides as fluoroalkylating reagents in the presence of simple acetoxime as an activator. The success achieved in the development of such a method is attributed to the discovery of the unprecedented acid-triggered reactivity umpolung of acetoxime ester toward single-electron reduction-induced cleavage of N–O σ bond.

Insights into the Mechanism of Metal-Catalyzed Transformation of Oxime Esters: Metal-Bound Radical Pathway vs Free Radical Pathway.

Controlling of radical reactivity by binding a radical to the metal center is an elegant strategy to overcome the challenge that radical intermediates are "too reactive to be selective". Yet, its application has seemingly been limited to a few strained-ring substrates, azide compounds, and diazo compounds. Meanwhile, first-row transition-metal-catalyzed (mainly, Fe, Ni, Cu) transformations of oxime esters have been reported recently in which the activation processes are assumed to follow free-radical mechanisms. In this work, we show by means of density functional theory calculations that the activation of oxime esters catalyzed by Fe(II) and Cu(I) catalysts more likely affords a metal-bound iminyl radical, rather than the presumed free iminyl radical, and the whole process follows a metal-bound radical mechanism. The as-formed metal-bound radical intermediates are an Fe(III)-iminyl radical (Stotal = 2, SFe = 5/2, and Siminyl = -1/2) and a Cu(II)-iminyl radical (Stotal = 0, SCu = 1/2, and Siminyl = -1/2). The discovery of such novel substrates affording metal-bound radical intermediates may facilitate the experimental design of metal-catalyzed asymmetric synthesis using oxime esters to achieve the desired enantioselectivity.

Novel preparation of 2,5-diarylpyrroles from aromatic nitriles with 3-arylpropylmagnesium bromides, 1,3-diiodo-5,5-dimethylhydantoin, and tBuOK

Treatment of aromatic nitriles with 3-arylpropylmagnesium bromides under warming conditions and then water, followed by the reaction with DIH at room temperature under irradiation with a LED lamp and then with tBuOK gave 2,5-diarylpyrroles in moderate yields. The key step of the present method is the formation of N-iodo-2,5-diaryl-4,5-dihydropyrroles by the reaction of the formed imines with DIH, which proceeds through the 1,5-H shift of iminyl radical, 5-exo-tet cyclization by the imine group, and N-iodination of the formed 2,5-diaryldihydropyrroles. © 2022 Elsevier Science. All rights reserved.

Radical oxyamination of vinyl azides with N-hydroxyphthalimide under the action of [bis(trifluoroacetoxy)iodo]benzene

O,O′-Bis(phthalimido)-modified 2-(hydroxyimino)ethanols containing N–O–N fragment were synthesized in high yields via the reaction of vinyl azides with N-hydroxyphthalimide under the action of hypervalent iodine-based oxidant. The reaction proceeds under mild conditions and is compatible with a wide range of vinyl azides. Presumably, the process starts with the oxidative formation of phthalimide-N-oxyl radical, followed by its addition to vinyl azide with the subsequent trapping of the generated iminyl radical with the second phthalimide-N-oxyl radical.

A Combined Spectroscopic and Computational Study on the Mechanism of Iron-Catalyzed Aminofunctionalization of Olefins Using Hydroxylamine Derived N-O Reagent as the "Amino" Source and "Oxidant".

Herein, we study the mechanism of iron-catalyzed direct synthesis of unprotected aminoethers from olefins by a hydroxyl amine derived reagent using a wide range of analytical and spectroscopic techniques (Mössbauer, Electron Paramagnetic Resonance, Ultra-Violet Visible Spectroscopy, X-ray Absorption, Nuclear Resonance Vibrational Spectroscopy, and resonance Raman) along with high-level quantum chemical calculations. The hydroxyl amine derived triflic acid salt acts as the “oxidant” as well as “amino” group donor. It activates the high-spin Fe(II) (St = 2) catalyst [Fe(acac)2(H2O)2] (1) to generate a high-spin (St = 5/2) intermediate (Int I), which decays to a second intermediate (Int II) with St = 2. The analysis of spectroscopic and computational data leads to the formulation of Int I as [Fe(III)(acac)2-N-acyloxy] (an alkyl-peroxo-Fe(III) analogue). Furthermore, Int II is formed by N–O bond homolysis. However, it does not generate a high-valent Fe(IV)(NH) species (a Fe(IV)(O) analogue), but instead a high-spin Fe(III) center which is strongly antiferromagnetically coupled (J = −524 cm–1) to an iminyl radical, [Fe(III)(acac)2-NH·], giving St = 2. Though Fe(NH) complexes as isoelectronic surrogates to Fe(O) functionalities are known, detection of a high-spin Fe(III)-N-acyloxy intermediate (Int I), which undergoes N–O bond cleavage to generate the active iron–nitrogen intermediate (Int II), is unprecedented. Relative to Fe(IV)(O) centers, Int II features a weak elongated Fe–N bond which, together with the unpaired electron density along the Fe–N bond vector, helps to rationalize its propensity for N-transfer reactions onto styrenyl olefins, resulting in the overall formation of aminoethers. This study thus demonstrates the potential of utilizing the iron-coordinated nitrogen-centered radicals as powerful reactive intermediates in catalysis.

Electrochemical Decarboxylative Cyclization of α-Amino-Oxy Acids to Access Phenanthridine Derivatives.

Phenanthridines are a class of useful heterocycles in the field of drug development. In this work, a method via electrochemical decarboxylative cyclization of α-amino-oxy acids to access phenanthridine derivatives was developed. This reaction proceeded through iminyl radical formation cascade intramolecular cyclization from readily available materials under environmentally friendly conditions. A wide range of phenanthridine derivatives were obtained in moderate to high yields.

Radical Alkene-Trifluoromethylation-Triggered Nitrile Insertion/Remote Functionalization Relay Processes: Diverse Synthesis of Trifluoromethylated Azaheterocycles Enabled by Copper Catalysis.

A copper-catalyzed alkene-trifluoromethylation-triggered nitrile insertion/remote functionalization relay process has been achieved, in which "interrupted" remote 1,n-difunctionalizations of alkenes with nitrile insertion can deliver iminyl radical intermediates instead of C-based radicals, followed by subsequent 1,n-HAT to furnish corresponding remote functionalization. This relay protocol enables a straightforward approach to streamline the assembly of structurally diverse trifluoromethylated azaheterocycles.

Electrosynthesis of (hetero)aryl nitriles from α-imino-oxy acids via oxidative decarboxylation/N-O cleavage.

A new method for the synthesis of (hetero)aryl nitriles via iminyl radicals has been developed through the electrochemical oxidative decarboxylation of α-imino-oxy acids. This protocol provides an efficient approach to nitriles with a broad range of functional-group tolerance under ambient conditions and can be applied for one-pot gram-scale synthesis.

Iminyl radical-triggered relay annulation for the construction of bridged aza-tetracycles bearing four contiguous stereogenic centers.

Bridged tetracyclic nitrogen scaffolds are found in numerous biologically active molecules and medicinally relevant structures. Traditional methods usually require tedious reaction steps, and/or the use of structurally specific starting materials. We report an unprecedented, iminyl radical-triggered relay annulation from oxime-derived peresters and azadienes, which shows good substrate scope and functional group compatibility, and can deliver various bridged aza-tetracyclic compounds with complex molecular topology and four contiguous stereogenic centers (dr > 19 : 1) in a single operation. This transformation represents the first example of trifunctionalization of iminyl radicals through simultaneous formation of one C–N and two C–C bonds. DFT calculation studies were conducted to obtain an in-depth insight into the reaction pathways, which revealed that the reactions involved an interesting 1,6-hydrogen atom transfer process.

Reactivity of oximes for diverse methodologies and synthetic applications

Oximes are valuable synthetic building blocks with reactivity modes that enable their use in diverse methodologies, from cycloadditions to bioconjugation. Their reactivity towards photocatalysis and transition metals makes them ideal starting materials for N-containing heterocycles, amino alcohols and amines. Developments in oxime reactivity since 2016 have enabled transformations such as the addition of iminyl radicals to alkenes to generate functionalized imines, and [2 + 2]-cycloadditions to access azetidines. The unique properties imparted by the oxime N–O bond have also been used to integrate dynamic chemistries into materials. In this Review, we discuss the innovative use of this powerful functional group, with a focus on N–O bond fragmentation and cycloadditions, along with applications including dynamic materials, energetic materials and biocatalytic oxime reductions. We conclude by highlighting methodologies based on oxime starting materials, along with the challenges of using oximes for diverse applications, and offer insight into future directions in these areas.

Transition-Metal- and Light-Free Generation of an Iminyl Radical: Facile Approach to Oxindoles and Isoquinolinediones with a Quaternary Carbon Center via Cyanoalkylarylation

We have developed an efficient and non-toxic method for the environmental-friendly generation of an iminyl radical from cyclobutanone oxime ester via direct thermolysis in the absence of light, transition metals, "tin", and other activators. This redox-neutral cyanoalkylarylation protocol enjoys a wide substrate scope and a good functional group tolerance, providing facile access to oxindoles and isoquinolinediones with a quaternary carbon center that are difficult to prepare by traditional methods.

Remote C−H Pyridylation of Hydroxamates through Direct Photoexcitation of O‐Aryl Oxime Pyridinium Intermediates

AbstractHerein, we report an efficient strategy for the remote C−H pyridylation of hydroxamates with excellent ortho‐selectivity by designing a new class of photon‐absorbing O‐aryl oxime pyridinium salts generated in situ from the corresponding pyridines and hydroxamates. When irradiated by visible light, the photoexcitation of oxime pyridinium intermediates generates iminyl radicals via the photolytic N−O bond cleavage, which does not require an external photocatalyst. The efficiency of light absorption and N−O bond cleavage of the oxime pyridinium salts can be modulated through the electronic effect of substitution on the O‐aryl ring. The resultant iminyl radicals enable the installation of pyridyl rings at the γ‐CN position, which yields synthetically valuable C2‐substituted pyridyl derivatives. This novel synthetic approach provides significant advantages in terms of both efficiency and simplicity and exhibits broad functional group tolerance in complex settings under mild and metal‐free conditions.

Remote C-H Pyridylation of Hydroxamates through Direct Photoexcitation of O-Aryl Oxime Pyridinium Intermediates.

Herein, we report an efficient strategy for the remote C-H pyridylation of hydroxamates with excellent ortho-selectivity by designing a new class of photon-absorbing O-aryl oxime pyridinium salts generated in situ from the corresponding pyridines and hydroxamates. When irradiated by visible light, the photoexcitation of oxime pyridinium intermediates generates iminyl radicals via the photolytic N-O bond cleavage, which does not require an external photocatalyst. The efficiency of light absorption and N-O bond cleavage of the oxime pyridinium salts can be modulated through the electronic effect of substitution on the O-aryl ring. The resultant iminyl radicals enable the installation of pyridyl rings at the γ-CN position, which yields synthetically valuable C2-substituted pyridyl derivatives. This novel synthetic approach provides significant advantages in terms of both efficiency and simplicity and exhibits broad functional group tolerance in complex settings under mild and metal-free conditions.

One-Pot Synthesis of Primary and Secondary Aliphatic Amines via Mild and Selective sp3 C-H Imination.

The direct replacement of sp3 C-H bonds with simple amine units (-NH2 ) remains synthetically challenging, although primary aliphatic amines are ubiquitous in medicinal chemistry and natural product synthesis. We report a mild and selective protocol for preparing primary and secondary aliphatic amines in a single pot, based on intermolecular sp3 C-H imination. The first C-H imination of diverse alkanes, this method shows useful site-selectivity within substrates bearing multiple sp3 C-H bonds. Furthermore, this reaction tolerates polar functional groups relevant for complex molecule synthesis, highlighted in the synthesis of amine pharmaceuticals and amination of natural products. We characterize a unique C-H imination mechanism based on radical rebound to an iminyl radical, supported by kinetic isotope effects, stereoablation, resubmission, and computational modeling. This work constitutes a selective method for complex amine synthesis and a new mechanistic platform for C-H amination.

Mn(OAc)3‐Mediated Sulfonylation of Vinyl Azides Resulting in N‐Unsubstituted Enaminosulfones

AbstractMn(OAc)3‐mediated sulfonylation of vinyl azides with the use of sodium sulfinates was developed. As a result, N‐enaminosulfones are formed in high yields. The reaction proceeds through the generation of sulfonyl radical, its addition to the double bond of vinyl azide resulting in elimination of N2 molecule and formation of iminyl radical, which is converted on the final step to the desired product. One of the main features of the developed process is application of substoichiometric amount of Mn(OAc)3 due to participation of the generated iminyl radical in the oxidation of the starting sulfinate.

Photocatalytic Anti-Markovnikov Radical Hydro- and Aminooxygenation of Unactivated Alkenes Tuned by Ketoxime Carbonates.

A tunable photocatalytic method is reported for anti-Markovnikov hydro- and aminooxygenation of unactivated alkenes using readily accessible ketoxime carbonates as the diverse functionalization reagents. Mechanistic studies reveal that this reaction is initiated through an energy-transfer-promoted N-O bond homolysis of ketoxime carbonates leading to alkoxylcarbonyloxyl and iminyl radicals under visible-light photocatalysis, followed by the addition of alkoxylcarbonyloxyl radical to alkenes. By taking advantage of the different stability of the iminyl radicals, the generated carbon radical either abstracts a hydrogen atom from the media to form the anti-Markovnikov hydrooxygenation product, or it is trapped by the persistent iminyl radical to furnish the aminooxygenation product. Notably, this is the first example of direct hydrooxygenation of unactivated olefins with anti-Markovnikov regioselectivity involving an oxygen-centered radical.

Photocatalytic Anti‐Markovnikov Radical Hydro‐ and Aminooxygenation of Unactivated Alkenes Tuned by Ketoxime Carbonates

AbstractA tunable photocatalytic method is reported for anti‐Markovnikov hydro‐ and aminooxygenation of unactivated alkenes using readily accessible ketoxime carbonates as the diverse functionalization reagents. Mechanistic studies reveal that this reaction is initiated through an energy‐transfer‐promoted N−O bond homolysis of ketoxime carbonates leading to alkoxylcarbonyloxyl and iminyl radicals under visible‐light photocatalysis, followed by the addition of alkoxylcarbonyloxyl radical to alkenes. By taking advantage of the different stability of the iminyl radicals, the generated carbon radical either abstracts a hydrogen atom from the media to form the anti‐Markovnikov hydrooxygenation product, or it is trapped by the persistent iminyl radical to furnish the aminooxygenation product. Notably, this is the first example of direct hydrooxygenation of unactivated olefins with anti‐Markovnikov regioselectivity involving an oxygen‐centered radical.