Nitrene Precursors Research Articles

Mechanochemical Conditions for Intramolecular N−O Couplings via Rhodium Nitrenoids Generated from N‐Acyl Sulfonimidamides

AbstractStarting from N‐acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N−O couplings to provide unprecedented 1,3,2,4‐oxathiadiazole 3‐oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol % in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent‐free procedure. Under heat or blue light, the newly formed five‐membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide.

Mechanochemical Conditions for Intramolecular N-O Couplings via Rhodium Nitrenoids Generated from N-Acyl Sulfonimidamides.

Starting from N-acyl sulfonimidamides, mechanochemically generated rhodium nitrenoids undergo intramolecular N-O couplings to provide unprecedented 1,3,2,4-oxathiadiazole 3-oxides in good to excellent yields. The cyclization proceeds efficiently with a catalyst loading of only 0.5 mol% in the presence of phenyliodine(III) diacetate (PIDA) as oxidant. Neither an inert atmosphere nor additional heating is required in this solvent-free procedure. Under heat or blue light, the newly formed five-membered heterocycles function as nitrene precursors reacting with sulfoxides as exemplified by the imidation of dimethyl sulfoxide.

Recent Progress in Synthetic Applications of Hypervalent Iodine(III) Reagents.

Hypervalent iodine(III) compounds have found wide application in modern organic chemistry as environmentally friendly reagents and catalysts. Hypervalent iodine reagents are commonly used in synthetically important halogenations, oxidations, aminations, heterocyclizations, and various oxidative functionalizations of organic substrates. Iodonium salts are important arylating reagents, while iodonium ylides and imides are excellent carbene and nitrene precursors. Various derivatives of benziodoxoles, such as azidobenziodoxoles, trifluoromethylbenziodoxoles, alkynylbenziodoxoles, and alkenylbenziodoxoles have found wide application as group transfer reagents in the presence of transition metal catalysts, under metal-free conditions, or using photocatalysts under photoirradiation conditions. Development of hypervalent iodine catalytic systems and discovery of highly enantioselective reactions using chiral hypervalent iodine compounds represent a particularly important recent achievement in the field of hypervalent iodine chemistry. Chemical transformations promoted by hypervalent iodine in many cases are unique and cannot be performed by using any other common, non-iodine-based reagent. This review covers literature published mainly in the last 7-8 years, between 2016 and 2024.

Heme‐Enzymatic Biocatalysis for C−C or C−N Bond Formation

AbstractThe C−C or C−N bond formation is critical in the synthesis of pharmaceuticals and other value‐added products; however, traditional metal‐catalysed synthesis has brought about environmental and resource issues. A plethora of engineered heme‐dependent enzymes, such as cytochrome P450, have exhibited enormous potential in biocatalysis for C−C or C−N bond formation. With the development of computational and spectroscopic methods, the mechanisms underlying heme‐catalysed C−C or C−N bond formation have been extensively investigated. In the presence of carbene or nitrene precursor, an active iron porphyrin carbene (IPC) or iron porphyrin nitrene (IPN) is formed, which subsequently reacts with a second substrate to form new C−C or C−N bonds. Apart from the widely studied IPC/IPN‐facilitated catalytic pathway, halide‐initiated radical cyclization pathway and Cpd‐I‐catalysed diradical pathway have also been proposed. These mechanistic insights have enabled rational engineering and de novo design of heme enzymes. This review summarises recent mechanistic advances in heme enzymatic C−C or C−N bond formation and presents successful applications of mechanism‐based enzyme design. It would shed light on the development of tailored biocatalysts for the synthesis of complex but valuable industrial products.

Spin States Matter─from Fundamentals toward Synthetic Methodology Development and Drug Discovery.

ConspectusThe potent reactivity of carbenes and nitrenes has been traditionally harnessed by the employment of a transition-metal catalyst in which the reactivity of the metal carbene/nitrene intermediates can be controlled via the judicious tuning of the metal catalyst. In recent years, progress made in this research area has unveiled novel strategies to directly access free carbenes or nitrenes under visible-light-mediated conditions without the necessity of a metal catalyst for stabilization of the carbene/nitrene intermediate. Such photochemical approaches present new opportunities to leverage orthogonal reactions with classic metal-catalyzed transformations.In this Account, we describe the major contributions from our group over the past years pushing the boundaries of light-mediated carbene and nitrene transfer reactions. In the first section, the development from purely singlet carbene chemistry toward methods that allow access to triplet carbene intermediates will be dissected. We describe how the triplet spin state of reagents provides a rich array of novel synthetic methods that build on the fundamentals of spin conservation. We lay out the different strategies in accessing the triplet spin state of carbenes (i.e., via electronic stabilization, via triplet sensitization with suitable photocatalysts, or via exploitation of geometric features of these intermediates), followed by an analysis of how the triplet spin state can be employed to leverage reactions distinct to the classic singlet carbene chemistry.The second part focuses on free nitrene intermediates, whereby both photochemical and photocatalytic strategies are analyzed and compared. We initiate with a discussion of the reactivity of iminoiodinanes as nitrene precursors in the presence of a photocatalyst or under photochemical conditions and how these two approaches result in fundamentally distinct nitrogen-based intermediates. While a nitrene radical anion is formed under photocatalytic conditions, triplet nitrene is generated under photochemical conditions. We commence with an outline of the basic reactivity of nitrene transfer reactions under both conditions, with a focus on the reaction with substrates containing double bonds. Finally, the latest developments in advanced cycloaddition chemistry beyond classic aziridination reactions are examined, with a special emphasis on the relay of the triplet nitrene reactivity to enable a Pauson-Khand-like (2 + 2 + 1) cycloaddition reaction that offers convenient access to high value bioisosteres in drug discovery.The work from our group on spin-dependent reactivities offers insight into important fundamentals in synthesis, where the spin state of the reactive intermediate will dictate the reaction outcome. We hope this may inspire others to widen the scope of applications of light-mediated carbene and/or nitrene transfer reactions, and furthermore, we anticipate that these understandings may also enable the development of advanced catalytic systems featuring triplet metal carbene/nitrene intermediates.

Chemoselective Silver-Catalyzed Nitrene Transfer: Tunable Syntheses of Azepines and Cyclic Carbamimidates.

Azepines and their saturated azepane counterparts are important moieties in bioactive molecules but are under-represented in current drug screening libraries. Herein, we report a mild and efficient azepine formation via silver-catalyzed dearomative nitrene transfer. A 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidate nitrene precursor, coupled with the appropriate ligand for silver, is essential for achieving the unexpected chemoselectivity between arene dearomatization and benzylic C(sp3)-H amination. Potential applications in the late-stage diversification of azepines to complex molecular scaffolds and diastereoselective hydrogenations to sp3-rich derivatives are also highlighted.

Reaction Discovery Using Spectroscopic Insights from an Enzymatic C-H Amination Intermediate.

Engineered hemoproteins can selectively incorporate nitrogen from nitrene precursors like hydroxylamine, O-substituted hydroxylamines, and organic azides into organic molecules. Although iron-nitrenoids are often invoked as the reactive intermediates in these reactions, their innate reactivity and transient nature have made their characterization challenging. Here we characterize an iron-nitrosyl intermediate generated from NH2OH within a protoglobin active site that can undergo nitrogen-group transfer catalysis, using UV-vis, electron paramagnetic resonance (EPR) spectroscopy, and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) techniques. The mechanistic insights gained led to the discovery of aminating reagents─nitrite (NO2-), nitric oxide (NO), and nitroxyl (HNO)─that are new to both nature and synthetic chemistry. Based on the findings, we propose a catalytic cycle for C-H amination inspired by the nitrite reductase pathway. This study highlights the potential of engineered hemoproteins to access natural nitrogen sources for sustainable chemical synthesis and offers a new perspective on the use of biological nitrogen cycle intermediates in biocatalysis.

Iron-Catalyzed Asymmetric Imidation of Sulfides via Sterically Biased Nitrene Transfer.

Transition-metal-catalyzed enantioselective nitrene transfer to sulfides has emerged as one of the most powerful strategies for rapid construction of enantioenriched sulfimides. However, achieving stereocontrol over highly active earth-abundant transition-metal nitrenoid intermediates remains a formidable challenge compared with precious metals. Herein, we disclose a chiral iron(II)/N,N'-dioxide-catalyzed enantioselective imidation of dialkyl and alkyl aryl sulfides using iminoiodinanes as nitrene precursors. A series of chiral sulfimides were obtained in moderate-to-good yields with high enantioselectivities (56 examples, up to 99% yield, 98:2 e.r.). The utility of this methodology was demonstrated by late-stage modification of complex molecules and synthesis of the chiral insecticide sulfoxaflor and the intermediates of related bioactive compounds. Based on experimental studies and theoretical calculations, a water-bonded high-spin iron nitrenoid species was identified as the key intermediate. The observed stereoselectivity was original from the steric repulsion between the amide unit of the ligand in the chiral cave and the bulky substituent of sulfides. Additionally, dioxazolones proved to be suitable acylnitrene precursors in the presence of an iron(III)/N,N'-dioxide complex, resulting in the formation of enantioselectivity-reversed sulfimides (14 examples, up to 81% yield, 97:3 e.r.).

Intermolecular Enantioselective Amination Reactions Mediated by Visible Light and a Chiral Iron Porphyrin Complex.

In the presence of 1 mol % of a chiral iron porphyrin catalyst, various 3-arylmethyl-substituted 2-quinolones and 2-pyridones underwent an enantioselective amination reaction (20 examples; 93-99 % ee). The substrates were used as the limiting reagents, and fluorinated aryl azides (1.5 equivalents) served as nitrene precursors. The reaction is triggered by visible light which allows a facile dediazotation at ambient temperature. The selectivity of the reaction is governed by a two-point hydrogen bond interaction between the ligand of the iron catalyst and the substrate. Hydrogen bonding directs the amination to a specific hydrogen atom within the substrate that is displaced by the nitrogen substituent either in a concerted fashion or by a rebound mechanism.

Intermolecular Enantioselective Amination Reactions Mediated by Visible Light and a Chiral Iron Porphyrin Complex

AbstractIn the presence of 1 mol % of a chiral iron porphyrin catalyst, various 3‐arylmethyl‐substituted 2‐quinolones and 2‐pyridones underwent an enantioselective amination reaction (20 examples; 93–99 % ee). The substrates were used as the limiting reagents, and fluorinated aryl azides (1.5 equivalents) served as nitrene precursors. The reaction is triggered by visible light which allows a facile dediazotation at ambient temperature. The selectivity of the reaction is governed by a two‐point hydrogen bond interaction between the ligand of the iron catalyst and the substrate. Hydrogen bonding directs the amination to a specific hydrogen atom within the substrate that is displaced by the nitrogen substituent either in a concerted fashion or by a rebound mechanism.

Photosensitization enables Pauson-Khand-type reactions with nitrenes.

The Pauson-Khand reaction has in the past 50 years become one of the most common cycloaddition reactions in chemistry. Coupling two unsaturated bonds with carbon monoxide, the transformation remains limited to CO as a C1 building block. Herein we report analogous cycloaddition reactions with nitrenes as an N1 unit. The reaction of a nonconjugated diene with a nitrene precursor produces bicyclic bioisosteres of common saturated heterocycles such as piperidine, morpholine, and piperazine. Experimental and computational mechanistic studies support relaying of the diradical nature of triplet nitrene into the π-system. We showcase the reaction's utility in late-stage functionalization of drug compounds and discovery of soluble epoxide hydrolase inhibitors.

Myoglobin-Catalyzed Azide Reduction Proceeds via an Anionic Metal Amide Intermediate.

Nitrene transfer reactions catalyzed by heme proteins have broad potential for the stereoselective formation of carbon-nitrogen bonds. However, competition between productive nitrene transfer and the undesirable reduction of nitrene precursors limits the broad implementation of such biocatalytic methods. Here, we investigated the reduction of azides by the model heme protein myoglobin to gain mechanistic insights into the factors that control the fate of key reaction intermediates. In this system, the reaction proceeds via a proposed nitrene intermediate that is rapidly reduced and protonated to give a reactive ferrous amide species, which we characterized by UV/vis and Mössbauer spectroscopies, quantum mechanical calculations, and X-ray crystallography. Rate-limiting protonation of the ferrous amide to produce the corresponding amine is the final step in the catalytic cycle. These findings contribute to our understanding of the heme protein-catalyzed reduction of azides and provide a guide for future enzyme engineering campaigns to create more efficient nitrene transferases. Moreover, harnessing the reduction reaction in a chemoenzymatic cascade provided a potentially practical route to substituted pyrroles.

Nitrene-Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ-Aminomethyl-γ-Lactones.

Attaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral-at-ruthenium catalysts, chiral γ-aminomethyl-γ-lactones containing a quaternary carbon in γ-position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ-Aminomethyl-γ-lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ-lactams, 2-oxazolidinones, and tetrahydrofurans.

Nitrene‐Mediated Enantioselective Intramolecular Olefin Oxyamination to Access Chiral γ‐Aminomethyl‐γ‐Lactones

AbstractAttaching a nitrene precursor to an intramolecular nucleophile allows for a catalytic asymmetric intramolecular oxyamination of alkenes in which the nucleophile adds in an endocyclic position and the amine in an exocyclic fashion. Using chiral‐at‐ruthenium catalysts, chiral γ‐aminomethyl‐γ‐lactones containing a quaternary carbon in γ‐position are provided in high yields (up to 99 %) and with excellent enantioselectivities (up to 99 % ee). DFT calculations support the possibility of both a singlet (concerted oxyamination of the alkene) and triplet pathway (stepwise oxyamination) for the formation of the predominant stereoisomer. γ‐Aminomethyl‐γ‐lactones are versatile chiral building blocks and can be converted to other heterocycles such as δ‐lactams, 2‐oxazolidinones, and tetrahydrofurans.

Direct Synthesis of Unprotected Indolines Through Intramolecular sp3 C-H Amination Using Nitroarenes as Aryl Nitrene Precursors.

Given the prevalence of molecules containing nitro groups in organic synthesis, innovative methods to expand the reactivity of this functional group are of interest in both industrial and academic settings. In this report, a metal-free intramolecular benzylic sp3 C-H amination is disclosed using aryl nitro compounds as aryl nitrene precursors. Organosilicon reagent N,N'-bis(trimethylsilyl)-4,4'-bipyridinylidene (Si-DHBP) served as an efficient reductant in the transformation, enabling the in situ generation of aryl nitrene species for the direct, metal-free synthesis of unprotected 2-arylindolines from the corresponding nitroarene compounds.

Development of Nonclassical Photoprecursors for Rh2 Nitrenes.

Characterization of reactive intermediates in C-H functionalization is challenging due to the fleeting lifetimes of these species. Synthetic photochemistry provides a strategy to generate post-turnover-limiting-step intermediates in catalysis under cryogenic conditions that enable characterization. We have a long-standing interest in the structure and reactivity of Rh2 nitrene intermediates, which are implicated as transient intermediates in Rh2-catalyzed C-H amination. Previously, we demonstrated that Rh2 complexes bearing organic azide ligands can serve as solid-state and in crystallo photoprecursors in the synthesis of transient Rh2 nitrenoids. Complementary solution-phase experiments have not been available due to the weak binding of most organic azides to Rh2 complexes. Furthermore, the volatility of the N2 that is evolved during in crystallo nitrene synthesis from these precursors has prevented the in crystallo observation of C-H functionalization from lattice-confined nitrenes. Motivated by these challenges, here we describe the synthesis and photochemistry of nonclassical nitrene precursors based on sulfilimine ligands. Sulfilimines bind to Rh2 carboxylate complexes more tightly than the corresponding azides, which has enabled the full solid-state and solution-phase characterization of these new complexes. The higher binding affinity of sulfilimine ligands as compared with organic azides has enabled both solution-phase and solid-state nitrene photochemistry. Cryogenic photochemical studies of Rh2 sulfilimine complexes confined within polystyrene thin films demonstrate that sulfilimine photochemistry can be accomplished at low temperature but that C-H amination is rapid at temperatures compatible with N═S photoactivation. The potential of these structures to serve as platforms for multistep in crystallo cascades is discussed.

Computational Insights into the Reactivity Difference between Hypervalent Bromine(III) and Hypervalent Iodine(III) Reagent in the C−H Amination and Alkene Aziridination

AbstractWe present herein a computational exploration into the mechanism and origin of the reactivity difference between N‐triflylimino‐λ3‐iodane and N‐triflylimino‐λ3‐bromane in the C−H amination and alkene aziridination. Our calculations revealed that the preferred mechanism for C−H amination involves the generation of free nitrene intermediate, while the alkene aziridination proceeds via a concerted reaction mechanism. The superior reactivity of N‐triflylimino‐λ3‐bromane over N‐triflylimino‐λ3‐iodane could be mainly ascribed to better nucleofugality of the bromanyl moiety, which can be characterized by the strength of I−N and Br−N bond. The effect of solvent polarity on the reactivity of N‐triflylimino‐λ3‐bromane as a nitrene precursor will be discussed.

Ni-Catalyzed Mild Synthesis of Sulfonylurea via Tandem Coupling of Sulfonyl Azide, Isocyanide, and Water.

An efficient, mild, and novel route is developed to synthesize sulfonylurea via the nickel-catalyzed tandem coupling of sulfonyl azide, isocyanide, and water in aqueous media. The sulfonyl azide is expected to act as a nitrene precursor, which upon reaction with isocyanide generates carbodiimide. Herein, water acts as a nucleophile and reacts with carbodiimide to deliver the product. The protocol uses an inexpensive nickel catalyst, environmentally friendly water (as the nucleophile), and room temperature and provides products in moderate to good yields.

Chiral-at-Ruthenium Catalysts for Nitrene-Mediated Asymmetric C–H Functionalizations

ConspectusAsymmetric transition metal catalysis is an indispensable tool used both in academia and industry for forging chiral molecules in an enantioselective fashion. Its advancement relies in large part on the design and discovery of new chiral catalysts. In contrast to conventional endeavors of generating chiral transition metal catalysts from carefully tailored chiral ligands, the development of chiral transition metal catalysts containing solely achiral ligands (chiral-at-metal catalysts) has been neglected. This Account presents our recent work on the synthesis and catalytic applications of a new class of C2-symmetric chiral-at-ruthenium catalysts. These octahedral ruthenium(II) complexes are constructed from two achiral bidentate N-(2-pyridyl)-substituted N-heterocyclic carbene (PyNHC) ligands and two monodentate acetonitriles, and the dicationic complexes are typically complemented with two hexafluorophosphate anions. The chirality of these complexes originates from the helical cis-arrangement of the bidentate ligands, thereby generating a stereogenic metal center as the exclusive stereocenter in these complexes. The strong σ donor and π acceptor properties of the PyNHC ligands provide a strong ligand field that ensures a high constitutional and configurational inertness of the helical Ru(PyNHC)2 core, while at the same time, the trans-effect exerted by the σ-donating NHC ligands results in high lability of the MeCN ligands and, therefore, provides high catalytic activity. As a result, this chiral-at-ruthenium catalyst scaffold combines formidable structural robustness with high catalytic activity in a unique fashion. Asymmetric nitrene C-H insertion constitutes an efficient strategy for accessing chiral amines. The direct conversion of C(sp3)-H bonds into amine functionality circumvents the need for using functionalized starting materials. Our C2-symmetric chiral-at-ruthenium complexes display exceptionally high catalytic activity and excellent stereocontrol for various asymmetric nitrene C(sp3)-H insertion reactions. The ruthenium nitrene species can be generated from nitrene precursors, such as organic azides and hydroxylamine derivatives, which undergo ring-closing C-H aminations to afford chiral cyclic pyrrolidines, ureas, and carbamates in high yields and with excellent enantioselectivities at low catalyst loadings. Mechanistically, the turnover-determining C-H insertion is proposed to proceed in a concerted or stepwise fashion, depending on the nature of intermediate ruthenium nitrenes (singlet or triplet). Computational studies revealed that the stereocontrol originates from a better steric fit in combination with favorable catalyst/substrate π-π stacking effects for aminations at benzylic C-H bonds. In addition, we also present our research for exploring novel reaction patterns and reactivities of intermediate transition metal nitrenes. First, we discovered a novel chiral-at-ruthenium-catalyzed 1,3-migratory nitrene C(sp3)-H insertion to convert azanyl esters into nonracemic α-amino acids. Second, we found a chiral-at-ruthenium-catalyzed intramolecular C(sp3)-H oxygenation, thereby allowing for the construction of chiral cyclic carbonates and lactones via nitrene chemistry. We expect that our research program on catalyst development and reaction discovery will inspire the creation of novel types of chiral-at-metal catalysts and drive the development of new applications for nitrene-mediated asymmetric C-H functionalization reactions.

Origin of the Distinctive Electronic Structure of Co- and Fe-Porphyrin-Nitrene and Its Effect on Their Nitrene Transfer Reactivity

Metal-bound nitrene species are the crucial intermediate in catalytic nitrene transfer reactions exhibited by engineered enzymes and molecular catalysts. The electronic structure of such species and its correlation with nitrene transfer reactivity have not been fully understood yet. This work presents an in-depth electronic structure analysis and nitrene transfer reactivity of two prototypical metal-nitrene species derived from CoII(TPP) and FeII(TPP) (TPP = meso-tetraphenylporphyrin) complexes and tosyl azide nitrene precursor. Parallel to the well-known "cobalt(III)-imidyl" electronic structure of the Co-porphyrin-nitrene species, the formation mechanism and electronic structure of the elusive Fe-porphyrin-nitrene have been established using density functional theory (DFT) and multiconfigurational complete active-space self-consistent field (CASSCF) calculations. Electronic structure evolution analysis for the metal-nitrene formation step and CASSCF-derived natural orbitals advocates that the electronic nature of the metal-nitrene (M-N) core of Fe(TPP) is strikingly different from that of the Co(TPP). Specifically, the "imidyl" nature of the Co-porphyrin-nitrene [(TPP)CoIII-•NTos] (Tos = tosyl) (I1Co) is contrasted by the "imido-like" character of the Fe-porphyrin-nitrene [(TPP)FeIV[Formula: see text]NTos] (I1Fe). This difference between Co- and Fe-nitrene has been attributed to the additional interactions between Fe-dπ and N-pπ orbitals in Fe-nitrene, which is further complemented by the shortened Fe-N bond length of 1.71 Å. This stronger M-N bond in Fe-nitrene compared to the Co-nitrene is also reflected in the higher exothermicity (ΔΔH = 16 kcal/mol) of the Fe-nitrene formation step. The "imido-like" character renders a relatively lower spin population on the nitrene nitrogen (+0.42) in the Fe-nitrene complex I1Fe, which undergoes the nitrene transfer to the C═C bond of styrene with a considerably higher enthalpy barrier (ΔH‡ = 10.0 kcal/mol) compared to the Co congener I1Co (ΔH‡ = 5.6 kcal/mol) possessing a higher nitrogen spin population (+0.88) and a relatively weaker M-N bond (Co-N = 1.80 Å).