Aziridination Of Alkenes Research Articles

Design of Highly Electrophilic and Stable Metal Nitrido Complexes.

ConspectusMetal oxo (M═O) and nitrido (M≡N) complexes are two important classes of high-valent transition metal complexes. The use of M═O as oxidants in chemical and biological systems has been extensively investigated. Nature makes use of M═O in enzymes such as cytochrome P450 to oxidize a variety of substrates. Highly oxidizing oxo species have also been synthesized and they have been shown to oxidize organic and inorganic substrates via one-electron oxidation, O atom transfer, and H atom abstraction pathways. In contrast, the oxidation chemistry of M≡N is much less investigated. Although a variety of nitrido complexes are known, most of them are inert and do not show appreciable oxidizing properties, which is not unexpected since the N3- ligand is much more electron-donating than the O2- ligand. In principle, highly electrophilic/oxidizing nitrido complexes may be designed by using weakly coordinating ancillary ligands and/or by increasing the oxidation state of the metal centers. A number of such species have been generated in solution at low temperatures. However, attempts to isolate them are often hampered by their ease of decomposition via bimolecular N···N coupling to generate N2. In some cases, decomposition occurs by intramolecular nitrogenation of the ancillary ligand.In this account, we describe our recent efforts into the design of nitrido complexes that are highly oxidizing but stable enough so they can be isolated and characterized, and their reactivity toward organic substrates can be readily investigated.We have successfully isolated and determined the structure of the first stable manganese(VI) nitrido complex bearing an oxidation-resistant macrocyclic tetraamido TAML ligand, [MnVI(N)(TAML)]- (H4TAML = 3,3,6,6,9,9-hexamethyl-3,4,8,9-tetrahydro-1H-benzo[e][1,4,7,10] tetraazacyclotridecine-2,5,7,10(6H,11H)-tetraone). This complex readily undergoes direct aziridination of alkenes; it also abstracts hydrides from NADH analogues via a Separated CPET mechanism. Coupling of the nitrido ligands to give dinitrogen is a major decomposition pathway for electrophilic nitrido complexes. In order to shut down this pathway, we made use of a bulky trianionic corrole ligand TTPPC (H3TTPPC = 5,10,15-tris(2,4,6-triphenylphenyl)corrole) to prepare manganese nitrido complexes. Remarkably, we were able to isolate and determine the structures of [MnV(N)(TTPPC)]- and its one- and two-electron ligand-oxidized products, [MnV(N)(TTPPC+•)] and [MnV(N)(TTPPC2+)]+ ("TTPPC" has a 3- charge, 'TTPPC+•' has an overall 2- charge and 'TTPPC2+' has an overall 1- charge). Although [MnV(N)(TTPPC2+)]+ is formally a manganese(V) complex, it was found to be the most electrophilic among isolated metal nitrido complexes. The use of the bulky corrole ligand effectively prevents the decomposition of Mn≡N by N···N coupling.A number of luminescent M═O species that possess highly oxidizing excited states are known. We have also developed a strongly luminescent osmium(VI) nitrido complex, [OsVI(N)(L)(CN)3]- (OsN, HL = 2-(2-hydroxy-5-nitrophenyl)benzoxazole), that absorbs visible light to generate a highly oxidizing/electrophilic excited state. The excited state readily reacts with a wide variety of organic and inorganic substrates, many of these reactions are unprecedented. Notably, it reacts with cyclohexane to give an osmium(IV) cyclohexyliminato product, and with benzene to give an osmium(IV) p-benzoquinone iminato species.

Combined Synthetic, Spectroscopic, and Computational Insights Into a General Method for Photosensitized Alkene Aziridination

Combined Synthetic, Spectroscopic, and Computational Insights Into a General Method for Photosensitized Alkene Aziridination

Synthesis of N-H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent.

Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield. This method presents a promising avenue for synthesizing aziridines from a wide range of alkenes, featuring the benefits of straightforward operation, mild reaction conditions, extensive substrate compatibility, and scalability.

Aziridination via Nitrogen-Atom Transfer to Olefins from Photoexcited Azoxy-Triazenes.

Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C-H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene. Furthermore, a mild photoredox-catalyzed N-N cleavage of the protecting group to furnish the free aziridines is reported. Our findings contribute to the advancement of sustainable and practical methodologies for the synthesis of nitrogen-containing compounds, showcasing the potential for broader applications in synthetic chemistry.

Rhodium-Catalyzed Asymmetric Aziridination of Unactivated Terminal Olefins

Rhodium-Catalyzed Asymmetric Aziridination of Unactivated Terminal Olefins

Organic Dye-Sensitized Nitrene Generation: Intermolecular Aziridination of Unactivated Alkenes.

Aziridines are important structural motifs and intermediates, and several synthetic strategies for the direct aziridination of alkenes have been introduced. However, many of these strategies require an excess of activated alkene, suffer from competing side-reactions, have limited functional group tolerance, or involve precious transition metal-based catalysts. Herein, we demonstrate the direct aziridination of alkenes by combining sulfonyl azides as a triplet nitrene source with a catalytic amount of an organic dye functioning as photosensitizer. We show how the nature of the sulfonyl azide, in combination with the triplet-excited state energy of the photosensitizer, affects the aziridination yield and provide a mechanistic rationale to account for the observed dependence of the reaction yield on the nature of the organic dye and sulfonyl azide reagents. The optimized reaction conditions enable the aziridination of structurally diverse and complex alkenes, carrying various functional groups, with the alkene as the limiting reagent.

Unraveling the potential of backbone modifications in iron(II) NHC complexes for olefin aziridination and imination

A model catalysis reaction for a C2 + N1 type aziridination and imination of p-tolyl azide with cis-cyclooctene in toluene is reported. Applying 10 equivalents related to the azide, cis-cyclooctene is consumed within 24 h. A reaction temperature of 90 °C is chosen for solubility and activity reasons. A variety of Fe(II) N-heterocyclic carbene (NHC) complexes (1–5) are tested as additives. All show promising formation of aziridine and its imine isomer in the benchmark reaction. However, similar activities are also achieved by a metal-free control reaction together with a similar product distribution of A (aziridine), B (imine) and C (aziridine). The metal compounds cannot be considered as catalysts, but they do indeed influence the isomeric distribution of the reaction. To contextualize the conceivable product isomers, density functional theory calculations were performed (B3LYP/6–31G(d,p)) to determine the minimum ground state energies. As expected, these are nearly identical. However, the backbone modification of the open-chain NHC ligated iron(II) complex (5) allows switching of the predominant reaction, favoring imine (B) as main product.

Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst.

Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction.

Organic photosensitized aziridination of alkenes.

We report a new TADF-catalyzed aziridination of alkenes under visible light. In this protocol, a free triplet nitrene is in situ generated from the commercially available tosyl azide by energy transfer of the excited photocatalyst 4DPAIPN. Our finding enables the smooth installation of the strained aziridine ring into a remarkably wide scope of alkenes and pharmaceutical-derived olefins and natural products, as well as the synthesis of sitagliptin. This metal-free method provides a new opportunity for the late-stage modification of complex molecules or synthesis of nitrogen-containing pharmaceuticals.

Hydrogen-bond activation enables aziridination of unactivated olefins with simple iminoiodinanes.

Iminoiodinanes comprise a class of hypervalent iodine reagents that is often encountered in nitrogen-group transfer (NGT) catalysis. In general, transition metal catalysts are required to effect efficient NGT to unactivated olefins because iminoiodinanes are insufficiently electrophilic to engage in direct aziridination chemistry. Here, we demonstrate that 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) activates N-arylsulfonamide-derived iminoiodinanes for the metal-free aziridination of unactivated olefins. 1H NMR and cyclic voltammetry (CV) studies indicate that hydrogen-bonding between HFIP and the iminoiodinane generates an oxidant capable of direct NGT to unactivated olefins. Stereochemical scrambling during aziridination of 1,2-disubstituted olefins is observed and interpreted as evidence that aziridination proceeds via a carbocation intermediate that subsequently cyclizes. These results demonstrate a simple method for activating iminoiodinane reagents, provide analysis of the extent of activation achieved by H-bonding, and indicate the potential for chemical non-innocence of fluorinated alcohol solvents in NGT catalysis.

Generic and facile mechanochemical access to versatile lattice-confined Pd(ii)-based heterometallic sites.

Metal-organic frameworks (MOFs) show remarkable potential in a broad array of applications given their physical and chemical versatility. Classical synthesis of MOFs is performed using solution chemistry at elevated temperatures to achieve reversible metal-ligand bond formation. These harsh conditions may not be suitable for chemical species sensitive to high temperature or prone to deleterious reactions with solvents. For instance, Pd(ii) is susceptible to reduction under solvothermal conditions and is not a common metal node of MOFs. We report a generic and facile mechanochemical strategy that directly incorporates a series of Pd(ii)-based heterobimetallic clusters into MOFs as metal nodes without Pd(ii) being reduced to Pd(0). Mechanochemistry features advantages of short reaction time, minimum solvent, high reaction yield, and high degree of synthetic control. Catalytic performances of lattice-confined heterobimetallic sites are examined for nitrene transfer reactions and we demonstrate that the chemoselectivity for allylic amination versus olefin aziridination is readily tuned by the identity of the first-row metal ion in Pd(ii)-based heterobimetallic clusters.

Photocatalytic Generation of Trifluoromethyl Nitrene for Alkene Aziridination

AbstractN‐Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N‐trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe‐to‐use precursor, by visible light photocatalysis. The addition of CF3N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N‐trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N‐trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N‐CF3 compounds with possible applications in the life sciences.

Photocatalytic Generation of Trifluoromethyl Nitrene for Alkene Aziridination.

N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF3 N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF3 compounds with possible applications in the life sciences.

Stereospecific Aminative Cyclizations Triggered by Intermolecular Aza‐Prilezhaev Alkene Aziridination

AbstractUnder acidic reaction conditions (TFA), deprotection of BocNR(OSO2R) reagents triggers intermolecular aminative cyclizations of alkenes equipped with pendant nucleophiles. The processes are predicated on a sequence of stereospecific intermolecular aza‐Prilezhaev aziridination followed by stereospecific SN2‐like opening by the pendant nucleophile. The method offers broad scope with respect to the nucleophile (N‐, O‐ or C‐based), alkene and cyclization mode, allowing the installation of two contiguous stereocenters under operationally simple conditions.

Stereospecific Aminative Cyclizations Triggered by Intermolecular Aza-Prilezhaev Alkene Aziridination.

Under acidic reaction conditions (TFA), deprotection of BocNR(OSO2 R) reagents triggers intermolecular aminative cyclizations of alkenes equipped with pendant nucleophiles. The processes are predicated on a sequence of stereospecific intermolecular aza-Prilezhaev aziridination followed by stereospecific SN 2-like opening by the pendant nucleophile. The method offers broad scope with respect to the nucleophile (N-, O- or C-based), alkene and cyclization mode, allowing the installation of two contiguous stereocenters under operationally simple conditions.

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.

An insight on iron mediated aziridination reactions

Aziridines are three-membered N-heterocycles that are extremely strained and serve as a significant synthetic intermediate, similar to epoxides, and are found in several bioactive components. The researchers are interested in developing novel synthetic processes for the aziridine moiety in addition to using the currently available methods. The aziridination of alkenes, aided by complexes of transition metals, constitutes an intriguing and exciting synthetic approach. Among various transition metals, iron-catalysed reactions are increasingly prominent due to the biocompatibility and natural abundance of Fe as well as the requirement to develop catalysis that is realistically efficient and enduring for the fine chemical industries. This review highlights the synthesis of aziridines catalysed by an iron catalytic system.

Development of Practical Synthetic Methods Utilizing O-X or N-X Species

In chemical species containing of oxygen-halogens and nitrogen-halogens bonds, the halogen substituents show versatile reactivities, because oxygen and nitrogen atoms have higher electronegativity than halogen elements except for fluorine. I have focused on such monovalent halogen species and developed various synthetic methods utilizing O-X and N-X bonds which involves ionic and radical reactions. In this account, I describe such practical synthetic methodologies, which are CO2 fixation to unsaturated alcohols and amines, oxidative homo- and cross-coupling reactions of aromatic amines, novel generation of nitrile oxides from aldoximes, synthesis of oxazole-fused C60, iodoamination of alkenes in water, diaziridination of secondary amines, diastereodivergent diamination of unactivated alkenes, practical aziridination of electron-deficient alkenes, selective synthesis of nitrogen-bridged fullerenes, and benzylic C-H amidation.

Substrate-Directed Enantioselective Aziridination of Alkenyl Alcohols Controlled by a Chiral Cation.

Alkene aziridination is a highly versatile transformation for the construction of chiral nitrogen-containing compounds. Inspired by the success of analogous substrate-directed epoxidations, we report an enantioselective aziridination of alkenyl alcohols, which enables asymmetric nitrene transfer to alkenes with varied substitution patterns, including those not covered by the current protocols. We believe that our method is effective because it is substrate-directed, exploiting a network of attractive non-covalent interactions between the substrate, an achiral dianionic rhodium(II,II) tetracarboxylate dimer, and its two associated cinchona alkaloid-derived cations. It is these cations that provide a defined chiral pocket in which the aziridination can occur. In addition to a thorough evaluation of compatible alkene classes, we advance a practical mnemonic to predict reaction outcome and disclose a range of post-functionalization protocols that highlight the unique synthetic potential of the enantioenriched aziridine-alcohol products.

A Stereospecific Alkene 1,2‐Aminofunctionalization Platform for the Assembly of Complex Nitrogen‐Containing Ring Systems

AbstractTFA promoted deprotection of O−Ts activated N‐Boc hydroxylamines triggers aminofunctionalization‐based polycyclizations of tethered alkenes. The processes involve intramolecular stereospecific aza‐Prilezhaev alkene aziridination in advance of stereospecific C−N cleavage by a pendant nucleophile. Using this approach, a wide range of fully intramolecular alkene anti‐1,2‐difunctionalizations can be achieved, including diaminations, amino‐oxygenations and amino‐arylations. Trends associated with the regioselectivity of the C−N cleavage step are outlined. The method provides a broad and predictable platform for accessing diverse C(sp3)‐rich polyheterocycles of relevance to medicinal chemistry.