A Mechanistic Study on Iron-Based Styrene Aziridination: Understanding Epoxidation via Nitrene Hydrolysis.

Transition-metal-catalyzed nitrene transfer reactions are typically performed in organic solvents under inert and anhydrous conditions due to the involved air and water-sensitive nature of reactive intermediates. Overall, this study provides insights into the iron-based ([FeII(PBI)3](CF3SO3)2 (1), where PBI = 2-(2-pyridyl)benzimidazole), catalytic and stoichiometric aziridination of styrenes using PhINTs ([(N-tosylimino)iodo]benzene), highlighting the importance of reaction conditions including the effects of the solvent, co-ligands (para-substituted pyridines), and substrate substituents on the product yields, selectivity, and reaction kinetics. The aziridination reactions with 1/PhINTs showed higher conversion than epoxidation with 1/PhIO (iodosobenzene). However, the reaction with PhINTs was less selective and yielded more products, including styrene oxide, benzaldehyde, and 2-phenyl-1-tosylaziridine. Therefore, the main aim of this study was to investigate the potential role of water in the formation of oxygen-containing by-products during radical-type nitrene transfer catalysis. During the catalytic tests, a lower yield was obtained in a protic solvent (trifluoroethanol) than in acetonitrile. In the case of the catalytic oxidation of para-substituted styrenes containing electron-donating groups, higher yield, TON, and TOF were achieved than those with electron-withdrawing groups. Pseudo-first-order kinetics were observed for the stoichiometric oxidation, and the second-order rate constants (k2 = 7.16 × 10-3 M-1 s-1 in MeCN, 2.58 × 10-3 M-1 s-1 in CF3CH2OH) of the reaction were determined. The linear free energy relationships between the relative reaction rates (logkrel) and the total substituent effect (TE, 4R-PhCHCH2) parameters with slopes of 1.48 (MeCN) and 1.89 (CF3CH2OH) suggest that the stoichiometric aziridination of styrenes can be described through the formation of a radical intermediate in the rate-determining step. Styrene oxide formation during aqueous styrene aziridination most likely results from oxygen atom transfer via in situ iron oxo/oxyl radical complexes, which are formed through the hydrolysis of [FeIII(N•Ts)] under experimental conditions.

Chiral Cpx Rhodium(III)-Catalyzed Enantioselective Aziridination of Unactivated Terminal Alkenes.

Chiral cyclopentadienyl-rhodium(III) Cpx Rh(III) catalysis has been demonstrated to be competent for catalyzing highly enantioselective aziridination of challenging unactivated terminal alkenes and nitrene sources. The chiral Cpx Rh(III) catalysis system exhibited outstanding catalytic performance and wide functional group tolerance, yielding synthetically important and highly valuable chiral aziridines with good to excellent yields and enantioselectivities (up to 99 % yield, 93 % ee). This protocol presents a novel and effective strategy for synthesizing enantioenriched aziridines from simple alkenes. Various transformations were performed on the aziridine products, illustrating the versatility and synthetic potential of this protocol for constructing highly functionalized compounds.

Metalloradical Catalysis: General Approach for Controlling Reactivity and Selectivity of Homolytic Radical Reactions.

Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two-electron heterolytic ionic chemistry. While one-electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high-energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal-centered radicals present in open-shell metal complexes as one-electron catalysts for homolytic activation of substrates to generate metal-entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two-electron catalysis by transition metal complexes, MRC operates through one-electron chemistry utilizing stepwise radical mechanisms.

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.

Aziridination Reactivity of a Manganese(II) Complex with a Bulky Chelating Bis(Alkoxide) Ligand.

Treatment of Mn(N(SiMe3)2)2(THF)2 with bulky chelating bis(alkoxide) ligand [1,1':4',1''-terphenyl]-2,2''-diylbis(diphenylmethanol) (H2[O-terphenyl-O]Ph) formed a seesaw manganese(II) complex Mn[O-terphenyl-O]Ph(THF)2, characterized by structural, spectroscopic, magnetic, and analytical methods. The reactivity of Mn[O-terphenyl-O]Ph(THF)2 with various nitrene precursors was investigated. No reaction was observed between Mn[O-terphenyl-O]Ph(THF)2 and aryl azides. In contrast, the treatment of Mn[O-terphenyl-O]Ph(THF)2 with iminoiodinane PhINTs (Ts = p-toluenesulfonyl) was consistent with the formation of a metal-nitrene complex. In the presence of styrene, the reaction led to the formation of aziridine. Combining varying ratios of styrene and PhINTs in different solvents with 10 mol% of Mn[O-terphenyl-O]Ph(THF)2 at room temperature produced 2-phenylaziridine in up to a 79% yield. Exploration of the reactivity of Mn[O-terphenyl-O]Ph(THF)2 with various olefins revealed (1) moderate aziridination yields for p-substituted styrenes, irrespective of the electronic nature of the substituent; (2) moderate yield for 1,1'-disubstituted α-methylstyrene; (3) no aziridination for aliphatic α-olefins; (4) complex product mixtures for the ß-substituted styrenes. DFT calculations suggest that iminoiodinane is oxidatively added upon binding to Mn, and the resulting formal imido intermediate has a high-spin Mn(III) center antiferromagnetically coupled to an imidyl radical. This imidyl radical reacts with styrene to form a sextet intermediate that readily reductively eliminates the formation of a sextet Mn(II) aziridine complex.

Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts.

Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.

Intermolecular Metal-Free Cyclopropanation and Aziridination of Alkenes with XH2 (X=N, C) by Thianthrenation.

Three-membered cyclic structures are widely existing in natural products and serve as enabling intermediates in organic synthesis. However, the efficient and straightforward access to such structures with diversity remains a formidable challenge. Herein, a general and practical protocol to aziridines and cyclopropanes synthesis using free XH2 (X=C or N) with alkenes by thianthrenation is presented. This metal-free protocol features the direct aziridination and cyclopropanation with unprotected XH2 . Free sulfonamides, amides, carbamates, amines, and methylene with acidic protons, are good precursors, providing an attractive alternative for straightforward synthesis of aziridines and cyclopropanes from easily available starting materials.

Lipid Mass Tags via Aziridination for Probing Unsaturated Lipid Isomers and Accurate Relative Quantification.

Knowing concentrations of lipids is essential for understanding their physiological functions and discovering new disease biomarkers. However, it is highly challenging to accurately quantify lipids due to structural diversity and multiple isomeric forms of lipids. To address these critical gaps, we have developed a novel aziridine-based isobaric tag labelling strategy that allows (i) determination of lipid double-bond positional isomers, (ii) accurate relative quantification of unsaturated lipids, and (iii) improvement of ionization efficiencies of nonpolar lipids. The power of this method is demonstrated in characterization and quantification of various categories of lipids such as fatty acids, phosphoglycerol lipids, cholesteryl esters (CE), and glycerides. 17 CE lipid isomers were identified and quantified simultaneously from Alzheimer's disease (AD) mouse serum without using lipid standards. Among them, 6 CE isomers showed significant changes in concentrations in AD serum.

3-Arylaziridine-2-carboxylic Acid Derivatives and (3-Arylaziridin-2-yl)ketones: The Aziridination Approaches.

Aziridination reactions represent a powerful tool in aziridine synthesis. Significant progress has been achieved in this field in the last decades, whereas highly functionalized aziridines including 3-arylated aziridine-2-carbonyl compounds play an important role in both medical and synthetic chemistry. For the reasons listed, in the current review we have focused on the ways to obtain 3-arylated aziridines and on the recent advances (mainly since the year 2000) in the methodology of the synthesis of these compounds via aziridination.

Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid.

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution.

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1'-NR1 R2 and 1'-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Direct Stereoselective Aziridination of Cyclohexenols with 3-Amino-2-(trifluoromethyl)quinazolin-4(3H)-one in the Synthesis of Cyclitol Aziridine Glycosidase Inhibitors.

Cyclophellitol aziridine and its configurational and functional isomers are powerful covalent inhibitors of retaining glycosidases, and find application in fundamental studies on glycosidases, amongst others in relation to inherited lysosomal storage disorders caused by glycosidase malfunctioning. Few direct and stereoselective aziridination methodologies are known for the synthesis of cyclophellitol aziridines. Herein, we present our studies on the scope of direct 3-amino-2-(trifluoromethyl)quinazolin-4(3H)-one-mediated aziridination on a variety of configurational and functional cyclohexenol isosters. We demonstrate that the aziridination can be directed by an allylic or homoallylic hydroxyl through H-bonding and that steric hindrance plays a key role in the diastereoselectivity of the reaction.

Copper-Catalyzed Aziridination with Redox-Active Ligands: Molecular Spin Catalysis.

Small-molecule catalysts as mimics of biological systems illustrate the chemists' attempts at emulating the tantalizing abilities displayed by nature's metalloenzymes. Among these innate behaviors, spin multistate reactivity is used by biological systems as it offers thermodynamic leverage towards challenging chemical reactivity but this concept is difficult to translate into the realm of synthetic organometallic catalysis. Here, we report a rare example of molecular spin catalysis involving multistate reactivity in a small-molecule biomimetic copper catalyst applied to aziridination. This behavior is supported by spin state flexibility enabled by the redox-active ligand.

Photo-Induced Aziridination of Alkenes with N-Sulfonyliminoiodinanes.

Activation of N-sulfonyliminiodinanes was achieved by photo-irradiation at 375 nm, which enabled the reaction with several alkenes to afford the corresponding aziridines. Mechanistic studies suggested that the reaction would proceed through a stepwise mechanism via radical intermediates rather than through a concerted process.

Synthesis of 1,3-Amino Alcohols by Hydroxy-Directed Aziridination and Aziridine Hydrosilylation.

We describe an approach to N-tosyl 1,3-amino alcohols that consists of a diastereoselective aziridination reaction of acyclic allylic alcohols and an unprecedented regioselective hydrosilylation of α-hydroxy aziridines. The products contain up to three contiguous stereocenters. Computational studies outline key aspects of the aziridination mechanism, which is different and more intricate than anticipated.

Enantioselective Synthesis of the Cyclopiazonic Acid Family Using Sulfur Ylides.

A convergent, nine-step (LLS), enantioselective synthesis of α-cyclopiazonic acid and related natural products is reported. The route features a) an enantioselective aziridination of an imine with a chiral sulfur ylide; b) a bioinspired (3+2)-cycloaddition of the aziridine onto an alkene; and c) installation of the acetyltetramic acid by an unprecedented tandem carbonylative lactamization/N-O cleavage of a bromoisoxazole.

Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids.

A RhII -catalyzed direct and stereospecific N-H- and N-alkyl aziridination of olefins is reported that uses hydroxylamine-O-sulfonic acids as inexpensive, readily available, and nitro group-free aminating reagents. Unactivated olefins, featuring a wide range of functional groups, are converted into the corresponding N-H or N-alkyl aziridines in good to excellent yields. This operationally simple, scalable transformation proceeds efficiently at ambient temperature and is tolerant towards oxygen and trace moisture.

Intramolecular Radical Aziridination of Allylic Sulfamoyl Azides by Cobalt(II)-Based Metalloradical Catalysis: Effective Construction of Strained Heterobicyclic Structures.

Cobalt(II)-based metalloradical catalysis (MRC) has been successfully applied for effective construction of the highly strained 2-sulfonyl-1,3-diazabicyclo[3.1.0]hexane structures in high yields through intramolecular radical aziridination of allylic sulfamoyl azides. The resulting [3.1.0] bicyclic aziridines prove to be versatile synthons for the preparation of a diverse range of 1,2- and 1,3-diamine derivatives by selective ring-opening reactions. As a demonstration of its application for target synthesis, the metalloradical intramolecular aziridination reaction has been incorporated as a key step for efficient synthesis of a potent neurokinin 1 (NK1 ) antagonist in 60 % overall yield.

Spin-Selective Generation of Triplet Nitrenes: Olefin Aziridination through Visible-Light Photosensitization of Azidoformates.

Azidoformates are interesting potential nitrene precursors, but their direct photochemical activation can result in competitive formation of aziridination and allylic amination products. Herein, we show that visible-light-activated transition-metal complexes can be triplet sensitizers that selectively produce aziridines through the spin-selective photogeneration of triplet nitrenes from azidoformates. This approach enables the aziridination of a wide range of alkenes and the formal oxyamination of enol ethers using the alkene as the limiting reagent. Preparative-scale aziridinations can be easily achieved under continuous-flow conditions.

Unprecedented trinuclear Ag(I) complex with 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine as an efficient catalyst for the aziridination of olefins.

An unprecedented trinuclear heteroleptic Ag(I) complex was isolated using a stable multidentate 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine (TPymT) ligand. The obtained compound is an efficient catalyst for the direct aziridination of terminal olefins.