Recent Advances in Transition Metal-Catalyzed Ring-Opening Reaction of Aziridine

Abstract

The smallest strained, saturated N-heterocycles, such as aziridine, can be a valuable building block in synthetic organic chemistry. Ring-opening reactions with various nucleophiles could be the most important strategy to synthesize various value-added molecular entities. Therefore, regioselective ring-opening reactions of aziridines with various heteroatomic nucleophiles and carbon nucleophiles establish a useful synthetic methodology to synthesize biologically relevant β-functionalized alkylamines. The regio-selective ring-opening of aziridines is highly dependent on the substrate combination, and stereochemical control is challenging for Lewis acid-promoted reactions. Therefore, the development of a robust, catalytic ring-opening process that assists in the accurate prediction of regioselectivity and stereochemistry is highly desirable. Consequently, a large number of publications detailing distinct methods for aziridine ring-opening reactions can be found in the literature. In this review, we discuss several transition metal catalyzed cross-coupling reaction protocols for the ring opening of substituted aziridines with various carbon nucleophiles.

1. Introduction

Aziridines, three-membered, saturated, nitrogen-containing heterocycles, confer high reactivity due to the geometric constraints of the trigonal ring. Indeed, they facilitate various exciting synthetic prospects that can be exploited. Several types of ring-opening, ring-enlargement, tandem, and multicomponent reactions have been well studied for the aziridine system [1,2,3,4,5]. In addition, they are also attractive synthons for the convenient construction of useful nitrogen-containing compounds [6]. Overall, carbon-, nitrogen-, and oxygen-based nucleophiles have been extensively explored in the ring-opening reactions of aziridines [7,8].

Earlier, aziridines were challenging molecules to synthesize due to their instability. However, a variety of synthetic methods have been reported, including intramolecular substitution, annulation, cycloaddition, and metal catalysis. Currently, more-sustainable conditions have been established following green chemistry principles, involving flow chemistry techniques [9].

In the fields of medicinal chemistry and chemical biology, aziridines are of great interest for the synthesis of biomaterials like peptides [10,11]. They also play an important role in the preparation of various types of nitrogen-containing compounds, which are used extensively in medicinal chemistry [12,13]. Aziridines are used to synthesize various types of natural products [14,15] and drug molecules such as pseudoephedrine [16,17,18], sphingosine [19], and Tamiflu [20]. In addition, they can be used to make several catalysts, such as the Grubbs catalyst [21] and salen ligands [22].

Aziridines are categorized as either non-activated (substituted with electron-releasing groups) or activated (substituted with electron-withdrawing groups), depending on the substituents attached to the nitrogen atom. The regioselectivity of the ring-opening reactions of non-activated aziridines depends on a few variables, such as the type of electrophiles, substituents, and nucleophiles present in the reaction coordinates [23]. Over the years, many interesting reviews on metal-catalyzed ring-opening reactions of non-activated aziridines have been published [24,25,26].

The development of transition metal (TM)-catalyzed organic transformations under various conditions, which we are continuingly interested in, has become an attractive research area in recent years and is expanding rapidly [27,28,29,30]. The development of sophisticated synthetic methodologies has been facilitated by using transition metal complexes as catalysts in organic synthesis [31,32,33]. Presently, transition metal-catalyzed transformations, including C-H functionalization, olefin metathesis, cross-coupling, and selective hydrogenation, have revolutionized synthetic organic chemistry [34,35,36,37,38,39,40,41,42]. In correlation with the recent advancements in transition metal-catalyzed cross-coupling reactions, aziridines can be used as versatile coupling partners in regioselective and stereospecific cross-couplings.

In this review, we will discuss the transition metal-catalyzed regioselective and stereoselective cross-couplings of aziridines with various C-nucleophiles (Scheme 1). The developed methods allow for the synthesis of medicinally important amine compounds, such as β-phenethylamines and β-amino acids, from readily available aziridine substrates. Notably, the regioselectivity of the ring opening can be switched by appropriate selection of the catalyst combination. Overall, mechanistic studies suggest that the interactions (preferably oxidative addition) between the transition metal catalyst and the aziridine substrate play an important role in defining the regioselectivity of the aziridine ring-opening event. Our discussion will focus on the most recent advancements in the transition metal-catalyzed ring opening of aziridines with various carbon nucleophiles to generate new C-C bonds.

2. Palladium (Pd)-Catalyzed Aziridine Ring-Opening Reactions

The oxidative addition of aziridine with Pd(0) was first observed by the Wolfe group. They demonstrated that N-tosylaziridines can be converted to N-tosylketimines via a Pd-catalyzed isomerization reaction (Scheme 2). This protocol exhibited excellent functional group tolerance and was suitable for use in one-pot sequential reactions. In their proposed mechanism, they described that the oxidative addition of N-tosylaziridine to Pd(0) presumably occurs in an S_N2 fashion, resulting in the formation of either zwitterion 1 or azapalladacyclobutane 2. These species could then undergo β-hydride elimination to produce a hydrido-palladium intermediate 3. Subsequently, the reductive elimination of intermediate 3 yields N-tosylenamine, which then tautomerizes to form the desired imine products [43].

Tetrahydroquinolines are present in a variety of biologically active compounds. These compounds exhibit a wide range of pharmacological activities, including analgesic, cardiovascular, antitumor, and antiallergic effects [44]. Thus, synthesizing this core structure represents an important research area for synthetic organic chemists.

In 2011, the Ghorai group reported a method for synthesizing tetrahydroquinoline derivatives through a base-mediated, S_N2-type ring opening of N-tosyl aziridines with acrylonitriles, followed by Pd-catalyzed, intramolecular C–N coupling reactions (see Scheme 3). They developed this sequential reaction as a one-pot process with excellent yields [45].

New, medicinally important N-heterocyclic scaffolds, such as 1,4-benzoxazepine derivatives, can be synthesized through the ring opening of strained aziridine molecules. A novel and efficient method for synthesizing this seven-membered 1,4-benzoxazepine has been developed via a palladium-catalyzed, three-component domino reaction involving N-tosylaziridines, 2-iodophenol, and isocyanides (Scheme 4). This domino protocol proved compatible with a range of starting materials and generated the desired products at moderate to good yields.

Preliminary mechanistic experiments suggest that the plausible catalytic cycle involves the ring opening of aziridine with 2-iodophenol, forming amide derivative 4. This amide then undergoes oxidative addition with the Pd(0) catalyst to produce intermediate 5. Intermediate 5 subsequently reacts with isocyanide to form intermediate 6, which is converted to intermediate 7 through the extrusion of hydroiodic acid. Finally, the reductive elimination of intermediate 7 yields the desired 1,4-benzoxazepine products [46].

The palladium-catalyzed cross-coupling of vinyl aziridines with organoboronic acids was developed using 0.5–2.5 mol% of a pincer-complex catalyst (8) (Scheme 5a). This reaction proceeded under mild conditions, yielding allylic amine derivatives with high regioselectivity and excellent yields. The authors proposed that the reaction involves the transmetallation of the organoboronic acid with the Pd–pincer complex, followed by S_N2-type ring opening with the aziridine substrate, leading to allylic amines with high E-selectivity. Throughout the process, the oxidation state of palladium remained +2, and no oxidative side products were observed [47].

In 2014, the Hyland group reported a phenanthroline-ligated, palladium-catalyzed addition reaction of arylboronic acids to vinyl aziridines (see Scheme 5b). This reaction proceeded via an insertion/ring-opening mechanism, providing Z-selective allylsulfonamide products. This selectivity complements the E-selectivity observed with the Pd–pincer complex method. The protocol was highly compatible with electron-deficient arylboronic acids compared with their electron-donating counterparts [48].

β-Phenylethylamine is an important structural motif found in several organic molecules with distinct and desirable biological properties [49]. Therefore, synthesizing this motif is highly desirable in organic chemistry. A robust protocol for synthesizing substituted phenylethylamine analogs involves the palladium-catalyzed cross-coupling of 2-alkyl-substituted aziridines with arylboronic acids. Tri-1-naphthylphosphine has been identified as the ligand of choice for achieving the best yields. The steric bulk of this ligand likely plays a crucial role in preventing the formation of unwanted β-hydride elimination products. The reaction demonstrated high regioselectivity and was compatible with a range of functional groups.

The proposed mechanistic cycle begins with the oxidative addition of aziridine to Pd(0), forming azapalladacycle 9. This intermediate then converts to Pd-alkoxide 10 through protonolysis with an additive alcohol. Subsequently, intermediate 10 undergoes transmetallation and reductive elimination to produce the desired product (Scheme 6) [50].

Constructing a new stereogenic center in a highly stereocontrolled manner using transition metal catalysis has long been a challenging task in organic synthesis. In 2014, the Minakata group reported a Pd/NHC-catalyzed stereospecific and regioselective cross-coupling of enantiopure 2-arylaziridines with arylboronic acids, resulting in a series of enantiomerically enriched 2-arylphenylethylamine derivatives. A bench-stable catalyst, [SIPr-Pd(cinnamyl)Cl], was identified as an effective NHC-ligated Pd precatalyst for this reaction. The oxidative addition of aziridine to the precatalyst proceeds in an S_N2 manner, forming stereoinverted alkylpalladium intermediates 11 or 12. Transmetallation and simultaneous protonation of the amide ion by boronic acid or water generate T-shaped Pd-complex 13, which then undergoes reductive elimination to produce the desired product (Scheme 7) [51].

The role of the SIPr ligand is crucial; its strong σ-donating nature facilitates smooth oxidative addition, while the weak interaction between the methyl hydrogen of SIPr and the Pd center helps suppress β-hydride elimination. The Minakata group also employed density functional theory (DFT) calculations to elucidate the reaction mechanism. An energy decomposition analysis of the key transition states revealed that the interaction between Pd(0)SIPr and aziridine is significant for determining the correct selectivity. The theoretical mechanism of the catalytic cycle aligned with previous experimental observations [52].

In 2019, the same group developed an innovative protocol for the Pd-catalyzed, highly regioselective, and enantiospecific ring-opening cross-coupling of aziridine-2-carboxylates with arylboronic acids. Using this protocol, they synthesized enantiomerically enriched β²-aryl amino acids from commercially available serine esters (Scheme 8). A substantially σ-donating NHC ligand, featuring two NMe2 groups attached to the IPr core, was found to be optimal for achieving excellent selectivity. This NHC ligand participated in all the organometallic steps—oxidative addition, transmetallation, and reductive elimination—of the process. Additionally, the mechanism of the catalytic cycle was further rationalized through DFT studies [53].

The synthesis of diverse N-heterocycles has long been a central focus in organic synthesis. Despite substantial progress achieved through various synthetic methods, developing a practical ring-expansion strategy that employs formal cross-dimerization between aziridines and three- or four-membered ring ketones via synergistic bimetallic catalysis remains recommended. This approach could lead to the formation of various N-heterocycles, such as 3-benzazepinones, dihydropyridinones, and uracils, which serve as versatile core units in numerous drugs and biologically active compounds [54]. In 2021, the Zhao group introduced a novel synergistic bimetallic catalytic approach for synthesizing these heterocycles (Scheme 9). Based on both experimental and DFT studies, two distinct reaction pathways were proposed: Path A and Path B. Path A involves the C–N cleavage of aziridines followed by C–C cleavage, whereas Path B proceeds through the C–C cleavage of the ring ketone followed by C–N cleavage of the aziridine. Both pathways utilize synergistic palladium and Lewis acid catalysis to yield the same product (Scheme 10) [55].

3. Nickel (Ni)-Catalyzed Aziridine Ring-Opening Reactions

In the case of aziridines, oxidative addition with nickel is relatively facile, similar to that with palladium, and leads to the formation of isolable azametallacyclobutane intermediates by inserting into the less hindered C–N bond of the aziridine molecule. The Doyle group first reported a cross-coupling reaction between N-sulfonyl aziridines and organozinc reagents using an inexpensive and air-stable Ni(II) catalyst with dimethyl fumarate as the ligand (Scheme 11).

Unlike traditional nucleophilic aziridine ring-opening reactions, this mild protocol is compatible with a wide variety of functional groups. Although a Ni(I)/Ni(III) cycle cannot be excluded, a Ni(0)/Ni(II) cycle is proposed, as the Ni(II)-azametallacycle serves as a competent intermediate for C–C bond formation. Additionally, the dimethyl fumarate ligand is expected to accelerate reductive elimination by coordinating with the nickel center. The stereoselectivity of the reaction is maintained through a sulfonamide-directed C–C bond-formation mechanism [56].

The same group further applied their novel concept to the directed Negishi cross-coupling of alkyl aziridines with nickel catalysis. This methodology represents the first catalytic cross-coupling reaction involving a non-allylic and non-benzylic Csp³–N bond as an electrophile. They designed and introduced a new N-protecting group, cinsyl, which features an electron-deficient olefinic linkage that directs oxidative addition and facilitates reductive elimination. A plausible catalytic cycle was proposed based on several control experiments. Initially, the reduction of Ni(II) to Ni(0) occurred in the presence of LiCl, generating a Ni(0)–Cl complex that likely participates in the oxidative addition with aziridine. Transient coordination of Ni(0) with the olefinic double bond of the cinsyl group facilitates oxidative addition to the C–N bond. Subsequent transmetallation with the organozinc reagent cleaves the metallacyclic Ni–N bond, allowing efficient coordination of Ni to the electron-deficient double bond. Finally, Ni–olefin coordination effectively facilitates the reductive elimination process, yielding the desired cross-coupling product (Scheme 12) [57].

In 2017, the Doyle group discovered the Ni-catalyzed, reductive cross-coupling of styrenyl aziridines with aryl iodides. They first demonstrated the feasibility of this coupling reaction using racemic aziridines and the tridentate 2,6-bis(N-pyrazolyl)-pyridine (bpp) as the ligand. This reaction showed broad functional group compatibility for aziridine coupling partners, accommodating both electron-rich and electron-poor substituents on the aryl ring. Concurrently, an asymmetric version of this methodology was developed using a chiral bisoxazoline ligand, L3 (Scheme 13) [58]. This process enabled the facile synthesis of highly enantiomerically enriched 2-arylphenethylamines from racemic aziridines. Both electron-rich and electron-deficient aryl iodides were well tolerated, delivering the highest levels of enantioselectivity. Multivariate assessment revealed that ligand polarizability, among other factors, influenced the observed enantioselectivity.

In 2020, the Doyle group developed a unique photocatalytic, Ni-catalyzed cross-electrophile coupling strategy using aliphatic aziridines and aryl or heteroaryl iodides, yielding a broad range of β-phenethylamine derivatives (Scheme 14) [49]. The reaction proceeded efficiently in the presence of a carbazole-based photocatalyst (4CzIPN) under a 450 nm wavelength of blue LED light. Mechanistic studies indicated that the formation of an iodoamine through nucleophilic ring opening is essential for the reaction’s success. Notably, this aziridine activation mode differs from those in previous transition metal-catalyzed, oxidative C-N bond activation methods. The protocol was well tolerated with various aziridines and aryl iodides, including those with several electron-donating and electron-withdrawing substituents.

Following Doyle’s work, the Jamison group reported a ligand-controlled, nickel-catalyzed cross-coupling of aliphatic N-tosyl aziridines with aliphatic organozinc reagents. They developed an air-stable nickel(II) chloride/3,4,7,8-tetramethyl-1,10-phenanthroline (Me₄phen) catalytic system, which exhibited complete regioselectivity for reaction at the less hindered C-N bond, yielding the desired cross-coupling product at good to excellent yields (Scheme 15). Several control experiments, including deuterium-labeling studies, suggested that the reaction proceeded with an overall inversion of the configuration at the terminal position of the aziridine. The formation of the coupling product occurred via an S_N2-type aziridine ring opening by the nickel catalyst, involving configuration inversion, transmetallation (retention), and reductive elimination (retention). These results contrast with previously reported nickel-catalyzed reactions [59].

Coupling two electrophilic reagents has always been a challenging task for synthetic organic chemists. However, the Wang group developed a photoredox catalytic process that successfully couples aldehydes with aziridines, enabling the ring opening of N-tosyl styrenyl aziridines with aldehydes. This method provides access to a variety of β-amino ketones with complete regioselectivity (Scheme 16). Mechanistic studies indicated that the ring-opening reaction proceeded through a cooperative catalytic mode. In this process, the aldehyde generates acyl radicals via tertiary butyl ammonium decatungstate (TBADT) under photoirradiation, while the nickel catalyst is responsible for the ring opening of the aziridine [60].

Aziridines can be used as coupling partners in C-H activation protocols. In 2021, the Miura group developed a nickel-catalyzed C-H coupling method using 8-aminoquinoline-derived benzamides and aziridines. The reaction proceeded efficiently without the need for any external ligands. This method provided direct access to functionalized 3,4-dihydroisoquinolinones through a cascade of C-H alkylation and intramolecular amidation, with concomitant removal of the aminoquinoline directing group (Scheme 17). The reaction was compatible with both aryl- and alkyl-substituted aziridines, and the regioselectivity was controlled by the nature of the substituents. Mechanistic studies, including control experiments, suggested that the catalytic cycle begins with the chelation of the benzamide and Ni(II) complex, followed by reversible C-H cleavage to generate nickellacycle 14 and AcOH. Subsequent coordination of the aziridine nitrogen atom to the Ni(II) center leads to elongation of the C-N bond and promotes C-C coupling via an S_N2-type nucleophilic ring-opening process [61].

β-Amino acids are important biological motifs in organic chemistry. Organic chemists have faced many challenges in designing alternative catalytic carboxylation techniques to improve the synthetic methods for β-amino acid derivatives [62]. In 2021, the Martin group developed a mild and selective catalytic protocol for the nickel-catalyzed reductive carboxylation of aziridines, yielding valuable β-amino acid building blocks (Scheme 18). They identified a substituted bipyridine ligand, L5, as crucial to the success of this methodology. Additionally, the use of methanol as an additive, manganese as a reductant, and the specific ligand backbone was essential for the process [63].

In 2023, the Fan group reported a nickel-catalyzed, regioselective, cross-electrophilic ring-opening reaction of sulfonyl-protected aziridines with trifluoromethyl-substituted alkenes. This method provided a new and useful compound, gem-difluorobishomoallylic sulfonamides (Scheme 19). Through ligand screening, the biquinoline ligand, L6, was identified as the optimal choice. This protocol was compatible with various trifluoromethyl-substituted alkenes and sulfonyl aziridines. Additionally, the ring-opening products can be further transformed into 6-fluoro-1,2,3,4-tetrahydropyridine via NaH-mediated intramolecular defluorination and nucleophilic vinylic substitution [64].

4. Rhodium (Rh)-Catalyzed Aziridine Ring-Opening Reactions

In medicinal chemistry, azepine derivatives can be used for the development of pharmaceuticals, especially those intended to treat mental and neurological illnesses [65]. The azepine moiety can be synthesized via the Rh-catalyzed, intramolecular [5 + 2] cycloaddition of vinyl aziridines and alkyne (Scheme 20). This protocol exhibits an extensive reaction scope and is compatible with wide range of functional groups attached to the substrates. The mechanistic control experiments revealed that the chirality of aziridine–alkyne reactants can be completely transferred to the cycloaddition products, maintaining high atom economy and enantiospecific strategy for the generation of dihydroazepine derivatives [66].

In 2016, the Zhang group further developed the Rh-catalyzed, divergent, intermolecular cycloadditions of vinyl aziridines with alkynes. Two different feasible intermolecular [3 + 2] and [5 + 2] cycloadditions were achieved by using a Rh catalyst linked with different diene ligands such as norbornadiene (NBD) and cyclooctadiene (COD), affording five-membered dihydropyrroles and seven-membered dihydroazepines, respectively (Scheme 21). A mechanistic cycle was proposed based on the few control experiments. Initially, the coordination of the Rh catalyst to vinyl aziridine could generate intermediate 15, which further oxidized via oxidative addition process to form an intermediate product 16 and 17, which could be interchangeable. Next, the addition of alkyne into rhodium species 16 and 17 generates another two interchangeable (σ + π) rhodium complexes 18 and 19 and a further irreversible reductive elimination process produces [5 + 2] and [3 + 2] cycloaddition products, respectively [67].

Again, the same group developed a new chirality-transfer strategy to synthesize aryl ethylamine derivatives via the reaction of vinyl aziridine and naphthol using the Rh (I) catalyst (Scheme 22). This approach demonstrates a good-to-excellent product yield along with good functional group tolerance. The mechanistic analysis elucidated the formation of reactive Rh intermediates 20 and 21. Next, complex 21 reacts with naphthol to form an intermediate 22, which further delivered the product via a rearomatization process [68].

Other important heterocycles such as piperazine derivatives can be utilized for antimicrobial, antifungal, and antidepressant activities [69]. In 2020, the Schomaker group described the Rh-catalyzed ring opening of aziridine with N-sulfonyl-1, 2, 3-triazoles for synthesizing dehydropiperazine derivatives (Scheme 23). This protocol exhibits good substrate scope and is compatible with various substitutions at the substrates [70].

Four-membered aziridine molecules display a wide range of medicinal activities owing to their favorable pharmacokinetic properties, like antifungal activities, anticancer, antimicrobial, and antioxidant properties [71]. In fact, the synthesis of this material may prove to be a fruitful area of study for synthetic organic chemistry. Recently, the Bi group described the synthesis of vinyl azetidine derivatives via the Rh-catalyzed reaction of N-acyl aziridines with vinyl N-triftosylhydrazones. They proposed that the reaction proceeded via the formation of reactive vinyl carbene- and aziridinium ylide-type intermediates (Scheme 24) [72].

5. Other Transition Metal-Catalyzed Aziridine Ring-Opening Reactions

The first catalytic, radical–radical ring opening of N-acylated aziridines was achieved using a titanocene catalyst. This regioselective reaction exhibited a broad substrate scope with high functional group tolerance (Scheme 25). The absolute stereochemistry of the desired product was determined by measuring the specific rotation of β²-aryl amino acids, which was obtained quantitatively by hydrolyzing the ester group and removing the protecting group. In this novel, catalytic reaction, N-acylated aziridines were activated to undergo ring opening, forming higher-substituted radicals through electron transfer facilitated by titanocene(III) complexes. This reaction is particularly effective for constructing quaternary carbon centers and is suitable for conjugate additions, reductions, and cyclizations. The study demonstrated that N-acylated aziridines exhibit catalytic, radical ring opening. Computational studies using DFT confirmed that the ring opening of N-acyl aziridines via electron transfer proceeds through a concerted process [73].

In 2018, the Shi group developed a novel method for synthesizing para-quinone derivatives via transition metal-catalyzed (4 + 3) cyclization, followed by the ring opening of vinyl aziridines (Scheme 26). They employed iridium as the catalyst for this reaction, which led to the formation of seven-membered benzoxazepine scaffolds with good yields, ranging from approximately 40% to 96%. The authors observed that, when palladium was used as the catalyst, a mixture of stereoisomers was obtained with moderate diastereoselectivity and maximum enantioselectivity. In contrast, the use of the iridium catalyst resulted in an exclusively enantioselective product formation. Therefore, iridium catalysts were preferred for controlling the product mixture in this reaction. These findings underscore the importance of choosing the appropriate catalyst in metal-catalyzed reactions to control stereochemistry and product selectivity [74].

In 2009, Bera et al. developed a novel reaction process using Ag(I) as a catalyst to synthesize a variety of N, O-heterocycles, including oxazines, oxazepines, and oxazocines. This process involves a [Ag(COD)₂]PF₆-catalyzed cascade reaction that combines ring-opening and ring-closing steps between propargyl alcohols and N-tosylaziridines/azetidines (Scheme 27). The approach features endo-selective ring closing and efficient ring opening through the dual activation of propargylic alcohol and aziridine/azetidine by silver(I) catalysis. The yields for these products range from approximately 63% to 76% [75].

In 2010, Bera et al. developed a new method for synthesizing C-arylation derivatives from N-tosylaziridines using Ag(I)–diene complexes as catalysts, providing β-aryl amine derivatives with excellent regioselectivity (Scheme 28). These Ag(I)–diene complexes proved to be versatile catalysts for this process. The dienes utilized in the reaction include cyclooctadiene, norbornadiene, and 1,3-cyclohexadiene, with the anions being PF6⁻ or BF4⁻. Mechanistic studies indicated that the reactive species in this reaction are [Ag(diene)(arene)]⁺ and [Ag(arene)2]⁺ [76].

A new strategic technique was developed for synthesizing benzoimidazolylethylamine derivatives via the copper-catalyzed cross-coupling of 2-alkyl/2-arylaziridines with benzimidazoles. This method involves the regiospecific ring opening of aziridines with benzimidazoles, resulting in the formation of benzoimidazolylethylamine derivatives (Scheme 29). These derivatives then undergo dehydrogenative cross-coupling between C(Sp²)-H and N-H bonds to produce dihydroimidazobenzimidazoles. Notably, optically active 2-arylaziridines can be stereoinverted during cross-coupling with high enantiomeric purity. The aerobic catalytic system operates with inexpensive Cu(II) salts and a PCy₃ ligand at moderate temperatures. The reactions utilize readily accessible reagents and straightforward conditions, exhibiting high selectivity. This approach opens new avenues for the further development of the stereoselective cross-coupling of aziridines with diverse heterocyclic scaffolds [77].

Moving forward, the Ghorai group developed a novel Cu-catalyzed pathway for synthesizing C-C bond formations via the ring opening of aziridines. They discovered a simple and unexpected synthetic route to both racemic and scalemic tetrahydro dibenzoimidazoazepines. This approach involved an S_N2-type ring opening of N-activated aziridines with 2-bromobenzyl alcohol, followed by a cascade cyclization sequence comprising Cu-catalyzed cross-dehydrogenation C-N coupling and an unprecedented Ullmann C-C bond formation reaction. Additionally, they synthesized tetrahydrobenzoxazepine and tetrahydrobenzothiazepine derivatives through the ring opening of aziridines with 2-bromobenzyl alcohols and thiols, respectively, followed by Cu-catalyzed N-arylation reactions. This protocol holds significant potential for applications in organic synthesis, particularly in the stereoselective construction of seven-membered aza-heterocycles (Scheme 30) [78].

The Ghorai group further developed a new synthetic route to non-racemic tetrahydropyrrolo[2,3-b]indoles by employing an S_N2-type ring opening of enantiopure N-activated aziridines with 2-bromoindoles, followed by copper-catalyzed C-N cyclization. They explored various N-activated aziridines and 2-bromoindole derivatives with different substitution patterns. This method achieved the synthesis of tetrahydropyrrolo[2,3-b]indoles at good yields and with excellent enantiomeric excess (up to 99%) (Scheme 31). Particularly noteworthy was their success in synthesizing highly substituted tetrahydropyrrolo[2,3-b]indole as a single stereoisomer (de, ee > 99%) from enantiopure trans-disubstituted aziridine [79].

The same group further devised an innovative synthetic pathway for the rapid production of a new class of hexahydroimidazo[1,2-a]quinolines. Their method begins with a one-pot, Lewis acid-catalyzed, S_N2-type ring opening of the activated aziridines using N-propargylanilines, followed by sequential cascade cyclization steps involving intramolecular hydroarylation and hydroamination reactions (Scheme 32). This highly efficient approach adheres to the principles of modern organic synthesis, emphasizing atom economy, step economy, and redox efficiency, and is particularly notable for performing consecutive hydroarylation and hydroamination reactions on the same alkynyl group. The method achieved exceptional levels of diastereoselectivity and enantiospecificity, with product enantiomeric excesses exceeding 99%. Demonstrations across a broad range of activated aziridines and substituted N-propargylanilines highlight the method’s versatility and potential impact in both organic and medicinal chemistry research and practice [80]. A plausible mechanistic cycle was proposed for this chemical transformation (Scheme 32). Initially, Zn(OTf)₂ coordinates with the aziridine nitrogen, forming a reactive intermediate, which undergoes an S_N2-type reaction with N-propargylaniline, leading to a ring-opened product. Finally, the desired quinoline derivatives are generated via intramolecular hydroarylation, followed by cyclic hydroamination reactions.

S. Zhang et al. (2016) developed a novel cycloisomerization technique via the ring opening of aziridines. They devised a convenient synthetic method for constructing morpholine derivatives from readily available aziridines and propargyl alcohols (Scheme 33). This approach employs a tandem, nucleophilic ring opening of aziridines, followed by a 6-exo-dig cyclization and double-bond isomerization sequence using a single gold(I) catalyst under mild conditions. The gold(I) catalyst functions as both a π acid and a σ acid, enabling the dual activation of the reactants. The resulting unsaturated morpholine products can be easily hydrogenated to yield the target morpholine derivatives with excellent diastereoselectivity and high yields. The initial experiments showed promising results, with the reaction completing within 30 min at 0 °C and efficiently yielding the desired product 3a. Further optimization identified dichloromethane (DCM) as the optimal solvent, while other gold catalysts proved ineffective. These findings highlight the crucial role of the cationic gold catalyst in activating the aziridine, as confirmed by control experiments with AgOTf or HOTf, which yielded only ring-opening intermediates. Notably, the reaction exhibited selective attack by propargyl alcohol at the sterically hindered position of the aziridine, resulting in a single regioisomer [81].

6. Conclusions

The synthesis of various heterocyclic compounds greatly benefits from using the aziridine ring as a fundamental building block, facilitating the creation of both bioactive and non-bioactive molecules. Various methods, utilizing either metal or non-metal catalysts under specific conditions, are employed in this context. This discussion focuses specifically on the application of transition metals as catalysts in the ring opening of aziridines to form new C-C bonds, in addition to C-N, C-S, and C-O bonds. This review emphasizes the pivotal role of aziridines in modern synthetic chemistry, highlighting their versatility in producing N-heterocycles and functionalized compounds. The methodologies outlined adhere to the principles of atom economy, step efficiency, and redox neutrality, which are crucial for robust chemical synthesis. These approaches offer valuable insights into catalyst development, stereochemical control, and reaction optimization, thereby advancing fields such as medicinal chemistry, materials science, and beyond.