Christian
Dank
a and
Laura
Ielo
*b
aInstitute of Organic Chemistry, University of Vienna, Währinger Strasse 38, 1090 Vienna, Austria
bDepartment of Chemistry, University of Turin, Via P. Giuria 7, 10125 Torino, Italy. E-mail: laura.ielo@unito.it
First published on 15th May 2023
Compounds featuring aziridine moieties are widely known and extensively reported in the literature. Due to their great potential from both synthetic and pharmacological points of view, many researchers have focused their efforts on the development of new methodologies for the preparation and transformation of these interesting compounds. Over the years, more and more ways to obtain molecules bearing these three-membered functional groups, which are challenging due to their inherent reactivity, have been described. Among them, several are more sustainable. In this review, we report the recent advances in the biological and chemical evolution of aziridine derivatives, in particular, the variety of methodologies described for the synthesis of aziridines and their chemical transformations leading to the formation of interesting derivatives, such as 4–7 membered heterocycles of pharmaceutical interest due to their promising biological activities.
Gonnade and co-workers documented the syntheses of aziridine 7 which was then used for the preparation of the well-known Tamiflu (8), also called oseltamivir phosphate, which is used as a medicine to cure both influenza A and B and to prevent the spread of influenza. In one of the described procedures, cis-aziridine (7) was employed as a chiral synthon (Scheme 2).7
Watson and co-workers reported in 2022 the asymmetric synthesis of aziridines (13) via enantioselective protonation of catalytically generated enamines by using chiral Brønsted acids such as 11 ((S)-TCYP). The aziridine ring (13) is achieved after treating the so-formed α-chloroamine 12 with a base in a one-pot process (Scheme 3).8
Catalysis is one of the most used methodologies for preparing aziridine derivatives. Indeed, a lot of pathways have been described by using different catalysts.9 Among them, nickel was employed and in 2022 Wu and co-workers reported a nickel-catalyzed aminofluoroalkylative cyclization of unactive alkenes (15) with iododifluoromethyl ketones (14) to afford versatile difluoroalkylated nitrogen-containing hetorocycles including aziridines (18), as shown in Scheme 4.10 According to the authors, the transformation proceeds through a radical mechanism. Upon treatment with the Ni-catalyst and base, iododifluoromethyl ketones (14) are transformed into intermediates such as 16, which react with N-allyl anilines (15) to give radical species 17, from which the aziridine products (18) are obtained.
Berhal et al. documented the iron-catalyzed reaction between alkenes (20) and hydroxylamine derivatives (19) to give aziridines 22. In particular, they used simple iron(II) sources and readily available ligands rendering the reaction conditions more sustainable (Scheme 5).11 Considering the mechanism of the reaction, the in situ generated iron catalyst [Fe] provides an iron–nitrene intermediate (24 or 25) after reacting with the hydroxylamine derivative 19, releasing an equivalent amount of carboxylic acid (23). Since metal–nitrene complexes exist in two different spin states, the authors consider two possible reaction pathways. If the metal–nitrene complex predominantly exists in its singlet state (24), a concerted (2 + 1) cycloaddition could take place, leading to a stereospecific process (Scheme 5 – path a). On the other hand, if the iron–nitrene complex is in its triplet state (25), a radical addition followed by a radical-based ring closure could occur (Scheme 5 – path b). In this case, due to the multistep procedure, no stereoselectivity should be observed.
Driver et al. described an intermolecular Rh2(II)-catalyzed aziridination of olefins (28) using anilines (27) as non-activated nitrogen atom precursors and an iodine(III) reagent (30) as the stoichiometric oxidant. During the process, the N-aryl nitrene fragment is transferred from the intermediate iminoiodinane (31) to the Rh(II) carboxylate catalyst 29. The reaction proved to be stereospecific and chemo- and diastereoselective to produce N-aryl aziridine 33 as the only amination product (Scheme 6).12
After describing in 2022 the use of (NHC)M (M = Cu, Ag, Au) cores as catalysts for the olefin aziridination reaction,13 recently, Pérez and co-workers reported the copper-catalyzed aziridination of olefins.14 The authors highlighted the important role of the halide characterizing the copper catalyst (Scheme 7 – path a). Indeed, they demonstrated via mechanistic studies that the employed copper(I) complexes (TTM)CuCl (35) and [(TTM)Cu-(NCMe)]PF6 (36) (TTM = tris(triazolyl)methane ligand) possess different behaviors, from catalytic and mechanistic points of view, depending on the presence or absence of the chloride ligand bonded to the metal center. If coordination is present, the limiting step of the reaction concerns the formation of the carbon–nitrene bond (39). In case the chlorine atom is not present, the highest barrier corresponds to the formation of the copper–nitrene intermediate (40). Chen and co-workers selected bis(pyrazolyl)borate Cu(I) complexes (43) as catalysts for the aziridination of olefins (Scheme 7 – path b). The reaction was carried out starting from a suitable styrene (41) and [N-(sulfonyl)imino]phenyliodinane (42). During the catalytic process, a nitrene is generated and added to the double bond.15
Dauban et al. employed C4-symmetrical dirhodium(II) tetracarboxylates (48) as catalysts for the asymmetric intermolecular aziridination of substituted alkenes (47) with p-tBu-phenylsulfamates 49 (TBPhsNH2) (Scheme 8). The authors proposed a two-spin-state mechanism, involving a triplet Rh–nitrene species as the key intermediate (50) to direct the approach with stereocontrol and for the activation of the substrate. DFT studies support the proposed mechanism. An enantiomeric excess of up to 99% was observed.16
Zirconium has also been employed as a catalyst for the synthesis of aziridine derivatives. Moura-Letts and co-workers described the aziridination of alkenes (41) by using chloramine T17 (52) as the quantitative source of nitrogen (Scheme 9). Supported by kinetics and model reaction studies, the authors propose that the reaction mechanism involves the formation of a zirconooxaziridine complex (53) as the active catalyst.18
Jat and co-workers reported the iron(II) catalyzed direct N–H/N–Me aziridination of olefins (55) employing O-arylsulfonyl hydroxylamines (56). The one-pot methodology proved to be stereo- and regioselective, yielding a variety of unactivated aziridines (57) in good to excellent yields (Scheme 10).19
Mixed approaches of photo- and metal-catalysis have also been reported for the synthesis of aziridines.20 Koenigs et al. described the preparation of trifluoromethylated aziridines (62) starting from fluorinated olefins (58) and iodinanes (59), which undergo oxidative quenching in the presence of a Ru(bpy)3Cl2 catalyst (60), releasing a nitrene radical anion (61) (Scheme 11). Computational studies confirmed that the nitrene radical (61) serves as a reactive intermediate in direct aziridination reactions.21
Zhang and co-workers employed the carbonyl azide TrocN3 (65, 2,2,2-trichloroethoxycarbonyl azide), which is a potent nitrogen radical precursor for the aziridination of olefins (64) via Co(II)-based metalloradical catalysis (65) (Scheme 12). Chiral N-carbonyl aziridines (66) were prepared at room temperature in high yields with excellent enantioselectivities. The obtained N-Troc-aziridines (66) can be opened by different nucleophiles, achieving a variety of chiral amines with excellent stereospecificity (89–100% es).22
The major part of the reported methodologies for synthesizing aziridines rely on the transition-metal catalyzed reactions of alkenes with nitrene precursors or imines with carbene precursors.23 However, these pathways are limited by the use of hazardous and explosive carbene and nitrene precursors as well as additional steps for diazo synthesis and transition-metal residue removal. For these reasons, the development of more sustainable methodologies has been pursued by scientists.24 Different pathways employing electrochemical activation to facilitate oxidative cyclization were developed.25 Nevertheless, significant limitations and challenges are still to be overcome. Recently, the employment of thianthrenium salts was reported to be an alternative methodology.26 In 2021, Wickens et al. documented the electrochemical transformation of non-activated alkenes (67) into metastable, dicationic intermediates 69 and 70 that undergo aziridination with primary amines (71) under basic conditions (Scheme 13). This new approach allows the preparation of diverse aziridine building blocks (72) bearing sensitive functional groups, such as allyl and cyano groups, that are challenging to access through more conventional approaches.26
In 2022, Shu and co-workers developed a straightforward aziridination pathway using primary amines (73) with alkenes substituted with thianthrenes (74). The methodology works well for terminal, internal, aromatic, and aliphatic alkenes (Scheme 14).27 In comparison with the electrochemical thianthrene-mediated aziridine formation, which only allows functionalization of terminal olefins with primary amines26 (Scheme 13), this conventional approach allows aziridination of both terminal and internal alkenes. Furthermore it is not limited to the use of primary amines, but also tolerates primary amides, carbamates, and sulfonamides. The use of active methylenes instead leads to cyclopropanation, making the methodology even more versatile.27
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Scheme 14 Aziridination pathway using free primary amines and alkenes substituted with thianthrenes. |
The chemoselective aziridination of styrenes (76) performed in the presence of hydroxylamine derivatives (77) via cobalt single-atom catalysis was reported by Tang and co-workers in 2023 (Scheme 15). The developed methodology is carried out under mild conditions and has a wide scope and high atom economy. Catalyst 78 is recyclable and not air-sensitive. Several natural products and drug-derived olefins have also been subjected to aziridination.28
Díez-González and co-workers reported the preparation of aziridines (82) from readily available azides (80) and alkenes (81). The reaction was carried out without any further additive by using technical solvents without the need for an inert atmosphere as the reaction can proceed in reaction vessels open to air (Scheme 16). The so-prepared aziridines (82) were then subjected to ring opening and ring enlargement reactions.29
The presence of fluorine atoms within an organic compound can modulate its physico-chemical properties.32 Therefore, the employment of fluorinated derivatives in medicinal chemistry is very common and the development of new methodologies for the preparation of such interesting molecules is a central topic within the scientific community. In 2021, Njardarson and co-workers described the preparation of trisubstituted trifluoromethylthiolated (SCF3) aziridines (85) via the Darzens pathway. In particular, trisubstituted acetophenone nucleophiles (83) bearing SCF3 and bromine substituents at the α position undergo reactions with tosyl-protected imines (84) under mild conditions to achieve the desired aziridine derivatives (85) (Scheme 17).33
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Scheme 17 Preparation of trisubstituted trifluoromethylthiolated (SCF3) aziridines via the Darzens pathway. |
In 2022, Njandarson and co-workers documented a reaction for preparing aziridines (88) starting from benzothiophene 1,1-dioxide (86) and imines (87). This vinylogous aza-Darzens reaction is base dependent (Cs2CO3 is employed) and γ-selective, favouring the formation of trans-aziridines (Scheme 18).34
A telescoped reaction for the preparation of aziridines was described by Kürti and co-workers. Various electron-deficient O-sulfonyl oximes (90) were reacted with α,α-disubstituted acetophenone-derived enolates (89) to afford highly substituted aziridines (91) via an aza-quasi-Favorskii rearrangement (Scheme 19). This methodology was supported by computational studies which suggested a rearrangement pathway. The reaction of enolate 92 with imine 90 generates the N-activated β-aminoketone 93 which cyclizes to the N-activated azetidine 94. The so-formed azetidine 94 undergoes an aza-quasi-Favorskii rearrangement to yield the highly strained and substituted aziridines 91.35
Pace and co-workers reported an unprecedent homologation reaction via lithium carbenoids for synthesizing mono- (96) and bis-homologated (97) trifluoromethyl-aziridine derivatives. The potency of this methodology relies on the selectivity of the reaction. Indeed, just by adjusting the stoichiometry of the employed carbenoid by using either 1.2 or 2.8 equivalents, the authors were able to selectively obtain chloro(trifluoromethyl)- (96) or chloromethyl(trifluoromethyl)aziridine derivatives (97), respectively.36 A wide scope and full chemocontrol was observed by using LiCH2Cl or LiCH2F as the homologating agent, prepared via lithium-halogen exchange starting from ICH2Cl or ICH2F and MeLi-LiBr (Scheme 20 – path a).37 Later on, the same group, in collaboration with Luisi and co-workers, described the preparation of rare α-fluoroaziridines (100) by using the unknown LiCHFI as the homologating agent. In this case, it was prepared via lithium-proton exchange (deprotonation) in the presence of the lithium amide base LiN(i-Pr)Cy and ICH2F. After the homologation of the imine derivatives (98) with LiCHFI, a series of highly functionalized β-fluoroiodoamines (99) were isolated, which were subjected to deprotonation with NaH and after ring closure the desired α-fluoroaziridines (100) were achieved (Scheme 20 – path b). Only in the case of 102, the direct formation of the aziridine ring was observed (Scheme 20 – path c).38
In 2023, Aggarwal and co-workers described a two-step one-pot preparation of spirocyclic aziridines containing a cyclobutane motif. In the initial step, a bicyclo[1.1.0]butyl sulfoxide (104) is lithiated and added to a suitable imine (103). Afterward, the resulting intermediate (106) is cross-coupled with an aryl triflate (107) through a C–C σ-bond alkoxy- or aminopalladation, resulting in the related aziridine (108) formation (Scheme 21).39
Gnanaprakasam et al. described a mixed continuous flow/batch approach for the preparation of spiro-aziridines (116). In the first step of the reaction, a variety of spirooxindole 2H-azirines (114) were synthesized via intramolecular oxidative cyclization of 3-(amino(phenyl)methylene)-indolin-2-one derivatives (113) in the presence of I2 and Cs2CO3. The so-prepared spirooxindole 2H-azirines (114) were transformed into spiroaziridine derivatives (116) via the addition of Grignard reagents (115) (Scheme 23).41
In 2022, Uchiyama et al. reported the aziridination of L-Val (117) by using the non-heme iron enzyme Fe(II)/α-ketoglutarate-dependent oxygenase (118, TqaL) as catalyst, via cyclization proceeding through β-hydrogen abstraction (Scheme 24 – path a). This pathway proceeds through an unusual, diverse stereochemical route implying both retention (121) and inversion (122) of the C3(Cβ) stereocenter.42 Nishiyama et al. described the biosynthesis of the aziridine derivative vazabitide A (125) catalyzed by Vzb10/11 via sulfate elimination to give aziridine 124 (Scheme 24 – path b). Vazabitide A (125) has a similar structure to azinomycin B, which shows antitumoral activity by alkylating the DNA via aziridine ring opening. Through structural analysis, the authors were able to elucidate the biosynthetic reaction mechanism.43
With regard to copper-catalyzed aziridine formation, Oestreich et al. reported in 2023 the preparation of C-silylated unprotected aziridines (130) via an enantioselective copper-catalyzed (127) addition of a silicon nucleophile (129) to 3-substituted 2H-azirines (126). They employed an Si–B reagent44 and in particular, a silyl boronic ester (129) as a silicon pronucleophile (Scheme 25).45
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Scheme 25 Preparation of C-silylated unprotected aziridines via an enantioselective copper-catalyzed addition. |
Several chiral trans-substituted imidazolidines (134) were synthesized by Feng and co-workers via the enantioselective reaction of donor–acceptor aziridines (131) with N-aryl protected imines (132) using Ni(ClO4)2·6H2O/N,N′-dioxide (133) as the catalytic system (Scheme 26).49 The transformation appears to proceed through transition states such as 135, where the ring formation starts with the attack from the imine from the si-face as the re-face is blocked by the N-arylsulfonyl moiety. Ring closure occurs subsequently by the attack on the bond that is broken, forming a bond with the carbon bearing the aryl group.
Usually, the activation of aziridines requires the employment of either a strong Lewis acid or transition metals. Recently, Wang and co-workers described a cycloaddition reaction of a weakly bonded aziridine–selenide complex with non-activated alkenes (137) by using phosphonium selenide-based chalcogen bonding catalysts (138) (Scheme 27 – path a). This study was supported by computational calculation and NMR, demonstrating that an activation mode (145) involving the cooperative Se–O and Se–N interactions is involved. The scope of the methodology was extended to alkynes (141) (Scheme 27 – path b) and ketones (143) (Scheme 27 – path c).50
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Scheme 27 Cycloaddition of weakly bonded aziridine-selenide complexes with non-activated alkenes (a), alkynes (b), and ketones (c). |
Ye et al. reported in 2020 the synthesis of 4-benzoxazepinones (150) via a N-heterocyclic carbene/copper co-catalyzed reaction of salicylic aldehydes (146) with aziridines (147). The applied strategy allowed the authors to obtain compounds of this class, which are also interesting from a pharmaceutical viewpoint, in good yield and with full regioselectivity (Scheme 28).52
The spirooxindole-featuring azacycles have gained interest in the fields of synthetic as well as medicinal chemistry due to their peculiar three-dimensional architecture and interesting biological profiles. In 2022, Hajra and co-workers documented the Brønsted acid- and/or Lewis acid-catalyzed selective C3-allylation of spiro-aziridine oxindoles (151) with allyl silanes (152 and 153) or allyl Grignard reagents (154) to access 3-allyl-3-aminomethyl oxindoles (155) and 5-silyl methyl spiro[pyrrolidine-3,3′-oxindoles] (156), respectively (Scheme 29).53 When chiral spiroaziridines were used, the methodology did not show any stereoselectivity. In contrast, the catalyst-free reaction of nonracemic spiroaziridines with allyl-Grignard reagents provided 3-allyl-3-aminomethyl oxindoles (155) with good stereoselectivity (ee up to 80%). The pathway was applied for preparing coerulescine (157) and various 5′-substituted spiro[pyrrolidine-3,3′-oxindoles] (156).
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Scheme 29 Selective C3-allylation of spiro-aziridine oxindoles with allyl silanes and allyl Grignard reagents. |
A ring enlargement pathway was described as a useful method for the preparation of β-lactams (160) by Li and co-workers. They reported a palladium-catalyzed ring expansion reaction of vinyl aziridines (158) with commercially available sodium 2-chloro-2,2-difluoroacetate (ClCF2COONa, 159), which serves as the carbonyl source of a difluorocarbene precursor. The authors reported a difluorocarbene-involved (161) reaction of π-allyl Pd(II) complexes (Scheme 30 – path a).54
In 2023, Song et al. synthesized chiral γ-lactams (167) through an isothiourea (166, ITU)/iridium (164) co-catalyzed reaction of vinyl aziridines (163) with pentafluorophenyl esters (162). This methodology allowed the achievement of several optically active compounds in good yields and with high asymmetric induction (up to 98% ee) (Scheme 30 – path b).55
Pyridinium 1,4-zwitterionic thiolates (168) were employed by Chen and co-workers for the regioselective and stereospecific ring enlargement of aziridines (169). 3,4-Dihydro-2H-1,4-thiazines (170 and 171) were prepared via a domino SN2 ring-opening/N-Michael addition cyclization/retro-Michael addition/pyridine extrusion procedure under mild conditions without metal mediation or the need for a strong base (Scheme 31).108
Unprotected guanidine derivatives (176 and 177) were prepared via ring expansion of 2-substituted aziridines (172) and N-tosyl cyanamides (173) in a domino regioselective ring-opening/5-exo-dig cyclization. This metal-free methodology works well even with weaker bases such as cesium fluoride (CsF). Furthermore, the so-obtained compounds could be subjected to hydrolysis in order to obtain highly biologically interesting urea analogs (178 and 179) (Scheme 32).56
Schomaker et al. reported a [3 + 3] ring expansion of bicyclic aziridines (180) and rhodium-bound vinyl carbenes to synthesize a variety of dehydropiperidines (184). Supported by mechanistic studies, the authors supposed that the pathway proceeds via the formation of a vinyl aziridinium ylide (183) which undergoes a pseudo-[1,4]-sigmatropic rearrangement to yield heterocyclic products (184) with net retention of the configuration at the new CC bond (Scheme 33).57
In 2022, Feng et al. documented the ring enlargement of racemic donor–acceptor (D–A) aziridines (185) with isocyanides (186) catalyzed by a chiral N,N-dioxide (187)/Mg(II) complex, proceeding through ring opening via intermediates, such as 188, to yield enantioenriched exo-imido azetidines (189) (Scheme 34).109
The preparation of 2-(2-oxoalkylidene)-1,3-oxazolidine derivatives (193) was described by Xu and co-workers in 2021 via the catalyst-free electrophilic ring expansion of N-unprotected aziridines (191) and the ketene CO double bond of α-oxoketenes (192).58 Products 192 were prepared in situ through microwave-assisted Wolff rearrangement of 2-diazo-1,3-diketones (190) (Scheme 35). Products 193 were obtained with an E configuration via an SN1 mechanism.
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Scheme 35 Catalyst-free ring expansion of N-unprotected aziridines for preparing 2-(2-oxoalkylidene)-1,3-oxazolidine derivatives. |
Alkoxycarbonylketenes (196), generated from alkyl 2-diazo-3-oxoalkanoates (194), were employed as substrates for the electrophilic ring expansion of aziridines (195) in order to obtain alkyl 2-(oxazolin-2-yl)alkanoates (197) under microwave irradiation.59 The corresponding final compounds (197) were obtained in good yields; in all cases, the formation of 1:
1 mixtures of diastereomeric products was observed (Scheme 36).
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Scheme 36 Microwave-assisted ring expansion of aziridines to obtain alkyl 2-(oxazolin-2-yl)alkanoates. |
In 2022, Arnold and co-workers documented the biocatalytic enantioselective one-carbon ring expansion of aziridines (198) to yield azetidines (202) via [1,2]-Stevens rearrangement by using “carbene transferase” as enzymes (Scheme 37). The employment of biocatalysts was crucial for controlling the reactivity of the formed aziridinium ylide intermediates (201), which could be not controlled by using other catalyst classes.60
A typical ring enlargement reaction concerning aziridines is the one with CO2 (204).61 Indeed, different methodologies were described by using diverse catalysts.62 Among them, Caselli and co-workers reported the preparation of 5-substituted 1,3-oxazolidin-2-ones (206) catalysed by ammonium ferrates (205) (Scheme 38 – path a). Theoretical calculations clarified that the reaction mechanism involves just one ferrate molecule and the rate determining step is the 1,3-oxazolidin-2-one ring closure.63 Zhao and co-workers documented the reaction of CO2 (204) and aziridines (207) catalyzed by MOFs (metal–organic frameworks). In particular, they prepared three-dimensional cluster-based MOF {(NH2Me2)[Co3(μ3-OH)(BTB)2(H2O)]·9H2O·5DMF}n (208) with large pores assembled by BTB ligands (209, BTB = 1,3,5-tri(4-carboxyphenyl)benzene) and [Co3] clusters (Scheme 38 – path b). With this methodology they achieved oxazolidinones (210 and 211) in up to 99% yield.64 Recently, Venkatasubbaiah et al. described the solvent-free reaction of aziridines (212) and carbon dioxide (204), catalyzed by a zinc-salen having a B–N coordinated phenanthroimidazole motif (213) as a photocatalyst, for the synthesis of oxazolidinones (214) (Scheme 38 – path c).65
Schomaker et al. described a Rh catalyzed ring expansion of aziridines (215) and N-sulfonyl-1,2,3-triazoles (216). Instead of the expected dehydropiperazines (218), the authors observed the formation of [3,9]-bicyclic aziridines (217), see Scheme 39. The structure was confirmed by computational calculation and X-ray studies.66
A one-pot reaction for preparing benzooxepino-fused pyrrole derivatives (221) starting from substituted alkynyl aziridines (219) was reported by Sridhar and co-workers. In this metal-free procedure, two new CC bonds were established via the initial cleavage of the CC bond of the aziridine ring by the in situ generated azomethine ylides (220) (Scheme 40).67
Various N-(2,2-diphenylvinyl)-β-oxoamides (225) were prepared by Xu and co-workers, via a microwave-assisted catalyst-free methodology, starting from 2-diazo-1,3-dicarbonyl compounds (222) through an electrophilic ring opening of N-alkyl-2,2-diphenylaziridines (223).70 α-Oxoketenes (224), which then reacted with aziridines 223, were generated from 2-diazo-1,3-dicarbonyl derivatives (222) via a Wolff rearrangement (Scheme 41). The so-obtained N-(2,2-diphenylvinyl)-β-oxoamides (225) are useful molecules as synthons for the preparation of β-lactams but also common structural motifs in biologically active compounds.
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Scheme 41 N-(2,2-Diphenylvinyl)-β-oxoamide generation from 2-diazo-1,3-dicarbonyl compounds and N-alkyl-2,2-diphenylaziridines. |
Zhu and co-workers reported the synthesis of 4-spiroannulated tetrahydroisoquinolines (228) via a multistep procedure involving a sequential ring opening of aziridines 226 and the subsequent Pictet–Spengler reaction.71 The reaction proceeds under mild conditions with a broad scope. Considering the reaction mechanism, the TBS group is eliminated from derivative 229 by treatment with TBAF and the so-obtained free OH group (230) promoted an internal aziridine ring opening. The newly formed intermediate 231 reacted with formaldehyde (227) under acidic conditions to generate the iminium ion 232, which undergoes electrophilic cyclization to afford the final product 233 (Scheme 42).
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Scheme 42 Synthesis of 4-spiroannulated tetrahydroisoquinolines via a sequential ring opening of aziridines and the Pictet–Spengler reaction. |
C-Glycosyl-aminoethyl sulfide derivatives (246–249) were synthesized by Zawisza et al. via a reaction between tributyltin derivatives of glycals (234–235) and aziridinecarbaldehyde (236) and the regioselective ring opening of chiral aziridines (241–244) with thiophenol (245) (Scheme 43).72 Glycoconjugates are very interesting derivatives due to their participation in many important biochemical processes.
In 2022, Tang et al. described a methodology for the preparation of β-trifluoromethoxylated amines (252). This fascinating class of compounds was achieved via a silver-catalyzed ring opening of tosyl-aziridines (250) in the presence of trifluoromethyl arylsulfonate (251) (Scheme 44 – path a). A good chemo- and regioselectivity was observed under mild conditions.110 The same group accessed a series of β-trifluoromethylthiolated isothiocyanates (253) and amines (254) by using AgSCF3 and different iodine sources (TBAI, KI) (Scheme 44 – path b).73
In 2022, Doyle and co-workers reported an aziridine ring opening procedure with methyl/1°/2° aliphatic alcohols activated as benzaldehyde dialkyl acetals (256) via a Ni/photoredox cross-coupling.74 The activation of the benzaldehyde dialkyl acetal (256) is carried out through hydrogen atom abstraction and β-scission via a bromine radical. The authors demonstrated that aziridine activation proceeds through oxidative addition to Ni(I) rather than a Ni(II)azametallacycle, as reported previously (Scheme 45).75
Palladium is the catalyst employed by Zhou and co-workers in a three-component Catellani reaction76 starting from aryl iodides (260), typically for Catellani reactions with substituents at the ortho-position, aziridines (261), and (triisopropylsilyl)acetylene (262) as the building blocks. This first step of the reaction was useful for the preparation of the 2′-alkynylaryl-2-ethylamines (265), which were further reacted via a multistep procedure for preparing 1,3-trans-disubstituted tetrahydroisoquinolines 266 (THIQ), which is important from a biological point of view (Scheme 46).77
Han et al. instead documented the copper-catalyzed regioselective and stereospecific ring opening of aziridines with pyrydinyl Grignard nucleophiles. With this methodology, the preparation of β-pyridylethylamines (269) was achieved, which are potential scaffolds for the synthesis of biologically active molecules. Challenging chiral dihydroazaindoles (270) were prepared via a mild one-pot aziridine opening followed by nucleophilic cyclization (Scheme 47).78
Hayla and co-workers described a catalyst-free regioselective ring-opening of aziridines (274), including spiroaziridine oxindoles (271), with commercially available 50% aqueous hydrogen peroxide (272). The reaction, which can be carried out without any additional organic solvents and reagents, gives rise to secondary benzylic β-hydroperoxy amines (275) and tertiary 3-hydroperoxy oxindoles (273) (Scheme 48).79 The importance of this methodology relies on the utility of organic hydroperoxides, which are prevalent motifs in various biosynthetic intermediates, natural products, and bioactive compounds.80
Hou et al. reported the ring opening of diastereomerically pure 2-oxazolidinone-fused aziridines (276) via fluoride anions. This methodology allows the preparation of optically active, primary, secondary, and tertiary organofluorides (277), which are precursors of interesting compounds such as fluorinated amino acids (Scheme 49).81
Another important aspect is the preparation of amino acid derivatives from aziridine substrates. In recent years, the synthesis of functional quaternary amino acid derivatives has attracted considerable attention since they are key components in many active pharmaceutical ingredients. Among them, in 2022, Gao and co-workers reported the preparation of functionalized precursors of quaternary allylic amino acids(287) via a palladium-catalyzed allylic alkylation reaction of azalactones (284) with vinyl aziridine (285) (Scheme 51).83
The preparation of chiral pyridine-oxazolines (290) starting from (meso)-N-(2-picolinoyl)-aziridines (288) catalyzed by a chiral ytterbium(III)-N,N′-dioxide (289) complex was reported by Liu and Feng in 2022. The reaction proceeds via an asymmetric Heine reaction, giving excellent yields with very good enantioselectivities (Scheme 52).84
Martin and co-workers reported a nickel-catalyzed reductive carboxylation of N-substituted aziridines (291) with CO2 (204) at atmospheric pressure for accessing β-amino acids (293) (Scheme 53 – path a). The procedure works under mild conditions and exhibits high chemo- and regioselectivity.85 Wang et al. applied a combined nickel/photoco-catalyzed hydrogen-atom-transfer in order to achieve the ring opening of N-tosyl styrenyl aziridines (295) with aldehydes (294). This method is a novel and atom-economical synthetic path towards a variety of β-amino ketones (297) with complete regiocontrol (Scheme 53 – path b). With this strategy, the difficult coupling between aldehydes and aziridines, which are both electrophilic species, can be facilitated.86
Anderson and co-workers described the preparation of 1,3-disubstituted bicyclo[1.1.1]pentylamines (302, BCPAs) based on a radical functionalization strategy. In particular, sulfonamidyl radicals, obtained via α-iodoaziridine (298) fragmentation, undergo initial addition with [1.1.1]propellane (299) to afford iodo-BCPAs (300). Afterwards, the so-formed CI bond is functionalized via a silyl-mediated Giese reaction (Scheme 54 – path a).87 Xu et al. reported a radical addition/elimination strategy for preparing fluorinated allenes (305) starting from fluoroalkyl halides (304 and 306) and alkynyl aziridines (303) under visible-light irradiation (Scheme 54 – path b).88
Recently, the ring formation by the reaction of tosyl-aziridines (308) and indole derivatives (307) via [Cp*RhCl2]2 catalysis (309) was described by Zhu and co-workers. A series of cis-1,4-disubstitued tetrahydro-γ-carbolines (312) was formed in high yields and excellent cis-diastereoselectivity under mild conditions. The authors postulated a stepwise mechanism, proceeding through the rhodacyclic intermediate 310, which undergoes ring opening upon coordination of silver phosphate with nitrogen. The resulting intermediate 311 undergoes Michael addition to form a six-membered ring (Scheme 55).89 According to the authors, only the formations of the cis-1,4-diastereomers was observed.
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Scheme 55 Preparation of cis-1,4-disubstitued tetrahydro-γ-carbolines from aziridines and 3-vinyl indoles substituted with EWGs. |
In 2021, Pelletier et al. documented the synthesis of imidazo-[1,2-a]pyridines (317) by using 2-chloropyridines (313) and 2H-azirines (314) in the presence of triflic anhydride (315, Tf2O). An electrophilic 1-trifloyl-aziridin-2-yl triflate species is formed as the reaction intermediate which reacts in situ with the 2-halopyridines, forming transient pyridinium salts (316). These salts were treated in the same pot with triethylamine (Et3N), leading to the selective formation of the desired compounds (317) (Scheme 56).91
Another interesting example that highlights the use of aziridines as intermediates was reported in 2022 by Powers and co-workers. The authors described an olefin aziridination procedure by employing N-aminopyridinium reagents (319) as the activating group to afford N-pyridinium aziridines (320). The so-formed aziridines (320) then were subjected to a nickel-catalyzed C–N cross-coupling reaction with aryl boronic acids (321). The N-pyridinium aziridine intermediates (320) also participate in ring-opening chemistry with different nucleophiles to achieve 1,2-aminofunctionalization products. Mechanistic studies denote that the aziridine cross-coupling proceeds via a noncanonical mechanism involving initial aziridine opening (322), promoted by the bromide counterion of the nickel catalyst, and finally the formation of the aziridine moiety (323) by a ring-closing step (Scheme 57).92
In 2023, Bower and co-workers reported the preparation of stereochemically complex polyheterocyclic ring systems (327) via an aziridine intermediate (326). In particular, an intramolecular stereospecific aza-Prilezhaev aziridination occurs which is followed by a CN bond cleavage operated by a pendant nucleophile (Scheme 58). With this methodology, a variety of alkene anti-1,2-difunctionalizations (i.e., diaminations, amino-oxygenations and amino-arylations) can be facilitated. The majority of the obtained structures are relevant in medicinal chemistry.93
Luisi et al. employed aziridines as chiral nucleophiles in the enantioselective synthesis of oxaspirohexane sulfonamide derivatives (338). In particular, (S)-N-t-butylsulfonyl-2-phenylaziridine (333) was prepared starting from (S)-phenyl-glycinol (332). The lithiated intermediate 334 was trapped with 3-phenylcyclobutanone (331) to give a 90:
10 cis/trans diastereomeric mixture of aziridino cyclobutanol (335 and 336). The cis-stereoisomer underwent Payne rearrangement under basic conditions, leading to the desired 1-azaspiro[2,3]hexane (338) (Scheme 59).94
Aziridines were also reported to be useful catalysts.95 Rachwalski and co-workers described an asymmetric Morita–Baylis–Hillman reaction of methyl vinyl ketone and methyl acrylate (339) with various aromatic aldehydes (340) using chiral aziridine-phosphines (341) as chiral catalysts (Scheme 60).96
In 2021, Bulut and co-workers reported for the first time the synthesis of N-sugar substituted chiral aziridines via the Gabriel–Cromwell reaction. Among the newly prepared compounds were promising prodrug candidates for prostate (PC3) and cervical (HeLa) cancers. In particular, derivative 348 showed good activity with an IC50 value of 23.55 μM for PC3 and 25.88 μM for HeLa (Fig. 2).103
Kalvins et al. documented a class of acyl derivatives of aziridine-2-carboxylic acid as weak to moderately active PDIA1 (protein disulfide isomerase) inhibitors. Derivative 349 showed good inhibitory activity with an IC50 value of 26.0 μM. The in vitro cytotoxicity value toward a panel of cells was also evaluated and promising results were achieved (Fig. 2).104
In 2022, a series of trifluromethyl-aziridine derivatives were reported as proteasome inhibitors, selective for the β5 subunit. The in vitro biological activity, both enzymatic inhibition and anti-proliferative profile against two leukemia cells lines, was evaluated and promising results were achieved. The best result was obtained for derivative 350 with an IC50 value of 13.6 μM against the β5 subunit and 25.45 μM against drug-sensitive acute lymphocytic leukemia cells (CCRF-CEM) and 24.08 μM against a multidrug-resistant leukemia sub-cell line (CEM/ADR5000) (Fig. 2).105
Other anticancer aziridine bearing molecules were reported by Cheke et al. as inhibitors of the stem cell growth factor receptor often known as the c-KIT kinase domain. This is one of the 20 subfamilies of human receptor tyrosine kinases (RTKs) which is one of the main studied targets to fight cancer. The synthesized compounds were tested against the NCI-60 human cancer cell lines for a single-dose concentration. Derivative 351, which was one of the most promising ones, was evaluated for a five-dose anticancer study showing an IC50 value of 1.47 μM against different breast cancer cell lines (Fig. 2).106
Aziridines β-D-galactopyranoside derivatives were studied as anticancer agents by Calderón-Montaño and co-workers. The best result was obtained for compound 352, which proved to induce DNA damage. The authors suggested that 352 has an anticancer therapeutic potential future since it showed selective cytotoxicity against different malignant cells in comparison with normal cells. In particular, the highest selectivity was observed for two acute promyelocytic leukemia cell lines, human acute promyelocytic leukemia cells (HL-60) and human acute promyelocytic leukemia cells (NB4) with an IC50 value of 11.1 and 21.4 μM, respectively (Fig. 2).107
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