Recent advances in the stereoselective synthesis of aziridines.

Review pubs.acs.org/CR

Recent Advances in the Stereoselective Synthesis of Aziridines Leonardo Degennaro,* Piera Trinchera, and Renzo Luisi* Department of Pharmacy−Drug Sciences, University of Bari “A. Moro”, Via Edoardo Orabona 4, Bari 70125, Italy Acknowledgments References

1. INTRODUCTION Aziridines, the smallest nitrogen-containing heterocycles, are useful building blocks in synthesis, as well as important synthetic targets (Scheme 1).1 The interest toward synthetic methodologies for the preparation of the aziridinyl system has increased in the last decades. Such interest for this small heterocycle is dictated either by the biological activity, mainly as antitumor agents, displayed by some naturally occurring compounds bearing the aziridine ring or by the ring strain of those spring-loaded heterocycles that make them useful precursors of more complex molecules.2 By ring cleavage, several useful molecules, such as amines, amino acids, amino alcohols, and other nitrogen-containing compounds, could be obtained.3 Nowadays more than before, aziridines might be considered as the nitrogen equivalents of oxiranes. In fact, many efficient and more general synthetic strategies have been developed for the preparation of aziridines. This is particularly true for the stereoselective synthesis of aziridines. While general methods for the stereoselective synthesis of oxiranes are available, the same could not be said, until recently, for aziridines. However, this gap has been filled in the last decades, and several methodologies have been invented or improved and are now available for the preparation of aziridines in a highly stereo- and enantioselective manner. In this context, it might be noticed that several reviews concerning the synthesis of aziridines have appeared previously. General reviews, dealing with the synthesis of aziridines, included also epoxidation and some enantioselective aziridinations.4,5 Reviews on the asymmetric synthesis of aziridines were reported previously by Tanner in 19946 and by Osborn and Sweeney in 1997.7 Muller and Fruit in 2003 as well as Mossner and Bolm in 2004 reviewed the use of chiral catalysts for asymmetric aziridination covering the literature until the 2002.8 Very recently, Pellissier collected examples of asymmetric aziridinations in a review that appeared in 2010.9 This review aims to report some recent advances in the field of stereoselective synthesis of aziridines focusing on new methodologies, mechanistic insights, and the scope and limitations of each strategy. The adjective “stereoselective” will be used in a broad sense to identify synthetic processes creating new stereogenic centers and that occur with a control either on the absolute or relative configuration. Methodologies developed in the last 10 years will be described.

CONTENTS 1. Introduction 2. General Strategies for the Preparation of Aziridines 3. Stereoselective Aziridination by Transfer of Nitrogen to Olefins 3.1. Addition of Metal−Nitrenes to Olefins 3.1.1. Metal−Nitrenes from Iminoiodinanes 3.1.2. Metal−Nitrenes from Sulfonamides, Sulfonimidamides, and Sulfamates Derivatives 3.1.3. Metal−Nitrenes from Sulfonyloxycarbamate Derivatives 3.1.4. Metal−Nitrenes from Azides 3.2. Nitrogen Sources by Oxidation of N-Aminoimides and N-Aminoquinazolines 3.3. Addition of Amines to Olefins: Aza-MIRC Methodology 3.3.1. Asymmetric Catalytic Aziridination of α,β-Unsaturated Aldehydes 3.3.2. Asymmetric Catalytic Aziridination of Enones 3.3.3. Organocatalytic Synthesis of Terminal Aziridines Based on Noncovalent Interactions 4. Stereoselective Aziridination by Transfer of Carbon to Imines 4.1. Synthesis of Aziridines from Imines and Diazo Compounds 4.1.1. Carbene Addition to Imines 4.1.2. Direct Addition of Diazo Compounds to Activated Imines 4.2. Aza-Darzens Reaction 4.3. Ylide-Mediated Aziridination of Imines 5. Aziridines by Intramolecular Cyclization 6. Other Strategies 6.1. Aziridinyl Anion Strategy 6.2. Cross-Coupling Strategy 7. Concluding Remarks Author Information Corresponding Authors Notes Biographies © 2014 American Chemical Society

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Special Issue: 2014 Small Heterocycles in Synthesis Received: October 7, 2013 Published: May 13, 2014 7881

dx.doi.org/10.1021/cr400553c | Chem. Rev. 2014, 114, 7881−7929

Chemical Reviews

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Scheme 1. Biologically Relevant Aziridine-Bearing Compounds

2. GENERAL STRATEGIES FOR THE PREPARATION OF AZIRIDINES

3. STEREOSELECTIVE AZIRIDINATION BY TRANSFER OF NITROGEN TO OLEFINS

Several strategies are available for the synthesis of aziridines; however, the main routes involve transfer of a suitable nitrogen source to olefins, transfer of a suitable carbon source to imines, reduction of azirines, and intramolecular cyclization of amine derivatives (Scheme 2). The stereocontrol in all these synthetic strategies could be achieved by using an external controller, derived from a catalyst, a ligand, or a chiral reagent, or an internal controller, derived from a pre-existing stereogenic center in the reactants.

By analogy to alkene epoxidation, the “direct” aziridination of olefins could be achieved by using a suitable nitrogen source. Two main strategies will be discussed here: (a) addition of metal−nitrenes to olefins and (b) aza-Michael-initiated ring closure (aza-MIRC) reactions. 3.1. Addition of Metal−Nitrenes to Olefins

Nitrenes are reactive intermediates in which nitrogen bears one electron-withdrawing substituent (EWG) and two electron lone pairs and could be generated from several “nitrene sources”, such as aryl azides, sulfonyl azides, imino iodinanes, halo amines, and tosyloxy carbamates (Scheme 3). The aziridination usually occurs in the presence of a ligand (porphyrins, bisoxazolines, acetylacetone, imines, diimines) and catalytic amounts of metals from groups 7−11. The metal−nitrene (often reported as metal−nitrenoid) intermediates play an important role in the catalytic nitrogen transfer to the olefin; however, there are still uncertainties in the mechanism of this reaction and the nature of the active species involved. Insights have been gained recently on the structure of the electrophilic metal−nitrene intermediates, which are also involved in C−H

Scheme 2. Main Routes to Aziridines

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source. Different copper(II) aluminates were prepared and tested in stereoselective aziridination. As reported in Scheme 5, starting from cis- and trans-olefins a very good stereoselectivity was observed in the products 3 and 4 under mild conditions and with low catalyst loading (1−3%). In this work, the effect of the counterion was investigated on problematic systems such as the terminal olefin 5 (Scheme 5) and other nonaromatic olefins. Interestingly, aziridination of cisstilbene proved to be stereoselective, providing cis/trans ratios of the resulting aziridine up to 98:2. The authors stated that the very weak coordinating ability of WCAs [Al(OC(CF3)2R)4](R = CF3, Ph) was responsible for the reactivity and stereoselectivity.16 After the seminal works by the groups of Evans and Jacobsen,13,14,16 the enantioselective aziridination, by using a sulfonylimino iodinane as metal−nitrene source, has been a very active research area in the past decades. Suga reported a binaphthyldiimine ligand that in combination with Cu(I) salts provides an efficient catalytic system for enantioselective aziridination.17 Several trans-cinammyl esters and chalcones 7 were converted into the corresponding aziridines 8 with good to high enantioselectivity by using the BINIM-DC chiral ligand and [Cu(MeCN)4]PF6 as source of Cu(I) (Scheme 6). The authors reported that the reaction conditions such as temperature and solvent greatly affected the enantioselectivity. The best conditions were obtained at low temperature (−40 °C) and with CH2Cl2 as the solvent. Interestingly, it was demonstrated that the reaction does not occur with Cu(II) salts and that, under the optimized conditions, the reaction gave unsatisfactory results with aliphatic alkenes such as 9 and 10 (Scheme 6). A new C2-symmetric 1,4-diimine ligand, similar to the Jacobsen’s ligand,18 for the copper(I) catalyzed transfer of metal−nitrene to olefins has been reported by Wang and Ding.19 Chiral ligand 11a was prepared in large scale starting from D -mannitol (Scheme 7) and employed in the enantioselective aziridination of alkenes 12. Aziridines 13 were obtained with good yields and with good levels of enantioselectivity [up to >99:1 enantiomeric ratio (er)] by using [Cu(MeCN)4]ClO4 as source of Cu(I) and CH2Cl2 as the solvent. The reactions were performed at low temperature (−78 °C) and required an excess (5 equiv) of the olefin, which could be a drawback. The proposed model for the asymmetric induction involves a copper−nitrene species chelated to the ligand nitrogen atoms and to the carbonyl group of the alkene (Scheme 7). The presence of the carbonyl group seems to be essential for the stereocontrol. In fact, the Ding catalyst showed poor stereocontrol in the aziridination of terminal aromatic alkenes such as styrene (Scheme 8). It might be said that the aziridination of styrene has always been challenging; earlier

Scheme 3

amination reactions10 of ruthenium, copper, cobalt, rhodium, and iron.11 The proposed pathways for the metal−nitrene-mediated aziridination are reported in Scheme 4. Even if the metal− nitrene complexes seem to be the intermediates, their multiplicity (singlet or triplet) is still questionable but important from a stereochemical point of view. In fact, it is generally assumed that singlet species react stereospecifically, with retention of the alkene’s stereochemistry; instead, triplet species do not react stereospecifically. It is worth noting that recent mechanistic studies reported a stereospecific aziridination involving triplet copper−nitrene intermediates.12 The question is still open and experiments on the stereospecificity of the reaction are sometimes contradictory and substratedependent.13 Regardless of the mechanistic aspects, since the early reports on metal−nitrene aziridination by Evans et al.,14 advances have been made in the field, and new metal−ligand pairs and nitrenes sources have been introduced in order to get high level of stereocontrol and improve the synthetic versatility. 3.1.1. Metal−Nitrenes from Iminoiodinanes. A widely used nitrene source is sulfonylimino iodinanes such as [N-(ptoluenesulfonyl)imino]phenyliodinanes (PhINTs) or [N-(pnitrophenylsulfonyl)imino]phenyliodinanes (PhINNs), which can be easily generated from the corresponding sulfonyl amides. The main drawbacks in using such nitrogen sources are the removal of the N-sulfonyl group, which could be problematic, requiring harsh conditions often not compatible with the aziridino moiety, and the need to isolate the nitrene precursors. Nevertheless, novel catalytic systems with improved yields and selectivities have been recently described using sulfonylimino iodinanes. A recent advance in the stereoselective aziridination of alkenes has been reported by Kuhn and co-workers, who investigated the role of weakly coordinating anions (WCAs) in copper-mediated transfer of metal−nitrenes.15 The use of copper(II) complexes incorporating perfluorinated alkoxyaluminates (Scheme 5) allowed the aziridination of cis- and transolefins 1 and 2 in the presence of PhINTs as metal−nitrene Scheme 4

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Scheme 5

aziridination of olefins.20 The use of Fe(OTf)2 and ligand 11b furnished N-Ts-aziridine 14 with 70:30 er. Better results were obtained by Gullick et al.21 using a copper−zeolite (CuHY) catalyst under heterogeneous conditions and Evans’ ligand 11c.22 This heterogeneous catalyst seems to give a better asymmetric induction with respect to the homogeneous catalyzed reaction using the same chiral bis-oxazoline ligand. However, this protocol was applied only to styrene (Scheme 8). Hutchings and co-workers reported recently the preparation of more versatile N-Ns-aziridines, using the CuHY heterogeneous catalyst, demonstrating that either the heterogeneous or the homogeneous catalytic system afford mainly the C2 (R)configured aziridines.23 Surprisingly, the authors noticed also a different solubilty between the racemate and the pure enantiomer of N-Ns-aziridines, suggesting caution in analyzing the sample obtained by using both the homogeneous or heterogeneous protocols. Xu et al. introduced some bis-oxazoline ligands for the asymmetric copper-mediated aziridination of calchones 15.24 The developed protocol used Cu(I) salts as catalysts and PhI NTs as nitrogen source (Scheme 9) and a slight excess of alkene (1.5 equiv). The use of 1,8-bis-oxazolinylanthracene 17a (AnBOX) as the ligand furnished aziridines (2S,3R)-16 with good yields and up to 99:1 er, while with the cyclohexanelinked bis-oxazoline 17b [(S)-cHBOX] an inverse stereo-

Scheme 6

investigations by Evans et al. and Jacobsen and co-workers reported respectively 81:19 er with bis-oxazoline ligands and 83:17 er with diimine ligands.16,18 Attempts to develop a more efficient process has been done by Bolm and co-workers, who investigated the effect of iron catalysts in the asymmetric Scheme 7

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Scheme 8

Scheme 9

Scheme 10

induction was observed, leading to enantiomeric aziridine (2R,3S)-16 in good yield with a high level of enantioselectivity (Scheme 9). The Evans’ ligand 11c (BOX) behaves similarly to (S)cHBOX, showing the same stereoselectivity. The results show that the enantioselectivity is substituent-dependent on chalcones with AnBOX ligand. In particular, chalcones with electron-donating substituents show higher enantioselectivities than those with electron-withdrawing substituents. The proposed model for the asymmetric aziridination (Scheme 10) involves the coordination of the oxygen of the carbonyl group of the chalcone to the copper of the catalyst and attack of the metal−nitrene from the top. Reactivity experiments indicate also that the substituent-dependent enantioselectivity, in the asymmetric aziridination of chalcones using AnBOX ligand, is due to the π-stacking interactions between the ligand backbone and the substrates. The opposite enantioselectivities observed

with ligands 11c and likely 17b were explained with the model reported in Scheme 10, assuming the attack of the metal− nitrene from the bottom producing a 2R,3S-configuration in the aziridines 16. The enantioselectivity was not substituentdependent with respect to chalcones with ligands 11c and 17b. The same ligands 17a,b and 11c (AnBOX, cHBOX, and BOX) were employed also in the asymmetric aziridination of more challenging systems, such as 1,3-dienes 18, where regioand stereochemistry need to be addressed (Scheme 11).25 The aziridination of α,β,γ,δ-unsaturated ketones 18 was found to be highly regioselective, leading to cis-γ,δ-aziridinated products 19 in 28% yield with up to >99% diastereoselectivity and up to 80% enantioselectivity using ligand 11c, while the use of 17b gave a better yield but a lower enantioselectivity (86:14 er). Aziridination of 1,4-diphenyl-1,3-butadiene was highly regioselective but furnished a mixture of cis- and trans-aziridines 19 and 20 as major products. To explain the regio- and stereochemistry of the process, the authors proposed the formation of diradical intermediates A and B shown in Scheme 11. The metal−nitrene species TsNCuL undergoes an addition with radical character to the HOMO orbital of 1,4disubstituted-1,3-butadienes 18. Addition to the terminal carbon atom (which likely has higher electron density than the internal ones) of the 1,3-diene leads to a diradical intermediate A, that upon bond rotation forms the more stable intermediate B precursor of the cis-product 19. Conjugated dienes have been used as substrate with few aziridination methods, although limitations (including diene’s symmetry and the low cis/trans-selectivity) have prevented their employment in synthetic applications.26 Perez and coworkers developed a catalytic system useful in the regio- and stereoselective synthesis of vinylaziridines using nonsym7885


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Scheme 11

Scheme 12

Scheme 13

metal−nitrene source (PhINTs) were used under optimized reaction conditions. The Tpx,BrAg catalyst gave highly regioselective aziridination of the double bond (α in Scheme 12) next to the hydroxyl moiety, leading mainly to trans-aziridines 23. The presence of a

metrical dienes 22, with a good tolerance of functional groups.27 Several complexes containing the homoscorpionate ligand Tpx,Br and a metal catalyst (M = Cu, Ag) were developed for the aziridination reaction of dienes 22 (Scheme 12). A low catalyst loading and a stoichiometric amount of diene and 7886


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free hydroxyl group seems to be essential for the regioselectivity (α vs β) but not for the stereoselectivity (cis vs trans). This new methodology has been elegantly applied to the aziridination of dienes cis-24 and trans-25 (Scheme 13). In addition, vinylaziridine 26 was used as precursor for the synthesis of racemic sphingosine. An isolated example on the use of an N-heterocyclic carbene complex has been reported for the first time by Trost and Dong for a stereoselective catalytic aziridination of electron-deficient cyclopentene 27 (Scheme 14). The aziridine 28 was obtained with excellent stereoselectivity and used as substrate for the preparation of the natural product (+)-agelastatine A.28

Scheme 16

Scheme 14

The reaction was performed using Cu(MeCN)4PF6 as copper source and PhIO as oxidant for the generation of the metal− nitrene precursor from SesNH2. The reaction proceeded with low conversion and modest diastereoselectivity (up to 75:25), even in the presence of a bis-oxazolinyl chiral ligand (L* in Scheme 16), which does not significantly affect the yield or diastereomeric ratio (dr) for the reaction. The same authors reported on the use of sulfonimidamides as efficient chiral metal−nitrene precursors for diastereoselective copper-catalyzed aziridination of olefins.30 Sulfonimidamides are sulfur(VI) derivatives analogous to sulfonamides in which one oxygen atom has been replaced by an imido moiety, thereby offering the possibility of introducing various additional functionalities (such as alkyl groups and electron-withdrawing substituents). The use of racemic sulfonimidamides 33 and 34 allowed for the stereoselective aziridination of alkyl acrylates 31 using Cu(MeCN)4PF6 as catalyst and iodosylbenzene as the oxidant (Scheme 17). High levels of diastereoselectivity were obtained with tert-butyl acrylate, and the corresponding aziridines 32 were also subjected to regioselective nucleophilic

3.1.2. Metal−Nitrenes from Sulfonamides, Sulfonimidamides, and Sulfamates Derivatives. In the previous section, the use of iminoiodinanes as nitrogen source has been described. However, to extend the scope and the versatility of the direct aziridination reaction and to avoid the tedious isolation of the iminoiodinane reagent and the troublesome removal of the N-arylsulfonyl group, novel in situ procedures have emerged and new N-functionalities have been introduced. The active species (a formal metal−nitrene) could be generated in situ by oxidation of an amine reagent with a hypervalent iodine reagent. Sulfonamides, sulfonimidamides, and sulfamates proved to be useful nitrogen donors in the metal-catalyzed aziridination of olefin in the presence of an oxidant (Scheme 15). Dauban et al. reported the use of 2-trimethylsilylethanesulfonamide (SesNH2) as nitrogen donor in the copper-catalyzed aziridination of α-allylglycine derivatives (R)-29 (Scheme 16).29

Scheme 17

Scheme 15

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ring-opening reactions. The enantioenriched sulfonimidamide (S)-35b was used for the aziridination of styrene in the presence of a chiral bis-oxazoline ligand. 2-Aryl-substituted aziridine 36 was obtained in good yield and a reasonable distereoselectivity of 83:17 (Scheme 17). A reasonable level of stereoselectivity was observed for this double induction process, also in the case of enantioenriched sulfonimidamide (S)-35b, which gave aziridine 36 in 91% yield and 80:20 dr. A significant mismatched pair, leading to a 55:45 diastereomeric mixture of 36, resulted by using sulfonimidamide (R)-35b with the same bis-oxazoline ligand (Scheme 17). Other nitrogen sources, useful for stereoselective aziridinations of alkenes, are sulfamate esters that, in the presence of Rh catalysts, have been employed in C−H-amination reactions. Du Bois and co-workers reported on the use of chiral sulfamate esters 37 in a diastereoselective intramolecular aziridination reaction, leading to aziridines 39 (Scheme 18).31 The process

Scheme 19

Scheme 20

Scheme 18

development of efficient copper- and rhodium-catalyzed stereoselective aziridinations using readily available tosyloxycarbamates as nitrogen sources.33 This method shows several advantages, such as using a cheap and shelf stable nitrogen source, avoiding the use of an oxidant, and allowing for a removal of the N-substituent under mild conditions. They found that the use of trichloroethyl N-tosyloxycarbamate 48 and bis-oxazoline ligand 47 allowed the copper-catalyzed aziridination of styrenes, leading to aziridines 49 in good yields and acceptable enantioselectivity. A better enantioselectivity was obtained with electron-deficient styrenes, while an inversion of stereoselectivity was observed upon switching the solvent from acetonitrile (or PhCl) to nitromethane (Scheme 21). The N-protecting group could be removed by treatment of aziridines 49 with 5 equiv of LiOH, furnishing NH-aziridines 50 or the corresponding enantiomer ent-50 by performing the reaction in a different solvent (Scheme 21). Easily available chiral tosyloxycarbamates (R)- and (S)-51 were also employed in the copper-catalyzed diastereoselective aziridination of styrenes (Scheme 22). Several bis-oxazoline ligands were tested for this reaction, and 47 proved to be the better ligand. The protocol was applied to several styrenes, used in 3 equiv amount, producing good to excellent yields and stereoselectivities for aziridines 52. Matched and mismatched studies reveal that this is largely a catalyst-controlled process (see Scheme 25). The same authors developed the first rhodium-catalyzed aziridination of alkenes by using chiral tosyloxycarbamates as

requires a catalytic amount of rhodium (2 mol %) and a readily available oxidizing agent (1.3 equiv) such as PhI(OAc)2. The reactions were found to be highly stereoselective, and the stereoselectivity was explained with a chair-like transition state 38 that minimizes gauche and A1,3-type interactions. The methodology was applied to intermolecular aziridination of alkenes (Scheme 19). In this case, a sulfamate bearing the trichloroethoxysulfonyl (Tces) N-substituent was employed. The reaction was highly stereoselective with both cis- and transβ-methylstyrene, leading to aziridines 41 and 42, respectively, while the use of aliphatic alkenes bearing a stereogenic center resulted in a 1:1 mixture of diastereomers 43 and 44. Dauban et al. investigated the enantioselectivity of the copper-catalyzed intramolecular aziridination of sulfamates.32 The Evans bis-oxazoline ligand was used to control the enantioselectivity of the reaction. Using sulfamates 45, bicyclic aziridines 46a−e could be obtained in good yields and a good level of enantioselectivity (Scheme 20). These kinds of bicyclic aziridines undergo regio- and chemoselective sequential ringopening reactions, giving access to useful chiral amines such as spisulosine. 3.1.3. Metal−Nitrenes from Sulfonyloxycarbamate Derivatives. Lebel and co-workers contributed to the 7888


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Scheme 21

(see Scheme 25). The protocol was applied to the intermolecular aziridination of several styrene derivatives (Scheme 23), yielding higher levels of stereoinduction with para-substituted styrenes, while ortho- and meta-substituents decreased the stereoselectivity. However, the procedure is quite simple and the products 53a−e could be easily purified. No evidence for the mechanism was given, but from the reactions with cis- and trans-β-methylstyrenes, which occur with retention of the alkene geometry and a variable degree of facial selectivity, the authors proposed a concerted insertion of singlet metal−nitrene for this rhodium-catalyzed aziridination, leading to 54 and 55 (Scheme 24).

Scheme 22

the metal−nitrene precursor.34 In this case, only 1 equiv of alkene was required along with the use of a chiral rhodium catalyst (Scheme 23). Better yields and stereoselectivities were observed with the chiral tosyloxycarbamate (R)-51, with respect to the corresponding antipode (S)-51, by using the chiral rhodium dimer Rh2[(S)-Br-nttI]4. The authors reported that a match−mismatch situation is likely responsible for the different results obtained with (R)- and (S)-51, and in contrast to the reaction with catalyst 47, this reaction is under substrate control

Scheme 24

Scheme 23 It is remarkable that the two aziridination protocols developed by Lebel and co-workers occurred with opposite stereoinduction with reference to the stereogenic C2 of the aziridinyl ring (compare Schemes 22 and 23). In fact, the copper-catalyzed aziridination with tosyloxycarbamate (R)-51 gave mainly (S)-configured aziridines 52, while the rhodiumcatalyzed protocol led mainly to (R)-configured aziridines 53. In order to explain the opposite stereochemistry observed with the two protocols, the authors proposed that in the case of the copper-catalyzed protocol, the bis-oxazoline ligand controlled the stereoselectivity, regardless of the stereochemistry of the tosyloxycarbamate. In striking contrast, in the rhodium-catalyzed protocol, the stereoselectivity was depending on the stereochemistry of the tosyloxycarbamate, likely for a match−mismatched situation (Scheme 25). An advantage in using the N-tosyloxycarbamate reagent is the easy cleavage of the carbamoyl moiety in the resulting aziridines. It was demonstrated with chiral aziridine (R,R)-56 that the removal of the N-substituent under very mild conditions (LiOHaq) occurred without racemization of either the aziridine 57 or the chiral alcohol 58, which could be recovered and recycled. The N-protecting group allows also for 7889


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Scheme 25

Scheme 26

reactive, and their use as precursor requires harsh conditions, such as heating or UV irradiation. Seminal work by Jacobsen and co-workers relied on asymmetric aziridination with tosylazide (TsN3) in the presence of a chiral Cu−diimine catalyst.35 Muller et al. also reported a reaction with nosylazide (p-NsN3) catalyzed by a chiral Rh−bisnaphtholphosphate complex.36 In both reactions, UV irradiation was mandatory, and the levels of stereoselectivity were only modest. Such seminal works paved the way for the design of catalysts that could convert azide compounds into active species under mild conditions useful in the asymmetric aziridination of alkenes. Azide derivatives bearing readily removable N-sulfonyl groups, such as p-nitrobenzenesulfonyl (p-Ns) and 2-(trimethylsilyl)-

a highly regio- and stereoselective nucleophilic ring-opening of the aziridines (S,R)-56, leading to chiral products 59 that, upon N-deprotection, gave access to useful building blocks such as amino alcohol 60 (Scheme 26). 3.1.4. Metal−Nitrenes from Azides. Organic azides represent a useful nitrogen source for C−H aminations and aziridination reactions. Aryl azides can be easily synthesized from amines and are tolerant to a wide variety of functional groups. In addition, azides are ideal metal−nitrene precursors in terms of atom efficiency and sustainability, because they generate the necessary nitrenoid species simply by dissociating innocuous and ecofriendly molecular nitrogen. However, as a drawback, the preparation of the required azide derivative could need several synthetic steps. Nevertheless, azides are not very 7890


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model and X-ray analysis, the low turnover number observed was ascribed to an undesired intramolecular C−H amination reaction of the aryl group by the intermediate azide−Ru species. The introduction of m-chloro substituents enhances the durability of the catalyst. Besides the introduction of a more robust catalyst, such as 61c, Katsuki and co-workers demonstrated the usefulness of SESN3 as nitrogen source and of the SES moiety as an easily removable nitrogen protecting group. The methodology has been successfully applied to the synthesis of highly enantioenriched N-SES aziridines 63a−f (Scheme 28). Very good enantioselectivities were obtained with both aliphatic and aromatic alkenes, benzyl acrylate, and N-methoxy-N-benzyl-2propenamide, although the yields depended on the nature of the alkene. The easy removal of the SES group was demonstrated with aziridine carboxylate 63f (Scheme 28). This group could be cleaved by treatment of the N-SES-aziridine with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), furnishing the corresponding highly enantioenriched NHaziridine carboxylate. The same authors tested the Ru−Salen catalyst 61c for the intramolecular competitive aziridination reaction on p-vinylphenyl vinyl ketone 64 using SESN3 as nitrogen source (Scheme 29). A low regioselectivity resulted, and an almost equimolar amount of the corresponding aziridines 65 and 66 were obtained with a very good level of enantioselectivity. These results prompted Katsuki and co-workers to investigate the asymmetric aziridination of vinyl ketones 67, leading to terminal aziridines 68 with very good yields and high levels of enantioselectivity (Scheme 30).39 The methodology was exploited in the preparation of the pharmaceutical target 72. The asymmetric aziridination of 70 was the key step for controlling the stereochemistry of the final target (Scheme 31). A step forward was the preparation of a new Ru−Salen complex (73) efficient in the aziridination of aromatic and aliphatic terminal olefins. Aziridines 74 were obtained in high yields and enantioselectivities (Scheme 32).40 The only drawback of the methodology was the need of an excess of olefin (olefin/azide ratios 3:1). The regioselectivity of the aziridination was examined with alkadienes such as 7-methyl-1,6-octadiene and 1,4-hexadiene. In both reactions only terminal aziridines 74c,d formed in good yields (54% and 59% respectively) and high enantioselectivity (Scheme 32). Nevertheless, terminal allylic C−H amination was also observed in the reaction of 1,4-hexadiene. Styrene derivatives underwent aziridination in excellent yields and high enantioselectivity with a low catalyst loading (0.5−1 mol %). In particular, the reactions of cis-β-methylstyrene and indene proceeded with excellent enantioselectivities and moderate yields. In the case of trans-β-methylstyrene, no aziridination product was detected, and the reaction gave only the corresponding allylic amination product in low yield. Other catalysts for the asymmetric aziridination of olefins using azides as nitrogen sources have been introduced by Zhang and co-workers. They reported the use of D2-symmetric chiral porphyrins in the Co-catalyzed aziridination of styrenes.41 Several Co−porphyrins were tested by modifying the variability points indicated in Figure 2. However, Co−porphyrins 75a−c were the most effective in the asymmetric aziridination of styrenes.

ethanesulfonyl (SES), are privileged nitrenoid precursors in view of the atom efficiency and synthetic versatility. Significant results in the field of catalytic aziridination, by using azides, have been obtained in recent years by Katsuki and co-workers. They developed Ru−Salen−(CO) complexes for asymmetric aziridination reactions of alkenes.37 The chiral ruthenium−Salen complexes 61a−c were effective in the aziridination of styrene with sulfonyl azides (Scheme 27). Scheme 27

Highly enantioenriched chiral aziridines 62 were obtained with good yields using TsN3 and 2-(trimethylsilyl)ethansulfonyl azide (SESN3) as the nitrogen sources. The authors optimized the catalyst structure in order to get a high turnover number by introducing aryl groups bearing substituents at positions 3−5 (see Ar groups on catalysts 61b,c in Scheme 27) on the naphthyl groups linked at the C3 and C3′ carbons.38 The proposed mechanism for the asymmetric aziridination of styrene by the Ru−Salen complex is reported in Figure 1: the

Figure 1.

olefin should approach the imino species along the Ru−N bond (in red) adjacent to the downward naphthalene ring of the quasi-planar Salen ligand. The aryl group on the C2″ carbon (in purple), being close to the imino group, pushes the N-sulfonyl moiety (in the yellow circle) to the front. This arrangement allows for a preferential aziridination of styrene, approaching as indicated in Figure 1 to minimize steric repulsion, leading to the corresponding (S)-configured product. On the basis of this 7891


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Scheme 28

Scheme 29

(Scheme 34).42 The reaction occurred with moderate to good yields and high enantioselectivity (er > 90:10) with aromatic and aliphatic olefins leading to aziridines 77 (Scheme 34). It is worth mentioning that, in order to improve the yields, 5% of Pd(OAc)2, which likely behaves as a π-electrophilic Lewis acid activating the olefins, was required. Zhang and co-workers, recently reported a new effective aziridination protocol based on the use of fluoroaryl azides as metal−nitrene sources and Co−porphyrin 75c (Figure 2) as the chiral catalyst. This new methodology uses only 1 equiv of styrene and is strictly dependent on the nature of the fluoroaryl azides (Scheme 35).43 In particular, the authors postulated a metalloradical mechanism involving an unprecedented CoIII− nitrene radical intermediate and a stepwise radical addition− substitution pathway (Scheme 35). They reasoned that the amide moieties, in addition to serving as spacers to support and orient the chiral units in D2-symmetric amido porphyrins 75, could also act as hydrogen-bond donors toward a potential hydrogen-bond acceptor, such as the fluorine atom (complexes A and B in Scheme 35). Styrene reacted with several fluoroaryl azides in the presence of catalyst 75c in fluorobenzene as the solvent under mild conditions, furnishing enantioenriched Nfluoroarylaziridines with a good level of enantioselectivity (Scheme 35). It is worth mentioning that the presence of

Scheme 30

The readily available diphenylphosphoryl azide (DPPA) was used as the nitrogen source in the Co-mediated aziridination of styrenes by using 10% of porphyrin 75a. Low levels of enantioenrichment and moderate yields of N-phosporylated aziridines 76 were obtained (Scheme 33). This synthetic protocol required the use of an aromatic chlorinated solvent, such as chlorobenzene, and an excess of alkenes and was effective only with monosubstituted styrenes. The use of the catalytic protocol with multisubstituted aromatic olefins and aliphatic olefins was ineffective. Better results in terms of enantioselectivity have been obtained by using Co−porphyrin catalyst 75b and trichloroethoxysulfonyl azide (TcesN3) as a new metal−nitrene source Scheme 31

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Scheme 32

Scheme 34

Figure 2.

Scheme 33

remove the fluoroaryl group from the nitrogen atom of the aziridines ring. Nevertheless, examples of ring-opening reactions leading to chiral enantioenriched amino alcohols were given.

fluorine atoms at the ortho position of the aryl ring is mandatory to achieve a high level of enantioselectivity. In fact, no reaction was observed by using 3,4,5-trifluorophenyl azide, while high enantioselectivity (er 96:4) was observed with pentafluorophenyl azide (Scheme 35). The methodology was applied to the asymmetric aziridination of several aromatic olefins and styrene derivatives. Highly enantioenriched N-fluoroarylaziridines 78 were prepared using 1% of the catalyst 75c under mild conditions (Scheme 36). However, the authors did not mention about the possibility to

3.2. Nitrogen Sources by Oxidation of N-Aminoimides and N-Aminoquinazolines

N-Aminophtalimide can be used as nitrene source for stereoselective aziridination reactions. The mechanism of this reaction has been investigated by the groups of Atkinson,44 Chan,45 and Yudin,45 who reported that an N-acetoxyaminoph7893


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Scheme 35

Scheme 37

The mechanism of this aziridination reaction has also been investigated, demonstrating that 79 is the aziridinating species able to deliver the nitrogen atom. This methodology has been exploited in the stereoselective aziridination of stereodefined alkenes (Scheme 38). As a result, stereodefined aziridines 80a− g retaining the alkene geometry have been prepared.45

Scheme 36

Scheme 38

More recently, Walsh and co-workers reported the stereoselective preparation of novel aziridinylboranes by aziridination of the corresponding allyl alcohols bearing a boropinacolate (BPin) moiety on the C2.46 Starting from allylic alcohols 81, in the presence of N-aminophthalimide and PhI(OAc)2, aziridines 82 could be obtained with high diastereoselectivity (Scheme 39). Aziridine borane derivatives 82 have been successfully employed as precursors of stereodefined 2-keto-1,3-amino alcohols. Another aziridinating agent that behaves similarly to phthalimide derivative 79 is the 3-acetoxyaminoquinazoline (Q-NHOAc), which could be generated from the corresponding 3-aminoquinazolinone by reaction with Pd(OAc)4 (Scheme

thalimide 79 is the active aziridination species. However, such active species could be generated from N-aminophthalimide either in the presence of a chemical oxidant or electrochemically (Scheme 37). Seminal works demonstrated that the active aziridination agent 79 could be generated using lead(IV) acetate. Further contributions from Yudin et al. demonstrated that such active species could be obtained by using the less toxic PhI(OAc)2 or even electrochemically. It is instructive to remark that the combination of N-aminophthalimide and PhI(OAc)2 delivers an active aziridinating agent in the absence of any metal additive. 7894


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of stereocontrol would lead to the one-step preparation of highly enantioenriched chiral aziridines. One of the most widely recognized mechanisms for the stereoselective catalytic aza-MIRC reaction involves an organocatalyst able to integrate orthogonal activation modes (via iminium ion/enamine) into a more elaborate reaction sequence, promoting a nucleophilic addition of a N-centered nucleophile followed by an intramolecular cyclization (Scheme 41). The N-nucleophile, seldom reported as “nitrene equivalent”, needs to be ambiphilic in nature (including both nucleophilic and electrophilic parts). Chiral primary amines and chiral salts of primary amines are efficient activators of enones, while chiral secondary amines have been used as organocatalysts to activate α,β-unsaturated aldehydes, likely through an iminium ion mechanism. Scheme 41 summarizes some useful organocatalysts widely employed in asymmetric aziridination reactions.49 The aza-MIRC reaction on functionalized alkenes could be performed also by using N,N-ylides (reported also as aminimides or aminimines), generated in situ from tertiary amine and O-substituted hydroxylamines as N-nucleophiles. Reactive N,N-ylides are efficient NH-transfer agents for the aziridination of α,β-unsaturated carbonyl compounds, affording NH-aziridines. The amine promoter in this aziridination process can be used in a catalytic amount (up to 30 mol %), and a reasonable level of enantioselectivity could be obtained with chiral tertiary amines. A plausible catalytic cycle for this process is proposed in Scheme 42. 3.3.1. Asymmetric Catalytic Aziridination of α,βUnsaturated Aldehydes. In 2007 and 2011, Cordova and co-workers reported relevant examples of highly enantioselective asymmetric aziridination of α,β-unsaturated aldehydes, based on a sequential iminium ion/enamine activation mode, leading to 2-formylaziridines in good to high yields and with er > 93:7.50 After an extensive screening of several suitable nitrogen sources and organocatalysts, the authors found that acylated and tosylated N-hydroxycarbamates 85a,b and TMSprotected diphenylprolinol 86 allowed for an effective asymmetric aziridination reaction (Scheme 43).

Scheme 39

40). This strategy has been recently applied by Davies and coworkers in a stereodivergent aziridination of 3-amino cyclohexene derivatives 83. Interestingly, the authors reported that by using the active species Q-NHOAc, generated at −20 °C to avoid decomposition, syn products 84 could be obtained with sulfonamide, amide, and carbamate groups, while anti products 85 could be obtained with tertiary nitrogens substituted with more hindered groups (Scheme 40).47 The observed change in stereoselectivity was explained by considering an H-bonded control for syn adducts (via TS1 in Scheme 40) and a steric control, dictated by the N-protecting groups, for the anti adducts. Further examples on the use of QNHOAc in stereoselective aziridinations based on the use of chiral auxiliaries have also been reported.48 3.3. Addition of Amines to Olefins: Aza-MIRC Methodology

The aza-MIRC (Michael initiated ring closure) reaction represents a simple and useful strategy for the one-step stereoselective preparation of aziridines. In pioneering works, several authors highlighted the potential of the conjugate addition−cyclization reaction for direct access to aziridines from electron-deficient olefins. In principle, this strategy can be viewed as a platform for developing an asymmetric catalytic aziridination: a chiral catalyst able to promote the first aza-Michael step while enforcing a high level Scheme 40

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Scheme 41

Scheme 42

nucleophilic conjugate attack at the β-carbon atom of the electrophile. The chiral enamine intermediate undergoes a 3exo-tet intramolecular cyclization between the α-carbon and the electrophilic nitrogen atom. This intramolecular ring closure pushes the equilibrium forward, making the reaction irreversible. Further examples of secondary amine-catalyzed enantioselective aziridinations were reported by Hamada and coworkers.51 They described an aziridination reaction on α,βunsaturated aldehydes using N-tosyloxycarbamate 90 as nitrogen source (Scheme 44). Such carbamates (see section 3.1.3.) are very stable crystalline solids and have already been used in aziridination reactions via nitrene addition reactions, base-catalyzed tandem Michael substitution reactions, and metal-catalyzed aziridination reactions.52 This organocatalytic

The reaction tolerates several functionalized enals 87 and furnished mainly trans-configured aziridines 88 in good yields and high enantioselectivity. In the case of aromatic cinnamyl derivatives, variable amounts of byproduct 89 were also observed, depending on the electronic nature of the substituent on the aromatic ring. On the basis of the absolute configuration of aziridines 88, assigned by means of TD-DFT calculations and ECD spectra, the authors were able to propose a mechanism for this enantioselective aziridination based on a domino catalytic sequence via iminium ion and enamine activation mode (Scheme 43). The authors proposed that a shielding of the Si-face of the chiral iminium ion intermediate by the bulky aryl groups of 86 was responsible for the stereoselective 7896


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Scheme 43

Scheme 44

Scheme 45

synthesize N-(tert-butoxycarbonyl)aziridines (N-Boc-aziridines) 92 in good yields and high stereoselectivity (Scheme 44). Moreover, the N-Boc-aziridines 92 were directly oxidized with activated manganese dioxide in the presence of sodium cyanide in methanol to give the corresponding aziridinecarboxylate 93 or reduced to the corresponding ethers 94 without losing their optical purity (Scheme 44). An interesting access to functionalized trisubstituted and 2,2 disubstituted terminal aziridines has been developed independ-

approach is an efficient method applicable to aliphatic aldehydes, acrolein, and aromatic aldehydes, and it proceeds with high diastereoselectivity and excellent enantioselectivity. In the case of aliphatic substrates, the reaction was carried out using an excess of α,β-unsaturated aldehyde, 1 equiv of carbamate 90 in the presence of (S)-diphenylprolinol triethylsilyl ether, (S)-91 (0.05−0.3 equiv), and base (NaOAc or Na2CO3, 3 mol equiv) (Scheme 44). With aromatic substrates, the use of sodium acetate was mandatory to 7897


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Scheme 46

Scheme 47

TsONHBoc 90, as “nitrene equivalent”, in the presence of NaOAc in CH2Cl2 allowed for the regioselective formation of N-Boc-protected aziridines 97 in high yields and excellent enantioselectivity (Scheme 46). Structure and absolute configuration of the enantioenriched aziridines, ascertained by NMR analysis on derivatives bearing R1 = Me and R2 or R3 = isopropenyl, suggested that the 1,6addition occurs via a nucleophilic attack of 90 from the Re-face of the vinylogous iminium ion intermediate 98 (Scheme 46). It is worth mentioning that the strength of the catalyst control is also demonstrated by the high degree of facial selectivity observed in aziridines 97a,b, where a match−mismatch situation occurs (R1 = Me, R2 = isopropenyl, dr > 95:5; R1 = Me, R3 = isopropenyl, dr = 92:8; Scheme 46). 3.3.2. Asymmetric Catalytic Aziridination of Enones. In analogy to the efficient organocatalytic asymmetric aziridination of α,β-unsaturated aldehydes, based on the iminium ion−enamine mechanism, Melchiorre introduced, recently, a catalytic aza-MIRC process involving enones as substrates by using N-tosyloxycarbamates as the nitrogen source and a chiral salt of a primary amine as the catalyst. Such chiral salt could be easily made by combining the readily available quinine derivatives with N-Boc-protected chiral amino acids.55 The choice of a primary amine was dictated by the possibility of catalyzing processes between sterically demanding partners, overcoming the limits in using chiral secondary amine

ently by the groups of Greck and Cordova. Greck and coworkers reported the enantioselective aziridination of αsubstituted-α,β-unsaturated aldehydes using a combination of tosyloxytosylamide (TsNHOTs), as the nitrogen source, and proline-derived catalyst 95 (Scheme 45).53 This straightforward organocatalytic transformation takes place through the iminium ion/enamine mechanism and gives rise to terminal aziridines bearing a quaternary stereogenic center in good yields (up to 90%) and enantioselectivities (up to >95:5 er). Different alkyl groups (R1 = Bn, Me, n-pentyl, and iPr, Scheme 45) at the αposition of the enals were tolerated. Cordova and co-workers developed a similar aminocatalytic aziridination using N-Cbz- and N-Boc tosylated hydroxylamines as nitrogen sources in the presence of proline catalyst 86 and NaOAc as the additive.50 The process was found to be highly efficient and highly enantioselective, giving the corresponding N-Cbz- and N-Boc-protected terminal aziridines (Scheme 45). By using the above-reported methodology, the enantioselective aziridination of α,β-disubstituted enals gave trisubstituted aziridines, which are a challenging goal in organic synthesis, in good yields and enantioselectivities (Scheme 45). A vinylogous iminium ion−dienamine catalytic cascade reaction has been recently developed by Jorgensen and coworkers for the regio- and stereoselective remote aziridination of γ-substituted cyclic 2,4-dienals (Scheme 46).54 The use of TMS-protected prolinol catalyst 95 (10 mol %) and 7898


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Scheme 48

observed (Scheme 48). The relative and absolute configurations of some derivatives were assigned by combining NMR analysis and time-dependent DFT calculation of ECD spectra. The aziridination method is also effective with β-methylcyclohexenones, 2-cycloheptenones, and 2-cyclopentenones, allowing the creation of aziridines bearing quaternary stereogenic centers, whereas α-substituted cyclic enones proved to be unreactive. The influence of chiral counteranions on both the reactivity and stereoselectivity have also been established: although the chiral primary amine is mainly responsible for directing the process toward a stereoselective path, the chiral cocatalyst is important to improve the efficiency of the aziridination. A mismatched combination of the two chiral entities slightly decrease the stereoselectivity and the degree of asymmetric induction. As an application of the methodology, both antipodes 105 and ent-105 of aziridine deriving from indenone were prepared with good yield and high enantioselectivity. The potentially bioactive tricyclic compound NSC67689257 is an example of an aziridine-containing heterocycle that could be prepared by using the above-mentioned method (Scheme 49).

catalysts. After an extensive screening of the reaction conditions, it was found that by using catalyst salt 102 (obtained from 9-amino(9-deoxy)epi-hydroquinine and (+)-NBoc-phenylglycine), high reactivity and selectivity could be achieved in the enantioselective conjugate additions of Ncentered nucleophiles to α,β-unsaturated ketones (Scheme 47). The acylated carbamate AcONHBoc, which was successfully employed in the organocatalytic aziridination of enals with secondary amine catalysts,50 gave only the conjugate addition product 101 (Scheme 47). By installing a better leaving group, such as a tosyl group, a very selective tandem sequence was observed, leading to desired aziridines 100 (Scheme 47). Optimization of the reaction parameters revealed that a careful choice of solvent, reagent concentrations, and stoichiometric ratios of the reactants was important for the efficiency and generality of this catalytic process. The authors demonstrated that the p-toluenesulfonic acid, generated during the enamineinduced ring-closing step, affects the activity of the catalyst. Carrying out the aziridination in CHCl3 with 2 equiv of solid NaHCO3, high diastereo- and enantioselectivities were observed. The method proved to be useful for the synthesis of a wide range of N-Cbz as well as N-Boc-ketoaziridines 100 in good yield and with high levels of stereoselectivity (single diastereoisomer and very high er values). The reaction times were also optimized in order to reduce the catalyst loading up to 5 mol % without affecting the efficiency of the methodology. The success of this organocatalyzed aziridination on linear α,β-unsaturated ketones and cyclohexenone itself, based on the ability of quinine salts to promote a well-defined iminium ion− enamine tandem sequence, affording enantioenriched transaziridines, prompted Melchiorre and co-workers in 2010 to develop an easy and fast access to enantioenriched aziridines starting from polysubstituted cyclic enones 103 (Scheme 48).56 The authors disclosed a reliable and highly stereoselective strategy to prepare a wide variety of N-Boc-protected aziridines 104 in both antipodes, by selecting the appropriate catalyst. In fact, by using salt 102a [9-amino(9-deoxy)epi-hydroquinine and Boc-D-phenylglycine], aziridines 104 were obtained, while by using the pseudoenantiomer [9-amino(9-deoxy)epi-hydroquinidine and Boc-L-phenylglycine] 102b, the corresponding aziridines ent-104 having opposite absolute configuration were

Scheme 49

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Scheme 50

Scheme 51

Hamada and co-workers described an efficient asymmetric aziridination of cyclic enones 107 by using the N-neopentyl1,2-diphenylethylenediamine 106 as catalyst and its use in a formal total synthesis of (−)-agelastatin A.58 Such a simple chiral diamine, which can be easily prepared from the commercially available chiral 1,2-diphenylethylenediamine (DPEN), exhibited an excellent enantioselectivity for the aziridination of 2-cyclopenten-1-one (n = 1, Scheme 50). The corresponding chiral aziridine 108a (n = 1, PG = Cbz) was obtained in 75% yield and 98:2 er. The reaction of 2cyclohexen-1-one and 2-cyclohepten-1-one also proceeded efficiently, affording the corresponding aziridines 108c,d and 108e,f, respectively, with high enantioselectivity. The chiral ketoaziridine 108a was employed for the synthesis of Ichikawa’s key intermediate (Scheme 50) in the preparation of (−)-agelastatin A.

Until now, organocatalytic methods for the stereocontrolled preparation of aziridines mainly have typically involved protecting groups with the not always easily removable N-Ts or N-Boc groups. Two ingenious organocatalytic procedures to prepare NH-aziridines, showing excellent trans stereoselectivity (>99:1), were recently reported. These methods, as anticipated in section 3.3 (Scheme 42), require the amination of a tertiary amine, which in the presence of a base likely forms a reactive N,N-ylide, which by conjugate addition to α,β-unsaturated carbonyl compounds followed by intramolecular ring closure affords NH-aziridines such as 109 (Scheme 51). The feasibility of this aziridination protocol, using a catalytic amount of a tertiary amine and O-protected hydroxylamines in the presence of a base, prompted the groups of Shi and Armstrong, independently, to investigate an enantioselective version with a chiral tertiary amine. In the work of Shi and co-workers,59 by treating chalcone with 30 mol % of (+)-Tröger’s base, MSH, 7900


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positions or heteroaromatic groups were tolerated, leading to the corresponding aziridines 112 in high yields and up to 90:10 er. Alkenes bearing amido or phosphonate groups were also suitable substrates for this aziridination reaction (Scheme 53). These kinds of aziridines are synthetically useful by further regioselective ring-opening, leading to α,α-disubstituted αamino acid derivatives 113. Other alternative aza-MIRC reactions for the aziridination of electron-deficient olefins have been developed by Fioravanti et al.64 They developed an addition−cyclization method that allows the one-step aziridination of electron-deficient olefins using a combination of NsONHCO2Et 116 and bases. In this reaction, 2-(phenylsulfanyl)-2-cycloalkenones 115a−d were reacted under two different reaction conditions, using an aqueous NaHCO3 solution as base (Scheme 54, method A) or

and CsOH·H2O, the corresponding NH-aziridine was obtained in 81% yield and 77:23 er. Promising levels of asymmetric induction were observed also from Armstrong et al. employing a readily available chiral quinine analogue.60 In the best reaction conditions, E-chalcone could be aziridinated in 64% yield and 78:22 er (Scheme 51). According to the mechanism described in Scheme 51, vinylNH-aziridines 110 were also synthesized via an aminepromoted nucleophilic aziridination of α,β,γ,δ-unsaturated carbonyl compounds. The reaction was completely regioselective, involving exclusively the α,β-double bond and also diastereoselective obtaining only trans-configured aziridines (Scheme 52).61 Scheme 52

Scheme 54

3.3.3. Organocatalytic Synthesis of Terminal Aziridines Based on Noncovalent Interactions. Lattanzi and co-workers reported a noncovalent approach to the aza-MIRC reaction using amino thiourea catalysts for the stereoselective synthesis of novel terminal aziridines bearing a quaternary stereogenic center.62 The bifunctional amino thiourea 114, able to establish multiple hydrogen-bonding interactions with both Michael-acceptor 111 and nitrogen donor 90 (Scheme 53), was found to meet the requirements postulated in pioneering works by Takemoto and co-workers,63 concerning the need of multiple hydrogen-bonding interactions to achieve a high level of stereocontrol. A solvent screening revealed toluene as optimal reaction medium for the preparation of aziridines 112 in good yields and er values (Scheme 53). The nature of alkene 111 slightly influenced the stereochemical outcome of the reaction, while different electron-donating or -withdrawing substituents on the phenyl ring at para-, meta-, and ortho-

calcium oxide (Scheme 54, method B). Catalyst 119 was found to be more effective than catalyst 118; moreover, higher yields were obtained in the aza-MIRC reactions run under conditions of method A. In striking contrast, in the presence of a solid phase (method B), the expected aziridines 117 were obtained in reasonable enantiomeric ratios. Minakata developed an alternative method for the aziridination of terminal alkenes 120 using benzyltriethylammonium

Scheme 53

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Scheme 55

Scheme 56

4.1.1. Carbene Addition to Imines. The addition of metal carbenes generated from diazo compounds to imines has been reported to occur mainly in the presence of copper and rhodium catalysts. In particular, seminal works by the groups of Jacobsen and Jorgensen66,67 were based on the use of copper salts in combination with chiral bis-oxazoline ligands and ethyl diazoacetate (EDA) as the carbene fragment donor. Aziridines were obtained in variable yields (10−90%) and diasteroselectivities (dr cis/trans > 10:1), but the enantiomeric ratios were low in most cases. The same process was also pursued using rhodium acetate and other rhodium complexes, but with unsatisfactory results.68 The mechanism for this type of aziridination involves the initial reaction between the metal and the diazo compound to form a metal carbene complex that reacting with the imine nitrogen gives a metal-complexed azomethine ylide. The ylide could undergo an intramolecular ring-closure to afford the aziridine product, and enantioselectivity could be introduced in this step if a chiral ligand is coordinating the metal. Alternatively, the ylide could dissociate from the metal−ligand, furnishing a racemic aziridine by an intramolecular cyclization (Scheme 56). In the past decade, this approach to the stereoselective synthesis of aziridines has not received much attention, and only few works have been reported. In 2003, Tilley and coworkers described the use of a new catalyst for this reaction.69

chloride as phase-transfer catalyst and N-chloro-N-sodio benzyl carbamate 121 as nitrogen source (Scheme 55).65 This method was applied to the asymmetric synthesis of aziridines 122 by using ammonium salts 124 and 125, derived from cinchona alkaloids, as catalysts. Various electron-deficient olefins were then subjected to this catalytic aziridination protocol. Interestingly, it was established that the absolute configuration of the major chiral aziridines produced by cinchonidine derivative 124 was S, while by using the cinchonine derivative 125 the R-enantiomer predominates. Aziridines 122 could be converted into the corresponding carboxylate 123 by removal of the auxiliary groups (Aux in Scheme 55) with DMAP without loosing the optical purity.

4. STEREOSELECTIVE AZIRIDINATION BY TRANSFER OF CARBON TO IMINES 4.1. Synthesis of Aziridines from Imines and Diazo Compounds

Among the strategies developed for the preparation of 2,3disubstituted aziridines, the aziridination of imines with diazo compounds has attracted considerable attention. This process has been reported to occur via two different mechanisms: (a) transition-metal-catalyzed carbene addition to a free imine and (b) direct attack of a diazo compound to a Lewis or Bronsted acid-activated imine. 7902


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In two different recent works, Mezzetti and Ranocchiari described an enantioselective synthesis of aziridines catalyzed by the ruthenium complex 131 [RuCl(OEt2)(PNNP)]Y (PNNP = (1S,2S)-N,N′-bis[o-(diphenylphosphino)benzylidene]cyclohexane-1,2-diamine); interestingly, in this work the authors proposed an alternative carbene transfer reaction pathway.71,72 The reactions, performed on Nbenzhydryl imines 132 deriving from benzaldehyde and some para- and ortho-substituted aromatic aldehydes, in the presence of EDA, afforded the corresponding aziridines 133 in variable yields and a stereoselectivity (dr and er) depending on the counterion of complex 131. In an attempt to shed light on the mechanism of this aziridination reaction, multinuclear (1H, 13C, 31 P, and 15N) NMR experiments were performed on reaction mixtures containing 13C- or 15N-labeled EDA. These experiments revealed that the complex involved in the formation of aziridines was not the expected metal−carbene complex 134 but the diazo ester complex 135 that reacts with imines to afford the expected aziridines. In striking contrast, complex 134 reacting with EDA forms the corresponding diethyl maleate (Scheme 59). 4.1.2. Direct Addition of Diazo Compounds to Activated Imines. The Lewis or Bronsted acid-catalyzed reaction of α-diazocarbonyl compounds and aldimines is recognized as a reliable method for the synthesis of 2,3disubstituted aziridines. The widely accepted mechanism involves the nucleophilic attack of the diazo compound to the activated imine to form the α-diazonium-β-amino carbonyl intermediate 136 that, by an intramolecular nitrogen displacement, provides the corresponding aziridine. The reaction is also known to give variable amounts of the isomeric enamines 137 and 138, likely resulting respectively from a 1,2-carbon or 1,2hydrogen shift on the intermediate 136 (Scheme 60). Studies on the kinetic isotope effect reveal that the ring-closing C−N bond forming step is the diastereo- and enantioselectivitydetermining step of this process.73

Unlike traditional catalysts for carbene transfer reactions, this new catalyst involved a monomeric Rh(II) complex with a bisoxazoline ligand 128. The Rh-catalyzed reactions of a series of N-arylimines 126 with EDA in THF resulted in the formation of the corresponding aziridines 127 with 10−73% yields, variable diastereoselectivities in favor of the cis-isomer, and poor enantioselectivities (Scheme 57). Scheme 57

More recently Zhang et al. reported the diastereoselective synthesis of highly functionalized aziridines by reaction of diazoacetoacetate derivatives with N-p-methoxyphenyl imines 129 deriving from aromatic aldehydes.70 An initial screening of several catalysts suggested that the reaction likely proceeds through the metal−carbene route. Dirhodium tetraacetate proved to be the catalyst of choice, furnishing the expected aziridines 130 in high yields (84−99%) and excellent stereoselectivity (only cis-isomers were observed) (Scheme 58). Scheme 58

Scheme 59

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trans ratios from 79:21 to 93:7) (Scheme 62). On the contrary, the use of SnCl4 and 2,6-di-tert-butyl-4-methylphenyl diazo-

Scheme 60

Scheme 62

Looking at the topicity of this reaction, either the Si- or the Re-face of both activated imines (electrophiles) and diazo compounds (nucleophiles) could be involved. The four possible combinations (Si−Si, Re−Re, Si−Re, and Re−Si) give rise, after ring-closure, to four stereoisomeric aziridines (Scheme 61). In each case, the attack of a specific face of the diazo compound on a specific face of the activated imine could occur by either a syn-clinical approach, giving a cisoid transition state (TS), or an antiperiplanar approach, leading to a transoid TS. Such TSs gave, respectively, a gauche and an anti intermediate, which, in the end, furnish the same aziridine. The topicity of this reaction is important to propose a reasonable mechanism for stereoselective aziridinations. Templeton et al. reported the first general study on simple nonchiral Lewis acid-catalyzed synthesis of aziridines from imines and diazo esters.74 In 2003, Akiyama and co-workers reported a Lewis acid-catalyzed aziridination of a trifluoroacetaldehyde N,O-acetal, 139, a stable equivalent of a trifluoromethylated aldimine, with different diazoacetates.75 Both cisand trans-aziridines could be obtained stereoselectively with a proper choice of the substituents of the diazo compound and the catalyst. The use of BF3·Et2O was found to be very effective in the synthesis of aziridines 140 with high cis-selectivity (cis/

acetate (BDA) resulted in a reversal of stereoselectivity, affording preferentially the trans-isomer 141 (Scheme 62). In all cases, no traces of the generally formed enamine byproducts (see Scheme 60) were observed. Yadav and co-workers described a one-pot formation of cisaziridinecarboxylates 142 by reacting a variety of imines, generated in situ from aromatic and aliphatic aldehydes and Narylamines, with ethyl diazoacetate in the presence of LiClO4 (Scheme 63).76 In particular, the use of 10 mol % of LiClO4 furnished the cis-aziridines 142 in high yields (75−91%) and stereoselectivity without traces of the enamine byproducts. The synthesis of aziridine-2-phosphonates has also been reported in a more recent work of Pellicciari and co-workers in which the EDA is replaced by DIDAMP (diisopropyl

Scheme 61

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Scheme 63

Scheme 66

diazomethylphosphonate).77 By examining the effect of different factors, such as the imine nitrogen substituent, the Lewis acid, and the solvent, the authors found that better yields and diasteroselectivities, could be obtained when N-benzhydryl imines deriving from aromatic aldehydes reacted with DIDAMP in the presence of In(OTf)3 as catalyst in DCM at 0 °C. Under these conditions, aziridines 143 were obtained with reasonable cis/trans ratios (from 2:1 to 6:1) but high yields (80−91%) (Scheme 64).

trimethylsilyl imines, leading to aziridines in good yields and good stereoselectivities (Scheme 67).81 Indeed, reactions of NScheme 67

Scheme 64

Xia and co-workers described the formation of Narylaziridines with high cis-selectivity from EDA and imines derived from aromatic aldehydes in the presence of the ionic liquid bmimPF6 (1-n-butyl-3-methylimidazolium hexafluorophosphate) (Scheme 65a).78 Mayer and co-workers used

PMP imines deriving from aromatic aldhehydes with EDA in the presence of 145 gave, in most cases, only the cis-configured aziridines in 50−72% yields (Scheme 67). Variable amounts of trans-configured aziridines were observed with imines obtained from p-nitrobenzaldehyde and aliphatic aldehydes (Scheme 67). Moreover, the floronium cation allowed for the formation of protolytically labile cis-N-TMS-aziridines, which undergo TMS-cleavage by column chromatography, affording the corresponding NH-aziridines (Scheme 67). Antilla and Wulff brought a significant contribution to the stereoselective synthesis of aziridines from imines and diazo compounds. In particular, they developed an asymmetric aziridination reaction by using chiral catalysts prepared from the triphenylborate and chiral biaryl ligands VANOL and VAPOL (Figure 3).82,83 This asymmetric aziridination,

Scheme 65

pyridinium- and viologen-based ionic liquids for the synthesis of a variety of aziridines from different imines and phenyldiazomethane, obtaining mainly cis-aziridines (Scheme 65).79 In 2004, Williams and Johnston reported the first example of a Bronsted acid-catalyzed addition of diazo compounds to imines for the synthesis of aziridines.80 N-Benzhydrylaziridines 144 have been obtained in moderate to high yields and cisselectivity. In particular, better results were observed starting from α-imino glyoxalates, which provided the expected aziridines in 62−89% yields and high cis/trans ratios (>95:5). N-Benzhydryl imines derived from aromatic and aliphatic aldehydes gave aziridines 144 in variable cis/trans ratios (from 60:40 to 95:5) and 40−73% yields of the cis-isomers (Scheme 66). An alternative electrophilic species able to activate the imine was found to be the fluoronium cation F+. This type of catalysis has been reported recently by Bew and co-workers, who showed the ability of the N-fluoropyridinium triflate 145 to mediate the reaction between EDA and N-aryl or N-

Figure 3.

performed in the presence of EDA, provided ethyl aziridine2-carboxylates with high cis-selectivity and enantioselectively using N-benzhydryl imines obtained from aromatic and aliphatic aldehydes. Prevalent cis-selectivity has been observed in the reactions, as a consequence of the favored addition of the 7905


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Si-face of the EDA to the Si-face of the imines (see Scheme 61) using (S)-VANOL or VAPOL ligands. In a detailed paper by Wulff’s group, the best reaction conditions for the asymmetric aziridination, in terms of temperature, catalyst loading, and solvent, were described. They found that the use of 0.5−10 mol % of catalyst and 1.1− 1.2 equiv of EDA at 25 °C for 24 h in toluene furnished aziridines 146 in moderate to high yields, with er > 90:10 for aromatic imines and er > 88:12 for aliphatic imines. In almost all cases, high cis-selectivity was observed (Scheme 68).84

analysis (RHF/3-21G) performed on (S)-VANOL−catalyst− imine complex showed that, among the four oxygen atoms O1, O2, O3, and O4, able to bind the iminium ion, O2 has the highest electron density. In addition, the species resulting from the O2-iminium bond would benefit from stabilizing noncovalent interactions between the biaryl N-substituent and the VANOL/VAPOL ligand (Figure 6). This should make the O2bound iminium ion the preferred complex. ONIOM(B3LYP/631G*) calculations performed on the TSs involved in the carbon−carbon bond-forming step of the reaction of 148 with EDA catalyzed by the (S)-VANOL−B3 explained the observed stereoselectivity. Two TSs were identifiedTS1 and TS2 leading respectively to the observed cis- and trans-configured aziridines. The formation of the cis-isomer has to occur by a syn-clinical approach (cisoid TS in Scheme 61), while the formation of the trans-isomer has to occur by an antiperiplanar approach (transoid TS in Scheme 61). The cisoid TS1 is 3.1 kcal/mol lower in energy than transoid TS2, which explains the experimentally observed >50:1 cis/trans ratio for this reaction (Figure 6). Another aspect investigated in this asymmetric aziridination reaction was the role of the nitrogen substituent. In the original report, the benzhydryl group was proved to be the optimal choice between the readily available electron-neutral Nprotecting groups, affording high asymmetric inductions. However, removal of benzhydryl group requires strong acidic conditions, which often cause aziridine ring-opening. In an attempt to find an efficient and easily removable N-substituent, Wulff’s group undertook an extended investigation by evaluating the effect of different N-protecting groups.87,88 This study led to the identification of N-substituents superior to the benzhydryl group, giving cleaner and faster reactions with better yields and enantioselectivity. The N-substituents examined were DAM (dianisylmethyl), MEDPM (tetramethyldiphenylmethyl), MEDAM (tetramethyldianisylmethyl), and BUDAM (tetra-tert-butyldianisylmethyl). While MEDPM had the limitation of being difficult to remove, the acid-mediated cleavage of the other N-substituents, having a p-methoxy group, proved to be easier, due to the greater stability of the diarylmethyl cation that is formed in the cleavage process. The effect of these N-substituents on asymmetric aziridinations of aromatic and aliphatic imines has been evaluated.89 The results show that the MEDAM group is clearly the best N-substituent, leading to the formation of aziridines with high asymmetric inductions and cis-selectivity (Figure 7). Another important factor to be considered in this kind of aziridination methodology is the nature of the diazo compound.

Scheme 68

Concerning the nature of the catalyst, structural studies performed by Wulff and co-workers led to two hypothetical structures. In particular, 1H and 11B NMR and HRMS analyses revealed two species in 1:3−1:5 ratio: the mesoborate B1 (as the minor species), with one ligand molecule and one boron atom, and the pyroborate B2 (as the major species), with one ligand and two boron atoms (Figure 4). Further studies on different mixtures of B1 and B2 revealed that the likely active species in the catalytic asymmetric aziridination reactions could be B2, giving higher asymmetric inductions and rates than B1.82 However, further investigations on the catalyst’s structure suggested that the active catalyst was not a Lewis acid, as it had been assumed before, but a Bronsted acid of singular structure B3 obtainable by treatment of a mixture of B1 and B2 with 1 equiv of imine (Figure 4).85 This assumption was made after comparison of the 1H and 11 B NMR spectra of B3 with those of the crystalline DMAP boroxinate complex 147. In both cases, the 11B NMR spectrum showed a very sharp signal at 5.5 ppm for the four-coordinate boron atom, and the 1H NMR spectrum showed a doublet around 10.3 ppm (Figure 5). Thus, the structure of the active catalyst for the asymmetric aziridination reaction was assumed to be an ion pair consisting of a boroxinate anion and an iminium cation resulting from the protonation of the imine. More details about the structure of the active catalyst were also obtained by computational studies.86 In particular, NBO

Figure 4. 7906


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Figure 5.

Figure 7.

Figure 8.

for this purpose. BINOL-based catalysts have been shown to promote C−H insertion in the reactions of N-Boc imines with diazoacetate, while in the reactions with diazoacetamides, such catalysts lead to trans-aziridines. In particular, Maruoka and coworkers reported the use of chiral BINOL dicarboxylic acid (BINOL-C) in the reaction of N-Boc imines and diazoacetamides 151 to afford trans-N-Boc-aziridines 152 in moderate to good yields and high enantioselectivities (Scheme 69);91 the same authors reported the formation of products 153 in the reactions of N-Boc imines with α-diazoacetate 154 (Scheme 69).92 Similarly, Zhong and co-workers developed a clean and fast asymmetric aziridination of N-Boc imines with diazoacetamides 151 catalyzed by chiral BINOL hydrogen phosphate (BINOL-P), which led to the formation of trans-aziridines 152 in excellent yields (89−97%) and enantioselectivities (88−

Figure 6.

In particular, two variability points (X and Y in Figure 8) could be identified. Concerning the X group, the use of VANOL and VAPOL in the enantioselective synthesis of cis-aziridinyl vinyl ketones 149 from diazomethyl ketones 150 (Scheme 69) has been reported.90 Interestingly, it has been demonstrated that the asymmetric synthesis of trans-configured aziridines could be achieved by using diazoacetamides. The formation of optically active trans-aziridines from diazoacetamides has been described in various works, and different chiral catalysts have been used 7907


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Scheme 69

98%) (Scheme 69).93 The BINOL-P was reported to promote a C−H insertion by Terada and co-workers, in the reactions of N-Boc imines with α-diazoacetate ester 154, leading to β-amino diazo esters 153 (Scheme 69).94 Two different reaction mechanisms have been proposed to explain such results. In the reaction with diazoacetate, the process is considered to involve a hydrogen abstraction in the putative intermediate 156 to give the addition product, while using diazoacetamides, the lower acidity of the α-proton of the diazo compound might switch the reactivity toward the formation of the aziridine (Scheme 70).92,94 The trans-selectivity, observed in the reactions of N-Boc imines with diazoacetamides, was ascribed to a greater stability of the transition state TS-A (Scheme 70), bearing the

carboxamido group and the aryl group of the imine in an antiperiplanar orientation, with respect to the transition state TS-B, where such groups have a syn-clinal orientation. This different stability would derive from a balance between destabilizing steric repulsions of the two groups in the synclinal TS-B and the stabilizing hydrogen bond between the amidic N−H and the Boc group in the antiperiplanar TS-B (Scheme 70).91 Further progress have been made by Wulff and co-workers, who developed an unprecedented procedure for the stereoselective synthesis of both cis- and trans-aziridines starting from the same imine but using different diazo compounds. In particular, the use of (S)-VANOL−catalyst with diazoacetamides 151, gave trans-aziridinecarboxamides 152 with high enantioselectivity (Scheme 69).95 By contrast, as already reported, the use of (S)-VANOL−catalyst with diazoacetates such as 154 furnished cis-aziridines 155 (Scheme 69). This switch in the stereoselectivity using the VANOL/ VAPOL strategy has been rationalized by considering the ability of the diazoacetamides to form hydrogen bonds with the anionic boroxinate core of the catalyst. By ONIOM(B3LYP/631G*) calculations, transition states TS3 and TS4, leading to the observed cis- and trans-aziridines (2R,3R)-152 and (2R,3S)152 (Scheme 69), were postulated. The noncovalent Hbonding between the amidic hydrogen of 151 and the O3/O1 of the (S)-VANOL−catalyst could be the reason for the predominant trans-selectivity observed in this reaction (Figure 9). This hypothesis was validated by the observation that a tertiary diazoacetamide, lacking the N−H group, showed high cis-selectivity (Figure 9).86 The catalytic asymmetric aziridinations of imines with diazo compounds discussed until now require the generation of a precatalyst from the VAPOL or VANOL ligand and B(OPh)3 and the need to prepare an imine from the corresponding aldehyde and amine. The use of a preformed imine represents a limitation for this procedure, since many types of aliphatic aldehydes do not form stable imines. With the aim to overcome

Scheme 70

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of (R)- or (S)-VANOL−catalyst, reacted with both α-methyl-αdiazo esters 159 and α-methyl-α-diazo-N-acyloxazolidinones 160 to give trisubstituted aziridines 161 and 162 in variable yields and excellent diastereo- and enantioselectivities. Unexpectedly, the VAPOL−catalyst did not prove to be as efficient as the VANOL−catalyst, giving very low induction (Scheme 72).97 Maruoka and co-workers reported also the asymmetric synthesis of trisubstituted aziridines by using either a chiral auxiliary or a chiral ligand. They described the synthesis of trisubstituted aziridines in highly stereodefined manner in the presence of catalytic Lewis or Brönsted acids by using a variety of N-Boc aldimines 163a and α-substituted α-diazocarbonyl compounds 164a bearing the camphorsultam as chiral auxiliary (Scheme 73). This process proved to be effective with N-Boc imines deriving from aromatic aldehydes, while it was ineffective with imines obtained from aliphatic aldehydes. In all cases, only trans-aziridines 165 were observed. The easy removal of the chiral auxiliary gave the desired aziridines 166 in high enantiomeric ratios (Scheme 73). The same authors evaluated the possibility to obtain trisubstituted aziridines by reactions of ketimines and α-unsubstituted α-diazocarbonyl compounds. A range of trisubstituted trans-aziridines 167 were obtained in modest yields by reacting different N-Boc αketimino esters 163b with α-unsubstituted N-α-diazoacetyl camphorsultam 164b in the presence of Tf2NH as the catalyst (Scheme 73).98,99 In a following paper, Maruoka and co-workers performed the asymmetric synthesis of trisubstituted aziridines by using a chiral N-triflyl phosphoramide (S)-169, N-Boc imines, and αdiazocarbonyl compounds bearing an oxazolidinone as key template (Scheme 74). Several N-Boc aldimines 170 were reacted with α-alkyl α-diazocarbonyl compounds 172 in the presence of the chiral catalyst (S)-169 to afford trans-aziridines 174 in 71−91% yields and er > 87:13 (Scheme 74). In the reactions of N-Boc α-ketimino esters 171 with N-αdiazoacetyloxazolidinone 173 in the presence of (S)-169, trans-aziridines 175 were obtained in 74−92% yields and er > 94:6 (Scheme 74).100 Lee and Song described the asymmetric synthesis of cisaziridines 177 and 178 using chiral N-benzylimines 176, ethyl diazoacetate, and a Co(II) salt as Lewis acid. All of the

Figure 9.

this limitation, Wulff and co-workers introduced the first multicomponent catalytic asymmetric aziridination reaction (MCAZ) to give aziridine-2-carboxylic esters 155 with very high diastereo- and enantioselectivity by combining together an aldehyde, an amine, and a diazo compound (Scheme 71).96 The catalyst was a chiral polyborate anion B3−MEDAM (BOROX) that was assembled in situ from a biaryl ligand and B(OPh)3 by the amine substrate (NH2-MEDAM). This multicomponent reaction was employed with VAPOL−, VANOL− and t-Bu 2 VANOL−BOROX catalysts with MEDAM amine in the presence of different aldehydes. All three ligands gave very high asymmetric inductions for arenecarbaldehydes, but for aliphatic aldehydes t-Bu2VANOL ligand gave higher yields than unsubstituted VANOL and VAPOL (Scheme 71). By using hexadecanal as aldehyde, with the same MCAZ approach, the synthesis of all four stereoisomers of sphinganine has been very recently reported.96c Concerning the diazo compound used in the asymmetric aziridination of imines, the possibility to replace the α-hydrogen (Y in Figure 8) with a different group paves the way for planning the synthesis of trisubstituted aziridines. In a recent paper, Wulff and co-workers showed that, while unactivated (N-MEDAM) imines were not reactive toward α-substituted αdiazocarbonyl compounds, N-Boc imines 158, in the presence Scheme 71

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Scheme 72

Scheme 73

reactions, carried out in the presence of a catalytic amount of CoCl2 and AgBF4 in acetone at room temperature, furnished the desired aziridines in moderate yields (29−89%) and good cis-selectivity but low diastereoselectivity (Scheme 75).101 Wulff and co-workers reported an example of double stereodifferentiation, in which a chiral imine was used in combination with (S)- or (R)-VANOL or VAPOL with the aim to improve the asymmetric inductions imparted by using the

Scheme 74

Scheme 75

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In a recent paper, Yadav and co-workers reported the first example of diastereoselective nitroaziridination of N-tosylaldimines 184 with 1-bromonitroalkanes 185. MeOH/NaOAc was found to be the best solvent/base system for this procedure, furnishing aziridines 186 in good yields and with cis-selectivity (Scheme 79).108 An asymmetric version of the aza-Darzens aziridination could be realized by using a chiral auxiliary that could be part of either the imine or the anionic component. Concerning the use of chiral imines, chiral sulfinimines have been shown to be suitable substrates for this scope. Davis et al. described the aza-Darzens reaction of halomethylphosphonate anions and enantiopure sulfinimines for the asymmetric synthesis of aziridine-2phosphonates.109 By using (S)-N-(p-toluenesulfinyl)imines and dialkyl α-chloromethylphosphonates as starting materials, a two-step procedure involving an initial formation of syn- and anti-α-chloro-β-amino adducts 187 and 188, followed by their separation and intramolecular cyclization, furnished highly enantiopure cis- and trans-N-sulfinylaziridine-2-phosphonates 190 and 191. The reactions proceeded with high diasteroselectivity in favor of the (SS,2S,3R)-190 and (SS,2R,3R)-191 isomers, as only traces of the syn- and anti-α-chloro-β-amino derivatives 189 were detected in the crude reaction mixtures (Scheme 80). The observed stereoselectivity has been explained with a model involving the addition of the halomethylphosphonate anion to the C−N double bond on the opposite side to the bulky p-tolylsulfinyl group (TS-1 in Scheme 80). Better results, in terms of diastereoselectivity, could be obtained by using chiral N-(2,4,6-trimethylphenylsulfinyl)imines and diethyl iodomethylphosphonate as starting materials. Reactions on these substrates at −78 °C in the presence of 2 equiv of LiHMDS furnished the corresponding aziridines 192 in a onepot procedure as single cis-diasteroisomers and in 75−78% isolated yields (Scheme 80).110 The bulkier tert-butanesulfinimines are useful substrates for aza-Darzens reactions.111 Stockman and co-workers reacted both tert-butanesulfinyl aldimines 193 and ketimines 194 with ethyl bromoacetate under basic conditions to get 2,3-di- and 2,2′,3-trisubstituted aziridines, respectively.112 2,3-Disubstituted aziridines 195 were obtained in all cases in good cis/trans ratios (71:29 to 98:2), showing an increase in stereoselectivity compared to the reactions with p-toluenesulfinimines (Scheme 81). Similarly, most of the sulfinylketimines 194 that were used proved to give the expected trisubstituted aziridines 196 in high cis/trans ratios (71:29 to 93:7) and diastereoselectivities (Scheme 81). Yields were predictably lower with respect to aldimines substrates, due to increased steric interactions and lower reactivity of the ketimines. Savoia and co-workers113 described the synthesis of chiral monosubstituted aziridines by addition of chloromethyllithium, generated in situ from methyllithium, chloroiodomethane, and lithium bromide, to imines 197 derived from (S)-valinol, protected as O-trimethylsilyl ether, and 2-pyridinecarboxaldehyde or 2-quinolinecarboxaldehyde. The corresponding aziridines 199 were obtained as single diasteroisomers in moderate yields after NH4F-mediated desylilation. A similar reaction performed on imines deriving from (S)-valine methyl ester 198 gave aziridines 200 bearing the α-chloro ketone group, resulting from the nucleophilic attack of the chloromethyllithium to the ester functionality. The failure of this reaction using benzaldimine as starting material suggested that the chelating ability of the bidentate imines 197 and 198 was mandatory for the reaction to occur. In fact, the pyridyl and quinolyl groups

chiral ligand alone. Imines (R)-179 showed an inherent preference for (2R,3R)-aziridines 180, but this inherent preference was modest for aromatic imines and almost absent for aliphatic imines (dr 180/181 ≈ 58:42). Moreover, a strong matched case of the imines (R)-179 with (S)-catalyst was observed in all cases (Scheme 76).102 Scheme 76

4.2. Aza-Darzens Reaction

The aza-Darzens reaction, involving the reaction of imines with stabilized anions bearing α-leaving groups, is one of the oldest and most important methods for the synthesis of aziridines. The reaction mechanism consists of two different steps: an initial nucleophilic attack of the anion on the imine CN bond followed by a 3-exo-tet cyclization of the intermediate (Scheme 77). The anion involved in this reaction has shown to tolerate a Scheme 77

broad range of stabilizing groups (including carbonyl, alkenyl, benzylic groups, heterocycles), while the α-leaving group is generally a halogen.103 Moreover, some examples on the use of Darzens reagents for the synthesis of terminal aziridines have also been reported. In the last 10 years, several new examples of both asymmetric and stereoselective synthesis of aziridines by the aza-Darzens reaction has been shown. Troisi and co-workers, as a continuation of their research activity started some years before and devoted to the synthesis of heterocycle-substituted aziridines, reported different works on the aza-Darzens reaction between α-haloalkyl heterocycles and imines. They described the synthesis of trans-configured 2-aziridinylthiazoles by the coupling reaction of some 2-chloroalkylthiazolyllithiums, generated from the corresponding 2-chloroalkylthiazoles, and N-phenyl imines derived from aliphatic and aromatic aldehydes (Scheme 78).104,105 They also reported the preparation of dihetero-substituted aziridines through the coupling reaction between heterosubstituted chloroalkyllithiums and N-phenyl imines deriving from heteroaryl aldehydes (Scheme 78).106 The synthesis of aziridines carrying a third aza heterocycle as the nitrogen substituent has been also reported. Depending on the nature of the heterocycles R2 and R4, variable amounts of desired aziridines 182 and enamine byproducts 183a and 183b were observed. (Scheme 78).107 7911


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Scheme 78

organolithium reagent, promoting the C−C bond-forming reaction, leading to β-chloro lithium amide 202 (Scheme 82). The problem related to the poor reactivity of in situ generated halomethyllithiums toward poorly electrophilic compounds like imines was dealt with by Concellòn and coworkers by using imines bearing N-electron-withdrawing substituents.114,115 They reported an asymmetric version of this procedure using enantiopure imines 204 obtained from chiral aldehydes 203. Thus, N-tosyl imines 204 were reacted

Scheme 79

allow for the formation of stable chelate complexes 201 and, at the same time, increased the nucleophilic character of the Scheme 80

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Scheme 81

Scheme 83

Scheme 84

with diiodomethane and MeLi to afford the desired aziridines 205 with high diastereoselectivity (Scheme 83). The asymmetric induction in the aza-Darzens process has been reported to occur also by introducing chiral auxiliaries into the anion-bearing counterpart. Indeed, Sweeney and coworkers reported the asymmetric synthesis of aziridines by reacting N-diphenylphosphinyl (Dpp) imines 206 with the chiral 2-(R)-N-bromoacetylcamphorsultam 207.116 In all cases, aziridines 208 were isolated as cis-diastereoisomers. The absolute configuration suggested that the reactions proceed via a syn-selective aza aldol reaction involving the nucleophilic attack of the Si-face of the enolate on the Si-face of the imine (Scheme 84).

An example of double asymmetric induction, where both the imines and the anions are chiral, has been recently reported by Garcia-Ruano et al.117 The authors used chiral 2-p-tolylbutylsulfinyl benzyl iodide 210 as the anion source. Reactions of (S)-210 with (R) N-p-tolyl and N-tert-butylsulfinylimines 209, in THF at −78 °C in the presence of NaHDMS for just 1 min, afforded the corresponding aziridines 211 in good yields with excellent diastereoselectivity. A mismatch situation was found in the reaction of (S)-210 with imines (S)-209 under the same reaction conditions (Scheme 85).

Scheme 82

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this step could involve either the Si- or the Re-face of both the imine (electrophile) and the ylide (nucleophile), four possible nucleophilic addition combinations are possible: Si−Si (or Re− Re), leading to syn-betaine intermediates that will generate the corresponding cis-aziridines, and Si−Re (or Re−Si), leading to anti-betaine intermediates that will generate the corresponding trans-aziridines. In each case, a cisoid TS, which produces a gauche betaine, or a transoid TS, which produces a transbetaine, are possible (Scheme 87). In the case of semistabilized ylides (R2SCHR1 with R1 = aryl or alkenyl), the diasteroselectivity-determing step has been established to be the ylide addition to the imine, since in this case the reaction is irreversible and under kinetic control. This irreversibility was demonstrated through both crossover experiments122 and computational studies.123 In the case of stabilized ylides (R1 = CO2Me, CO2NEt2), the situation is slightly different: crossover experiments122 and computational studies demonstrated that the diastereoselectivity-determining step of the reaction is not the betaine formation but the cyclization step. Due to stabilization of the ylide, likely the addition step should be reversible, making the ring-closure TS the highest point on the energy profile of the entire process. However, the reported studies are not conclusive and a variable degree of stereoselectivity can be observed, depending on the nature of both ylide and imine.124 As a general rule, semistabilized ylides give low trans-selectivity; instead, stabilized ylides show low cis-selectivity. The literature reported over the past years on the asymmetric ylide-mediated aziridinations is based on a substrate-control approach realized by employing either optically active sulfinimines or, more frequently, chiral ylides. Concerning the use of chiral sulfinylimines, after the pioneering works of the groups of Garcia-Ruano125 and Davis,126 several papers described the use of chiral tert-butylsulfinyl imines for the synthesis of mono-, di-, and trisubstituted aziridines. Stockman and co-workers investigated the aziridination of aromatic and aliphatic (RS)-tert-butylsulfinyl imines with dimethylsulfonium methylide in DMSO, by using sodium hydride for ylide generation, and obtained the expected aziridines 217 in good yields and diasteroselectivity (Scheme 88). The stereochemistry at the aziridine C2 was confirmed to be S (Scheme 88).127 The same authors described the preparation of chiral 2,3disubstituted vinylaziridines by reactions of (RS)-tert-butylsulfinyl imines with the ylide generated from S-allyltetrahydrothiophenium bromide 218. The reactions, performed in THF in the presence of tBuOLi, furnished the corresponding (2S,3S)-trans-aziridines 219 and (2S,3R)-cis-aziridines 220 in good yields (44−82%), with moderate trans-selectivity and good diastereoselectivity (Scheme 88).128 The same protocol could be applied successfully for the synthesis of 2,2,3trisubstituted aziridines using tert-butylsulfinylketimines. Vinyl aziridines 221 and 222 were obtained in good yields (42− 85%), with excellent diastereoselectivities (90 → 95%) and reasonable cis/trans-selectivity using ylide generated from 218 (Scheme 88).129 The application of enantiopure sulfur ylides in the asymmetric synthesis of aziridines initially developed by the groups of Aggarwal and Dai130,131 has become a useful strategy in asymmetric aziridination. Solladiè-Cavallo and co-workers reported an asymmetric synthesis of 2,3-disubstituted Ntosylaziridines from N-tosylimines, deriving from rather bulky aromatic and aliphatic aldehydes, using the chiral sulfonium salt 223. In this reaction, a phosphazene base EtP2 ([Me2N]3P

Scheme 85

A nice example on the use of halomethyllithium reagents for the aziridination of imines has been recently reported by Bull and co-workers, who employed this strategy to develop an unprecedented synthesis of iodoaziridines.118,119 For this purpose, they used diiodomethyllithium, an unstabilized and substituted reagent (LiCHI2) able to afford disubstituted aziridines. This strategy has been applied to the aziridination of N-Boc and N-tosyl imines 212 (or the corresponding imine precursors 213). By a one-pot procedure, involving generation of diiodomethyllithium by deprotonation of CH2I2 with LiHMDS at −78 °C, addition to the imine. and intramolecular cyclization of the diiodo intermediate, iodo aziridines 214 were obtained with an excellent cis-selectivity (Scheme 86). While Scheme 86

aromatic imines proved to be successful in all cases, aliphatic NBoc imines did not give the expected products. An example of asymmetric synthesis was also reported by using chiral tertbutylsulfinyl imines 215, which allowed for the preparation of cis-configured iodoaziridines 216a and 216b (Scheme 86). The high cis-selectivity observed was explained by assuming the intermediacy of the more stable conformer A lacking eclipsing interactions between groups. 4.3. Ylide-Mediated Aziridination of Imines

The sulfonium ylide-mediated aziridination of imines is the aza analogue of the highly successful Johnson−Corey−Chaykovsky reaction,120,121 and it has proved to be particularly useful for the synthesis of aziridines, with excellent levels of enantiocontrol and moderate to good diasteroselectivity. The generally accepted mechanism for this reaction involves three steps: addition, bond rotation, and intramolecular cyclization (elimination). As the initial step, the addition of the ylide to the imine to form a betaine intermediate occurs, and often this is the stereoselectivity-determining step. Since 7914


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Scheme 87

Scheme 88

selectivity: Boc > SES > Ts > o-Ns. Moreover, computational studies established that the cis-selectivity observed in the reactions of 223 with more bulky imines could be ascribed to a reversible betaine formation. (Scheme 89).133,134 Huang and co-workers used a chiral sulfonium ylide generated in situ from the C2-symmetric sulfide 224 and benzyl bromide in the presence of potassium carbonate, for the aziridination of aromatic N-Ts imines. By performing the reactions in acetonitrile and in the presence of tetrabutylammonium iodide (TBAI), as phase-transfer catalyst, the desired chiral trans-configured aziridines 225 were obtained in good yields and excellent enantioselectivities (Scheme 90).135 The use of another semistabilized ylide, prepared from the sulfonium salt 226, was reported by Aggarwal and co-workers.

NP(NEt)[NMe2]2) was employed to generate the ylide. A very high enantioselectivity for both cis- and trans-aziridines was observed and explained considering a very selective approach of the imines to the Re-face of the ylide generated from the conformer K1 of 223 (Scheme 89).132 Hameršak and coworkers, in two different works, demonstrated the possibility to replace the toxic and expensive phosphazene base EtP2 with NaH without any loss of yield, enantioselectivity, or diastereoselectivity and, most importantly, investigated the effect of the N-imine substituents on the stereoselectivity of the process. Imines bearing four different N-substituents, such as tosyl (Ts), 2-(trimethylsilyl)ethanesulfonyl (SES), Boc, and onitrobenzenesulfonyl (o-Ns), were subjected to aziridination with 223, establishing the following order of decreasing trans7915


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In a very recent paper, Connon and co-workers reported an asymmetric synthesis of terminal aziridines by methylene transfer from a chiral sulfonium ylide. TPS-substituted imines 231 obtained from aromatic, aliphatic and α,β-unsaturated aldehydes were converted into the corresponding aziridines 232 in good yields by means of the ylide generated from the chiral sulfonium salt 230 in the presence of a strong organic base. Despite the poor enantioselectivity (er up to 65:35), this work, however, is a rare example describing this type of approach for the synthesis of chiral terminal aziridines (Scheme 91).138

Scheme 89

Scheme 91

In the reactions with aromatic and unsaturated N-tosyl imines, trans-aziridines 227 were prepared with high levels of enantioselectivity and good yields. The high enantioselectivity was explained by suggesting that of the two possible ylide conformers A and B, the ylide A should be favored likely for steric reasons, and this conformer should react with imines on its Re-face since the Si-face is inaccessible by a flanking methyl group (Scheme 90).136 The stabilized ylide 228, containing an enantiopure sulfinyl group bonded to the ylide carbon atom, was employed by Midura to prepare a range of chiral sulfinyl aziridines. This ylide was first prepared and then reacted in acetonitrile with a variety of aromatic and aliphatic N-tosyl imines to give in all cases only the cis-(2S,3R)-aziridines 229. This observed facial selectivity can be explained by the reasonable assumption that ylide adopts the conformation C that likely affects the stereochemical course of the reaction (Scheme 90).137

A very interesting case of diasteroselective ylide-mediated aziridination of imines was reported by Aggarwal and coworkers, who described the first study of cis/trans-selectivity in the reactions of imines with nonstabilized sulfur ylides. They

Scheme 90

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reported a three-component reaction involving the diphenylvinyl sulfonium triflate 233, a nucleophile, and an imine (Scheme 92). In this reaction, the nucleophile reacts with the

Scheme 93

Scheme 92

chiral 1,2-vicinal haloamines or amino alcohols. In this section, general procedures to stereoselectively synthesize aziridines by intramolecular cyclization will be discussed. Strategies leading to stereodefined aziridines based on the asymmetric kinetic resolution of racemic terminal epoxides in the presence of carbamates as nucleophiles or, otherwise, relying on stereoselective reductions of α-selenyl β-imino esters derived from αoxo esters will be also considered. Lindsley developed a three-step, one-pot protocol involving initial catalytic enantioselective α-chlorination of aldehydes, subsequent reductive amination with a primary amine, and intramolecular displacement, leading to chiral terminal aziridines.142 To find the optimal reaction conditions for the enantioselective α-chlorination of 239, the authors evaluated a number of different organocatalysts, employing N-chlorosuccinimide (NCS) as chlorinating agent, demonstrating that catalyst (R,R)-241143 afforded α-chloro aldehydes 240 in excellent enantioselectivity (er up to 97:3). As shown in Scheme 94, by using catalyst (R,R)-241 and performing the reductive amination at −78 °C, the enantioselective synthesis of aziridines (R)-242 was accomplished in good yields for the three steps (∼90% per step) with high er (up to 98:2). As expected, catalyst (S,S)-241 furnished the opposite enantiomer (S)-242 in good yield and excellent enantioselectivity (up to 97:3 er). Synthetically useful enantioenriched aziridines 246, bearing a β-hydroxyethyl moiety, have been prepared with excellent enantioselectivity by Hayashi and co-workers.144 The authors developed a one-pot synthesis of such substituted aziridines starting from aliphatic aldehydes 243 and N-(2-chloro-1phenylsulfonylethyl)-p-toluenesulfonamide 244. The diarylprolinol silyl ether 95 catalyzes an enantioselective Mannich reaction, on the in situ generated imines, leading to the putative amino aldehyde intermediates 245, which are further reduced to aziridines 246. Aziridines 247 bearing an α,β-unsaturated moiety and aziridines 248 bearing an acetal moiety were also synthesized (Scheme 95). Wei reported a very rapid and simple method for the preparation of N-Ts-aziridines 250 from 1,2-vicinal haloamines 249 by grinding the substrate, anhydrous K2CO3, and a catalytic amount of urea at room temperature and under solvent-free conditions. Various vicinal haloamines deriving from electron-deficient conjugated olefins could be converted into the corresponding aziridines by this method.145 According to the nature of urea, as a strong H-bond donor and acceptor, the authors proposed a mechanism for this urea-catalyzed aziridination (Scheme 96).

sulfonium salt to give a nonstabilized ylide, which in turn reacts with the imine to produce the desired aziridine. A range of aromatic N-tosyl imines 234 and different nucleophiles, including N-methyl tosylamide, malonate derivatives, and alcohols, were reacted with the sulfonium salt 233 to produce aziridines 235 in moderate to good yields. In almost all cases, selectivity in favor of the cis-isomer was observed, with higher dr values obtained by using electron-rich imines and lower ones with electron-poor imines. The preferential formation of transisomers was observed only by using an alcohol as the nucleophile. The model proposed to explain the observed diastereoselectivity involves a syn-transoid transition state TS1, leading to cis-aziridines, favored with electron-rich imines by π−π interactions between groups. In the presence of an alcohol as the nucleophile, it was assumed that the β-alkoxy group of the ylide could form a stabilizing hydrogen bond with the imine C−H in the anti-cisoid TS2, leading to the trans-configured aziridine (Scheme 92).139 Tang and co-workers reported the use of a tellurium ylide for the synthesis of vinylaziridines. At first, they took advantage of the higher reactivity of an allylic tellurium ylide 236, with respect to the corresponding sulfur ylides, to prepare Nphenylaziridines by using rather unreactive aromatic Nphenyaldimines. By performing the reactions in the presence of the salt 236, LiHMDS, and HMPA in toluene at −78 °C, vinylaziridines 237 were obtained in 52−84% yields and excellent trans-selectivity (Scheme 93). In contrast, the reactions with aliphatic N-Boc-vinylaziridines gave high cisselectivity (Scheme 93).140 A chiral version of this procedure was developed by employing chiral tert-butylsulfinylimines as starting materials. By using the tellurium ylide generated from 236, several aryl, heteroaryl, alkyl, and α,β-unsaturated aldimines proved to be effective, affording optically active cis2-substituted-vinylaziridines 238 in good to excellent yields (Scheme 93).141

5. AZIRIDINES BY INTRAMOLECULAR CYCLIZATION Although the stereoselective preparation of aziridines could be generally achieved by direct aziridination of alkenes with metal−nitrene precursors, by addition of metal carbenes to Schiff bases, or by catalytic aza-MIRC strategy, a useful alternative is represented by the intramolecular cyclization of 7917


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Scheme 94

Scheme 95

Scheme 96

aziridines 256 bearing a labile N-sulfonyl protecting group (Scheme 97).146 This synthetic strategy relies on the asymmetric “indirect” kinetic resolution of racemic terminal

Jacobsen reported a new and practical route to highly enantioenriched 1,2-amino alcohols 252 from racemic epoxides (±)-251 and their conversion into the corresponding terminal 7918


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Scheme 97

Scheme 98

Scheme 99

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Scheme 100

the β-selenyl α-amino esters 261. In order to synthesize chiral nonracemic aziridino esters, two approaches were proposed: (a) the diastereoselective reductions of β-selenyl α-imino esters 263, deriving from α-oxo esters 260 and (R)-phenethylamine [(R)-PEA], which lead to cis chiral aziridines 264 and 265, and (b) the diastereoselective conjugate additions of a chiral amide bis-{(S)-1-phenylethyl}amine [(R)-BPEA] to α,β-unsaturated esters 266, providing both cis and trans chiral aziridines 264 and 267 (Scheme 99). The diastereoselective addition of organometallics to Nsulfinyl imines (see section 4.2),109,110 pioneered by Davis et al.152 and Ellman,153 has proven to be a straightforward method for the synthesis of chiral amines, amino alcohols, and amino acids, among other interesting compounds. In a recent work, the stereoselective synthesis of aziridines 270 via addition of Grignard reagents to α-halo N-sulfinyl imines 268, carrying a chiral (RS)-tert-butylsulfinyl group, has been tuned by De Kimpe and co-workers (Scheme 100).154 The best results were obtained when 1.1 equiv of a Grignard reagents was allowed to react with aldimine (RS)-268 in dichloromethane at −78 °C for 4−5 h, affording β-chloro Nsulfinamides 269, the precursor of the corresponding aziridines 270, in high yields (82−99%) with diastereoselectivity (62:38− 96:4). Moreover, if the reaction mixture was allowed to stir at room temperature after completion of the addition at −78 °C, the desired aziridines 270 could be directly isolated in excellent yields. All the chiral aziridines were obtained as single diastereomers [(RS,R)-270] after flash chromatography. From the X-ray diffraction analysis of N-(tert-butanesulfinyl)-2,2dimethyl-3-phenylaziridine, the absolute configuration was undoubtedly assigned as being (RS,R). The stereochemical outcome of the reaction is likely attributed to the αcoordinating ability of the chlorine atom, as depicted in the transition state reported in Scheme 100, analogously to the results obtained with other N-sulfinyl imines containing an αcoordinating group, such as nitrogen or oxygen atoms.155 After removal of the sulfinyl group, chiral aziridines (R)-271 could be obtained without loss of enantiomeric purity. The development of a synthetic protocol for obtaining chiral aziridines from N-tert-butylsulfinyl α-halo ketimines was also pursued by De Kimpe and co-workers.156 Reduction of N-tert butylsulfinyl α-chloro ketimines (RS)-272 with NaBH4 in THF, in the presence of 10 equiv of MeOH, gave (RS,S)-β-halo sulfonamides (RS,S)-273 in excellent yields (up to 98%) and

epoxide (±)-251 using carbamates 253a,b as nucleophiles and the CoIII−Salen complex (S,S)-254 as the catalyst. Being that the catalyst complex is highly effective in the hydrolytic kinetic resolution (HKR) of terminal epoxides,147 this result suggested that the highly selective HKR would be followed by a ringopening of the “mismatched”, unreacted (R)-enantiomer of the epoxide 251 by carbamate 253a,b promoted by the same catalyst. A range of terminal aziridines 255 and 256 bearing aliphatic and aromatic substituents was synthesized in high enantiomeric purity (>99%). The N-nosyl protecting group was found to be useful because nosylaziridines are 50−60 times more reactive toward nucleophilic addition than the corresponding tosylaziridines. In addition, N-nosylamines obtained after aziridine ring-opening are alkylated and/or deprotected selectively under mild conditions.148 Unfortunately, nitro groups were not compatible with strongly basic carbon nucleophiles, and this imposes the use of the SES protecting group, compatible with anionic carbon nucleophiles and easily removed by treatment with fluoride ion. The utility of these aziridines in representative nucleophilic ring-opening reactions are also reported (Scheme 97). Similarly, Bartoli et al. developed a CoIII−Salen-catalyzed asymmetric aminolytic kinetic resolution (AKR) of racemic terminal epoxides with N-Boc carbamate providing a general method for the synthesis of enantiopure N-Boc-protected amino alcohols 258. By using a practical one-pot procedure starting from racemic epoxide (±)-251, the highly enantioenriched N-Boc-protected aziridine 259 was synthesized in good yield (78%) based on carbamate 257 (Scheme 98).149 A different approach based on phenylselenyl group activation has been proposed by Miniejew et al.150 The selenyl group is known to be easily displaced under mild conditions by nucleophiles when it has an higher oxidation state, as in selenone or selenonium salt. The authors focused their attention on the preparation of chiral aziridino esters via cyclization of α-amino β-selenyl esters 261, prepared from βselenyl α-oxo esters 260 by conversion into N-benzyl imines and reduction with sodium cyanoborohydride (Scheme 99). Bromination with NBS151 and treatment with a base led to aziridino esters 262 in 45−67% yields. Only one diastereomer was observed in the NMR of the crude reaction mixture of the corresponding β-selenyl α-amino esters 261, and considering that the cyclization proceeds through an SN2 mechanism leading to cis-aziridine 262, syn-configurations were assigned to 7920


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Scheme 101

very good stereoselectivity (>98:2). Simple treatment of (RS,S)273 with KOH afforded the corresponding (RS,S)-N-(tertbutylsulfinyl)aziridines (RS,S)-274 in quantitative yield. Alternatively, reduction of ketimine (RS)-272 with LiBHEt3 in dry THF at −78 °C afforded β-chloro sulfinamide (RS,R)-273 together with aziridine (RS,R)-274 (∼9:1 mixture) in 87% yield with 78:22 dr (Scheme 101). Subsequent treatment with KOH of sulfinamide (RS,R)-273 gave the corresponding aziridine (RS,R)-274 in quantitative yield, preserving the dr of the starting material. Thus, N-(tert-butylsulfinyl)aziridines (RS,R)274 and (RS,S)-274 could be synthesized separately in high yields and excellent stereoselectivity, depending on the reducing agent used. The origin of the reversed diastereofacial attack upon changing the reducing agent from NaBH4 to a lithiated hydride species was explained as follow: if the sulfinyl oxygen atom participates in the delivery of the hydride (NaBH4 reduction, Scheme 101, TS-B), the chlorine atom is assumed to form a complex with the reducing agent, provoking a flip of the haloalkyl substituent in the Zimmerman−Traxler-like TS-B from the equatorial toward the axial position. More reactive reagents, such as LiBHEt3, react too fast with N-tertbutylsulfinyl ketimines (RS)-272 to allow the haloalkyl substituent to flip toward an axial position (Scheme 101, TSA). Another very efficient methodology to obtain optically active nitrogen-containing heterocycles with different ring sizes, based on the asymmetric transfer hydrogenation (ATH) on N-(tertbutylsulfinyl)haloimines followed by intramolecular cyclization, has been recently developed by Guijarro and co-workers.157 Optically active haloimines were subjected to a one-pot ATHcyclization sequence by employing isopropyl alcohol as the hydrogen source, a ruthenium catalyst, a ligand, and tBuOK and heating the mixture at 50 °C. Under such conditions, exploited for the preparation of pyrrolidines, piperidines, and azepanes, also N-protected three-membered ring heterocycles with aromatic and aliphatic substituents were synthesized in high yields and diastereomeric ratios. Both enantiomers of the heterocycles could be prepared by changing the absolute configuration at the sulfur atom of the sulfinyl group. This strategy, in comparison with that reported by De Kimpe and co-workers, has the advantage of using a catalytic amount of an

achiral ligand and isopropyl alcohol as hydrogen source, which also is the environmentally friendly solvent of the reaction (Scheme 102). Scheme 102

Hodgson et al. also described the direct formation of terminal N-(tert-butylsulfinyl)aziridines 276, by addition of Grignard reagents or organoceriums to readily prepared tBuSONH2-derived N-(2-chloroethylidene)-tert-butylsulfinamide 275.158 The reactions proceed in good yields and (mainly with organoceriums) good diastereomeric ratios. Oxidation of the sulfur of terminal N-(tert-butylsulfinyl)aziridines 276, including selective oxidation in the presence of unsaturation (TPAP/NMO in MeCN),159 provided terminal N-Busaziridines 277 of highly synthetic utility.160 By using one of the commercially available t-BuSONH2 enantiomers, the authors also demonstrated that this chemistry provides an entry to terminal N-Bus-aziridine functionality in high enantiomeric ratio. The absolute configurations were established either by chemical correlation or by X-ray crystallographic analysis. The sense of asymmetric induction found using imine (RS)-275 with t-BuMgCl correlates well with that observed in De Kimpe et al.’s study154 (and in most other reports concerning N-sulfinyl imines containing α-coordinating groups). To explain the stereochemical outcome with αcoordinating groups, the authors proposed that such groups either override sulfinyl oxygen chelation as in TS-B or bring additional chelation, as in TS-C, the latter being possible upon E- to Z-imine isomerization likely occurring under the reaction conditions. Moreover, stereochemical analysis established that PhMgBr gave the opposite sense of asymmetric induction with respect to mesitylMgBr. Perhaps the more sterically demanding 7921


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Scheme 103

Scheme 104

mesityl group prevents coordination to the α-chloro group, resulting in reaction proceeding by TS-A (Scheme 103).161

methodology.162 Oshima and Yorimitsu presented preliminary results on the Pd-mediated intramolecular carboamination of allylamines for the synthesis of aziridines.163 Starting from allylamines 278, bearing a quaternary carbon at the allylic position, several substituted racemic aziridines were prepared in excellent yield using Pd2(dba)3 as the catalyst, SPhos as the ligand, and potassium tert-butoxide as the base (Scheme 104). This aziridination/arylation process was conducted also on allylamines 278 containing a chiral center, leading to the formation of diastereoisomeric aziridines 279 and 280. It was found that the size of the substituents at the allylic aminated carbon affected the reaction. In particular, both yields and

6. OTHER STRATEGIES During the past decade, new strategies to build the aziridinyl ring have been introduced. Such new strategies rely on the use of Pd chemistry to perform the synthesis of the aziridine ring or, alternatively, on the functionalization of a simpler aziridine in order to increase the molecular complexity. Concerning the palladium-catalyzed synthesis of strained heterocycles, this is a challenging topic for organic chemists. A number of fivemembered heterocycles have been synthesized by using this 7922


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Scheme 105

stereoselectivities diminished when a more bulky tert-butylsubstituted allylamine was used as a substrate. X-ray analysis and NOE experiments revealed that the larger group (RL in Scheme 104) and the benzyl moiety were oriented in a cisconfiguration in the major diastereomer 279. Stereochemical information was used to propose the mechanism of the reaction shown in Scheme 104. It was assumed that the reaction proceeds through a syn aminopalladation, and the observed diastereoselectivity would be determined in the latter step. In the proposed transition states (TS1 and TS2 in Scheme 104) 1,3-allylic interactions between the substituents RL or RS and the hydrogen atom at the alkene terminus and 1,2 pseudoequatorial repulsions between the phenyl group attached to the nitrogen atom and either RL or RS need to be considered. The transition state TS1 would be favored over TS2 because of its reduced steric interaction; however, as RL becomes bigger, the 1,3-allylic interactions cannot be negligible in TS1, resulting in a lower stereoselectivity. Another strategy recently introduced by Toyokazu and Ishikawa relies on the use of guanidinium ylides for the stereoselective synthesis of aziridines (Scheme 105).164 In this strategy, two-steps are involved in the aziridine synthesis: a C− C bond formation by nucleophilic addition of guanidinium ylides 282 to aryl aldehydes (step 1) followed by the fragmentation of the intermediate adducts to aziridine products 283 by intramolecular nucleophilic substitution (step 2). Two different reaction mechanisms, controlled by the nature of the para-substituents on the aryl ring of the aldehyde, have been proposed. A SNi-like mechanism, via cationic-like transition state, is proposed in the stereoselective synthesis of aziridines 283 using EDG-substituted benzaldehydes, whereas with EWGsubstituted benzaldehydes, a SN2-like mechanism should be favored. Experimental evidence from a Hammet-plot supports

the proposed models. A nice application of this methodology is the straightforward preparation of aziridinomitosene precursor 284, a basic core of mitomycin antibiotics, realized by cyclization of cis-3-(1H-indol-2-yl)aziridine-2-carboxylate prepared by guanidinium ylide-mediated aziridination of 1Hindole-2-carboxaldehyde (Scheme 105).165 6.1. Aziridinyl Anion Strategy

In order to access a range of substituted aziridines, a clever strategy relies on the functionalization of an already constructed aziridine scaffold. Such functionalization could be achieved through the use of the aziridinyl anion methodology that allows for the introduction of new C−C or C−X bonds on the aziridine ring. The required anions can be generated by deprotonation with organolithiums or lithium amides or, alternatively, by a metal−functional-group exchange. Deprotonation of aziridines with strong bases is one the most useful methodologies to generate aziridinyl anions also in a stereoselective manner. Metalated aziridines enjoy a very rich chemistry substantially resulting from either nucleophilic or carbenoid reactivity, often determined by structural features and experimental conditions. After the first difficulties related to the experimental conditions (temperature, solvent, cosolvent, ligand, lithiating agent), generation of lithiated aziridines is no longer a problem and several kinds of lithiated aziridines can be generated and reacted with many electrophilic species. A particular aspect to be considered in planning a stereoselective synthesis of aziridines by using this methodology, is the configurational stability (or instability) of the aziridinyl anion. With a proper choice of the starting aziridines and reaction conditions, the simple metalation−electrophile trapping sequence could give access to new aziridinyl systems (Scheme 106). Many aspects on the reactivity of aziridinyl anions 7923


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and B in Scheme 107) were used for the coupling reactions with several aryl and vinyl iodides obtaining more functionalized aziridines 286. Another example of direct cross-coupling of aziridinylmetal derivatives has been reported by Bull and co-workers.170 An alternative approach based on the metal−functional-group exchange, for the generation of an aziridinylmetal species, has been used in this work. In particular, a magnesium−sulfinyl exchange reaction on stereodefined aziridines 288 generated the aziridinylmagnesium employed for the palladium-catalyzed cross-coupling reactions with aryl halides. A wide range of electron-rich and electron-poor aryl bromides was utilized to afford the functionalized aziridine products as single diastereoisomers with retention of configuration at the reacting center. The authors assessed that the rate-determining step was the reductive elimination from the palladium(II) species bearing both the aziridine and aryl groups. The reaction proceeded smoothly, affording novel highly substituted aziridines 289 in high yields and diastereoselectivity (Scheme 108).

including their use in modern synthesis have been recently reviewed and will not be discussed here.166 Scheme 106

6.2. Cross-Coupling Strategy

Another option for the direct functionalization of an already available aziridine scaffold is by Pd-mediated cross-coupling reactions. In this context, Vedejs and Nelson reported the first example of palladium-catalyzed cross-coupling of an aziridinyl metal species with aryl and vinyl halides. In this report (a modified Negishi coupling), readily available aziridinyltin compounds 285 were reacted with butyllithium at −78 °C, to promote Sn/Li exchange, and the aziridinyllithium was converted into the corresponding organozinc before the addition of a Pd source and aryl halide to give the crosscoupling reaction.167 A CH2OBn group was installed on the aziridine in a cis relationship with respect to the metal. The presence of the CH2OBn moiety was essential in stabilizing, likely by coordinating the metal, the intermediate species. In order to avoid the thermal decomposition of the putative aziridinylzinc intermediate, the use of the more reactive Pd2(dba)3/[(tBu)3PH]BF4 was necessary. This method provided coupling products 286 in good yields (up to 80%) and with complete retention of the starting aziridine stereochemistry. More recently, Theddu and Vedejs described an alternative Stille coupling procedure using a readily accessible aziridinyltin derivative that avoided the Li/Zn exchange reaction required for the Negishi coupling.168 In particular, it was a modified Stille coupling reaction using a more strongly polarized trideoxastannatrane derivative 287 in place of a tributyltin derivative to improve C−Sn reactivity.169 This approach allowed for an efficient cross-coupling to give substituted aziridines under mild conditions. Both Pd(tBu3P)2/CuDPP and Pd(tBu3P)2/CuI/CsF (conditions A

Scheme 108

7. CONCLUDING REMARKS This review, far from being exhaustive, reports advances made in the past decade in the field of the stereoselective synthesis of aziridines. As reported, several methodologies have been introduced and improved for this purpose. Because of the high importance of the aziridine ring in synthesis, the availability of an “arsenal” of different aziridination procedures is a great advantage for synthetic chemists. This is particularly relevant if we consider the possibility to introduce stereocontrol

Scheme 107

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in the process. Nowadays more than in the past, thanks to many outstanding contributions from researchers worldwide, new, reliable, and efficient methodologies have became available and are highlighted in this review. New strategies, such as the one based on the use of N,N-ylides affording NH-aziridines, as well as new effective catalytic systems, such as the one based on homoscorpionate ligands, have been invented. Another important progress in the field has been the introduction of new nitrogen sources capable of installing “easily” removable Nprotecting groups. The development of organocatalytic methods paved the way for the preparation of highly enantioenriched and structurally complex aziridines starting from relatively cheap materials. Advances have been made also from a mechanistic point of view as reported in the case of VANOL- and VAPOL-mediated aziridination reactions. However, regioselectivity and stereoselectivity, as well as the stoichiometry of the reactants and the complexity of the catalysts to be prepared, are in some cases still problematic, needing further improvement. Such needs could be future challenges to be addressed, making the stereoselective synthesis of aziridines a field still rich with opportunities.

investigations have been undertaken by using microstructured devices for the development of sustainable chemical processes.

Piera Trinchera was born and grew up in Brindisi, Italy. She received her Master’s degree in Biotechnological Sciences at the University of Salento (Lecce, Italy) in 2009. In 2012, she got her Ph.D. in Applied Chemical and Enzymatic Synthesis at the University of Bari (Bari, Italy) under the supervision of Prof. R. Luisi, focusing on the chemistry of nitrogen-containing heterocycles and organoboron compounds. She has been Visiting Scholar at the University of Toronto (Toronto, Canada) working in the group of Prof. A. Yudin. In 2013, she got a position as a post-doc at the University of Toronto in the group of Prof. A. Yudin.

AUTHOR INFORMATION Corresponding Authors

*L.D. e-mail: [email protected]. *R.L. e-mail: [email protected] Notes

The authors declare no competing financial interest. Biographies

Renzo Luisi was born in 1971 and is Associate Professor of Organic Chemistry at the University of Bari “A. Moro” (Bari, Italy). He graduated summa cum laude in Chemistry and Pharmaceutical Technology at the University of Bari (Bari, Italy) in 1996. In 2000, he obtained his Ph.D. in Chemical Sciences (supervised by Prof. S. Florio), and in 2001, was hired as Assistant Professor at the University of Bari. Four years later, in 2005, was appointed Associate Professor of Organic Chemistry at the same university. He has been Visiting Scholar at the University of Illinois (Urbana−Champaign, IL), working in the group of Prof. P. Beak, and visiting Professor at the University of Manchester (Manchester, UK), Brown University (Providence, RI), and the University of North Carolina (Charlotte, NC). His main research interests rely on organometallic chemistry (mainly lithium and boron chemistry), synthesis and reactivity of small heterocyles, asymmetric synthesis, and dynamic NMR spectroscopy. In 2010, he was awarded with a special funding program for young scientists from the Italian Ministry of Education and Research to start research in the field of sustainable chemistry and microreactor technology. His research activity has been highlighted in more than 75 papers in peer-reviewed international journals, book chapters, reviews, and several international collaborations.

Leonardo Degennaro was born in Bitonto (Bari), Italy, in 1972 and is Assistant Professor at the University of Bari (Bari, Italy). He obtained his M.S. in Chemistry and Pharmaceutical Technology at the University of Bari in 1999. In 2003, he got his Ph.D. in Chemical Applied and Enzymatic Synthesis (supervised by Prof. S. Florio). In 2002, he was Visiting Scholar at the Institute of Organische en Moleculair Anorganische Chemie, University of Groningen (Groningen, Netherlands), under the supervision of Prof. B. L. Feringa. In 2006, he was appointed Assistant Professor in Organic Chemistry at the Faculty of Pharmacy. In 2011, he was Visiting Assistant Professor at the Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University (Kyoto, Japan), working in the group of Prof. J.-i. Yoshida. His research activity is aimed at developing new stereocontrolled synthesis mediated by organometallic reagents, the chemistry of three- and four-membered heterocycles, the NMR study of reactive intermediates, and the study of dynamic phenomena at the molecular level. Recently, new 7925


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