The high synthetic usefulness of aziridines has been often confined to their electrophilic nature, undergoing nucleophilic ring-opening reactions, as usually taught in organic chemistry courses. The aim of this review is to highlight other aspects of aziridine reactivity, now well out of their infancy. Indeed, aziridines can be easily metalated, generating the corresponding aziridinyl anions, which could act as nucleophiles leaving the three-membered ring functionality intact or, under certain circumstances, as carbenoids thus disclosing an interesting reactional scenery. Even if the reactivity of aziridinyl anions closely mirrors that of the corresponding oxiranyl anions, the investigations of the last 10 years demonstrated that additional factors should be taken into consideration when the generation of metalated aziridines is concern.

BH3 complexes of N-alkyl-2-phenylaziridines have been synthesized and their structure and stereochemistry proved with DFT calculations and NMR experiments. It has been demonstrated that the Lewis acid complexation is able to promote a regioselective β-lithiation in 2-phenylaziridino-borane complexes. The lithiated intermediates were configurationally stable, allowing an enantioselective preparation of cis- 2,3-disubstituted aziridines.

S-Alkenyl-N-arylthiocarbamates are formed from allylic alcohols by sigmatropic rearrangement and isomerization or C═C bond cleavage. They undergo carbolithiation with a range of organolithium reagents, generating benzyllithium intermediates in a stereospecific manner which may undergo N to C aryl migration to yield thiocarbamates with tertiary substituents. A simple base-promoted alcoholysis reveals a series of hindered tertiary thiols with branched carbon skeletons.

Among the artificial switchable catalysts, those catalysts whose activity can be switched by an external stimulus, only a few cases offer the possibility to develop an effective chiral switchable system that could selectively accelerate the formation of a given enantiomer in one state, whereas in the other state it prefers accelerating the formation of the opposite enantiomer. Many pharmacological investigations need both enantiomers to study potentially different activities and side effects. Thus, chiral switchable catalysts could be a very important tool to achieve this goal because their use will eliminate the need to have the two enantiomers of a designed catalyst. This perspective summarizes, discusses, and emphasizes important developments in the chiral switchable catalyst area for the dynamic control of enantioselectivity, highlighting their advantages and showing some perspectives of this field that is still in its infancy.

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

The microreactor technology has the potential to change the way to perform synthetic chemistry. Efforts in this field need to be promoted at the best. This will reduce waste, increase the safety, save energy, improve the product quality, reduce the time for drug discovery and improve the reliability and quality of commercially available microreactors. Research, education and training can play a key role for the widespread use of this new technology

Microreactor-mediated organocatalysed Michael reactions have been developed. By using a soluble proline-derived catalyst, Michael-type reactions, leading to γ-nitroketones, have been optimized in homogeneous and continuous-flow conditions. As proof of principle, an integrated microfluidic system able to perform domino processes useful in the preparation of bicyclo[4.4.0]decanes with six contiguous stereogenic centres has been set up.

this work describes the preparation of new shelf-stable aziridinyldifluoroborates even in enantioenriched form that can serve either as Suzuki–Miyaura reagents and as new bifunctional Lewis pairs potentially useful as catalysts or tweezers for small-molecule binding. Such thus far undescribed aziridinedifluoroborates, which can be used for the ortho-functionalization of aromatic aziridines, are, to the best of our knowledge, the first examples of aziridine-functionalized cross-coupling reagents. The methodology could be expanded to other benzylamine derivatives and aryl-substituted N-heterocycles in order to obtain new shelf-stable organoboron reagents. More work is underway in our laboratory in order to expand the synthetic utility of these new reagents.

Diastereomeric oxazolinylaziridines (R, R)-9 and (R, S)-9 have been regioselectively lithiated at the aposition with respect to the oxazolinyl ring. The resulting aziridinyllithium compounds proved to be chemically and configurationally stable under the experimental conditions used, thus furnishing, upon trapping with electrophiles, chiral 2,2-disubstituted aziridines, in contrast to the corresponding alpha-lithiated oxazolinyloxiranes that have been reported to be chemically stable but configurationally unstable. This peculiar behavior of the nitrogen-bearing heterocycle has been rationalized on the basis of DFT calculations and the observed dynamics of the aziridine nitrogen atom. The DFT analysis allowed the disclosure of a solvent-dependent differing stability of diastereomeric lithiated aziridines (R, R)-9-Li and (R, S)-9-Li, suggesting eta(3)-coordinated oxazolinylaziridinyllithium compounds as likely intermediates. Such intermediates could be the result of a dynamically controlled lithiation that relies on the preliminary formation of a complex between the lithiating agent and the oxazolinyl ring. According to this model, the competing complexation of the lithiating agent by the lone pair of electrons on the aziridine nitrogen would cause addition to the oxazoline C=N bond, thus ending up with the formation of oxazolidines, which are precursors of useful chiral ketoaziridines. The proposed model has been also supported by estimating the nitrogen inversion barrier by dynamic NMR spectroscopic experiments.

Herein we report a new straightforward synthesis of cis and trans 2,5-disubstituted N,N-dialkylpiperazines, even in enantioenriched form, by reacting non-activated N-alkyl arylaziridines in the presence of a catalytic amount of a Lewis acid. A stereochemical and NMR investigation revealed useful mechanistic insights for this process.

We have investigated the regio- and stereochemistry of the reductive dealkoxylation of alkyl aryl ethers. Chiral non-racemic secondary alcohols were converted into the corresponding m-terphenyl or 2-biphenyl ethers either via inversion of configuration under Mitsunobu reaction conditions or with retention of configuration under SNAr conditions. The successive cleavage of the aromatic CAO bond occurred in the presence of a stoichiometric amount of Na metal in dry tetrahydrofuran at rt with retention of configuration, thus highlighting that the overall inversion or retention of configuration for the whole two-step procedure is dictated by the stereochemistry of the first synthetic step

The regioselective lithiation–functionalization of 2-arylazetidines has been explored. The nature of the N-substituent is mainly responsible for a regioselectivity switch. ortho-Lithiation occurred, using hexyllithium as a greener base, in N-alkylazetidines, while abenzylic lithiation has been observed with N-Boc azetidines.

A highly stereo- and regioselective functionalisation of chiral nonracemic aziridines is reported. By starting from a parent enantioenriched aziridine and finely tuning the reaction conditions, it is possible to address the regio- and stereoselectivity of the lithiation/ electrophile trapping sequence, thereby allowing the preparation of highly enantioenriched functionalised aziridines. From chiral N-alkyl trans- 2,3-diphenylaziridines (S,S)-1a,b, two differently configured chiral aziridinyllithiums could be generated (trans- 1a,b-Li in toluene and cis-1a,b-Li in THF), thus disclosing a solvent-dependent reactivity that is useful for the synthesis of chiral tri-substituted aziridines with different stereochemistry. In contrast, chiral aziridine (S,S)-1c showed a temperature-dependent reactivity to give chiral ortho-lithiated aziridine 1c-ortho-Li at 78 8C and a-lithiated aziridine 1c-a-Li at 0 8C. Both lithiated intermediates react with electrophiles to give enantioenriched ortho- and a-functionalised aziridines. The reaction of all the lithiated aziridines with carbonyl compounds furnished useful chiral hydroxyalkylated derivatives, the stereochemistry of which was ascertained by X-ray and NMR spectroscopic analysis. The usefulness of chiral non-racemic functionalised aziridines has been demonstrated by reductive ring-opening reactions furnishing chiral amines that bear quaternary stereogenic centres and chiral 1,2-, 1,3- and 1,5-aminoalcohols. It is remarkable that the solvent-dependent reactivity observed with (S,S)-1a,b permits the preparation of both the enantiomers of amines (11 and ent-11) and 1,2-aminoalcohols (13 and ent-13) starting from the same parent aziridine. Interestingly, for the first time, a configurationally stable chiral a-lithiated aziridine (1c-a-Li) has been generated at 0 8C. In addition, ortho-hydroxyalkylated aziridines have been easily converted into chiral aminoalkyl phthalans, which are useful building blocks in medicinal chemistry.

The origin of the stereoselectivity in the lithiation/trapping of 2-alkylideneaziridines bearing a chiral group as the nitrogen substituent was investigated. Optimal reaction conditions were discovered by in situ FT-IR monitoring. In addition, it has been found that the solvent and the alkene substitution pattern are important factors able to impart a switch in stereoselectivity. While lithiation of the alkylideneaziridine ring flanked by either a fully substituted or a Z-configured alkene pendant occurs stereoselectively in THF, in contrast unsubstituted 2-methyleneaziridine undergoes lithiation in toluene with the opposite sense of stereoinduction. Lithiation experiments, on deuterium labelled 2-alkylideneaziridines, confirmed the configurational stability of the lithiated intermediates. A model based on complexation and proximity effects was proposed to rationalize the reactivity. This model assumes that slowly equilibrating N-invertomers undergo deprotonation (lithiation) at different rates and that the stereochemical outcome is established during the deprotonation step.

A strategy for the stereoselective functionalization of thietane 1-oxide has been developed by using the corresponding organometallic intermediates that reacted with electrophiles leaving intact the 4-membered ring.

A flow-microreactor-mediated synthesis of 1,2,3,4-tetrahydroisoquinolines (THIQs) is reported (see scheme). Starting from a laterally lithiated aziridine, a tetrahydroisoquinoline lithiated at C4 was generated by thermally induced isomerization. Because the reaction temperature is a crucial parameter, the exquisite thermal control possible in a flow-microreactor system allowed for fast, efficient, and highly reproducible synthesis of functionalized aziridines or THIQs.

By using the Suzuki-Miyaura protocol, a simple straightforward synthesis of functionalized 2-arylaziridines has been developed. By means of this synthetic strategy from readily available ortho-, meta- and para-bromophenylaziridines and aryl-or heteroarylboronic acids, new aziridines could be obtained. The cross-coupling reactions occurred without ring opening of the three membered ring. Preliminary results on the antimicrobial activity of the heterosubstituted biaryl compounds have been also included.