Water opens the door to organolithiums and Grignard reagents: exploring and comparing the reactivity of highly polar organometallic compounds in unconventional reaction media towards the synthesis of tetrahydrofurans.

It has always been a firm conviction of the scientific community that the employment of both anhydrous conditions and water-free reaction media is required for the successful handling of organometallic compounds with highly polarised metal-carbon bonds. Herein, we describe how, under heterogeneous conditions, Grignard and organolithium reagents can smoothly undergo nucleophilic additions to γ-chloroketones, on the way to 2,2-disubstituted tetrahydrofurans, "on water", competitively with protonolysis, under batch conditions, at room temperature and under air. The reactivity of the above organometallic reagents has also been investigated in conventional anhydrous organic solvents and in bio-based eutectic and low melting mixtures for comparison. The scope and limitations of this kind of reaction are discussed.

Nitrogen Stereodynamics and Complexation Phenomena as Key Factors in the Deprotonative Dynamic Resolution of Alkylideneaziridines: A Spectroscopic and Computational Study.

The present work is aimed at shedding light on the origin of the stereoselectivity observed in the reactions of chiral heterosubstituted organolithiums, generated by lithiation of alkylideneaziridines. Factors such as the nitrogen inversion barrier, the stereochemistry at the nitrogen atom, the substitution pattern of the alkylideneaziridines, and the reaction conditions are taken into consideration. The interplay between nitrogen stereodynamics and complexation phenomena seems to be crucial in determining the stereochemical outcome of the lithiation/trapping sequence. The findings were rationalized by a synergistic use of NMR experiments, run on the lithiated intermediates, alongside computational data. It has been demonstrated that, in such systems, the stereochemistry-determining step is the deprotonation reaction, and a model based on a deprotonative dynamic resolution has been proposed. Such findings could find application in dynamic systems other than aziridines.

Stereocontrolled lithiation/trapping of chiral 2-alkylideneaziridines: investigation into the role of the aziridine nitrogen stereodynamics.

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.

Regioselective desymmetrization of diaryltetrahydrofurans via directed ortho-lithiation: an unexpected help from green chemistry.

An efficient functionalization of diaryltetrahydrofurans via a regioselective THF-directed ortho-lithiation is first described. This reaction can be successfully carried out in cyclopentyl methyl ether as a "greener" alternative to Et2O, with better results in terms of yield and selectivity and, surprisingly, also in protic eutectic mixtures competitively with protonolysis.

Gated access to α-lithiated phenyltetrahydrofuran: functionalisation via direct lithiation of the parent oxygen heterocycle.

Cycloreversion of α-lithiated phenyltetrahydrofuran was successfully tamed at -78 °C in a non-coordinating solvent in the presence of TMEDA. This anion showed excellent nucleophilicity and could be intercepted with a variety of structurally different electrophiles to give 2,2-disubstituted derivatives which can be further elaborated to γ-butyrolactones.

Dynamic resolution of lithiated ortho-trifluoromethyl styrene oxide and the effect of chiral diamines on the barrier to enantiomerisation.

The first dynamic thermodynamic resolution of a racemic oxiranyllithium is described with selectivities of up to 82 : 18 from a selection of three types of chiral ligands (seven ligands in total). Both (-)-sparteine and its (+)-surrogate were surprisingly found to increase the enantiomerisation barrier.

Nitrogen dynamics and reactivity of chiral aziridines: generation of configurationally stable aziridinyllithium compounds.

Diastereomeric oxazolinylaziridines (R,R)-9 and (R,S)-9 have been regioselectively lithiated at the α-position 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 α-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 η(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.

Regio- and stereoselective lithiation of terminal oxazolinylaziridines: the aziridine N-substituent and the oxazolinyl group effect.

The regioselective lithiation of terminal oxazolinylaziridines has been investigated. The steric hindrance of the nitrogen substituent in 1-trityl-2-oxazolinylaziridine 3a, combined with the coordinating ability of the oxazolinyl group, causes beta-lithiation, whereas a completely regioselective alpha-lithiation is observed with the much less sterically demanding 1-benzyl-2-oxazolinylaziridine 3c and a competition between alpha- and beta-lithiation occurs with 1-cumyl-2-oxazolinylaziridine 3b in which the N-substituent has a steric hindrance in between the trityl and the benzyl groups. The application of the lithiation-trapping sequence for the preparation of enantioenriched 2,3-cis-disubstituted oxazolinylaziridines and aziridino-gamma-lactones is also reported.