Filippo Maria Perna

Use of readily available chiral compounds related to the betti base in the enantioselective addition of diethylzinc to aryl aldehydes

Abstract Readily available members of the family of chiral non-racemic aminonaphthols related to the Betti base 1 were tested as complexing agents in the catalytic enantioselective addition of diethylzinc to aryl aldehydes. The use of these bases gave high ee values (up to > 99%). The highest ee values were obtained with the tertiary aminonaphthol 2. An important role was played by the solvent. The effect of the nature and the position of the substituents on the aromatic ring of the aldehyde was also investigated.

Direct observation of a lithiated oxirane: a synergistic study using spectroscopic, crystallographic, and theoretical methods on the structure and stereodynamics of lithiated ortho-trifluoromethyl styrene oxide

α-Lithiated epoxides, long considered “fleeting” intermediates in the reactions of epoxides with strong bases, have nowadays proven to be key synthons for asymmetric synthesis. In this study, the solution and the solid state structure of an α-lithiated aryloxirane, namely α-lithiated ortho-trifluoromethyl styrene oxide (1-Li), were determined. Single crystal X-ray diffraction analysis of 1-Li performed at 100 K applying the X-TEMP-2 device revealed a self-assembled heterochiral dimeric structure with a rare central six-membered (O–Li–C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance (1H, 13C, 19F, 7Li) studies suggested that 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single σ-contact between lithium and a carbon atom. Line shape analysis provided activation parameters for both the dynamic interconversion of the two dimers and the enantiomerisation of 1-Li, which proved to be mostly entropy controlled. The structural assignment in solution was supported by density functional theory computations through the investigation of conformers of monomeric and dimeric complexes of 1-Li featuring different degrees of specific solvation. A mechanism based on the equilibration of six-membered homo- and heterochiral dimers was proposed to explain the configurational instability exhibited by 1-Li in THF.

2-Lithiated-2-phenyloxetane: a new attractive synthon for the preparation of oxetane derivatives

A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. Evidence is presented to show that electron-transfer processes are also operative in the coupling reactions with electrophiles.

Stereoselective organocatalysed reactions in deep eutectic solvents: highly tunable and biorenewable reaction media for sustainable organic synthesis

Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.

Exploiting the Lithiation‐Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2‐Aryloxetane Scaffolds under Mild Conditions

inde-pendently observed that the lithiation of an aromatic ringcouldbeachievedorthotoasubstituent,andhenceopenedupnew horizons for obtaining differently functionalized organo-lithium derivatives through what is today known as thedirected ortho metalation (DoM) reaction. Since then, andparticularly thanks to seminal contributions from the groupsof Hauser, Meyers, Gschwend, Beak, Snieckus, and others,

Lithiated Fluorinated Styrene Oxides: Configurational Stability, Synthetic Applications, and Mechanistic Insight

The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents alpha-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, alpha-5-Li, and alpha-6-Li) are all configurationally stable in the reaction time scale, whereas alpha-lithiated ortho-, meta-, and para-trifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated beta-amino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.

Unprecedented Nucleophilic Additions of Highly Polar Organometallic Compounds to Imines and Nitriles Using Water as a Non‐Innocent Reaction Medium

In contrast to classic methods carried out under inert atmospheres with dry volatile organic solvents and often low temperatures, the addition of highly polar organometallic compounds to non-activated imines and nitriles proceeds quickly, efficiently, and chemoselectively with a broad range of substrates at room temperature and under air with water as the only reaction medium. Secondary amines and tertiary carbinamines are furnished in yields of up to and over 99 %. The significant solvent D/H isotope effect observed for the on-water nucleophilic additions of organolithium compounds to imines suggests that the on-water catalysis arises from proton transfer across the organic-water interface. The strong intermolecular hydrogen bonds between water molecules may play a key role in disfavoring protonolysis, which occurs extensively in other protic media such as methanol. This work lays the foundation for reshaping many fundamental s-block metal-mediated organic transformations in water.

Preparation of Polysubstituted Isochromanes by Addition of ortho-Lithiated Aryloxiranes to Enaminones

The reaction of ortho-lithiated aryloxiranes with various enaminones straightforwardly affords new functionalized isochromanes as mixtures of two epimeric stereoisomers in reasonable to very good yields (50-90%). The two diastereomers, which show a high structural variability, can be easily separated by column chromatography.

One-pot sustainable synthesis of tertiary alcohols by combining ruthenium-catalysed isomerisation of allylic alcohols and chemoselective addition of polar organometallic reagents in deep eutectic solvents

Ru(IV)-Catalysed redox isomerisation of allylic alcohols has, for the first time, been successfully assembled with the chemoselective addition of organolithium or organomagnesium reagents to the in situ formed ketones, en route to tertiary alcohols, employing deep eutectic solvents as environmentally friendly reaction media. The overall transformation, which formally involves three consecutive and different steps such as (i) the reduction of a C–C double bond, (ii) the oxidation of a secondary carbinol moiety, and (iii) a chemoselective C–C bond formation, takes place in protic and biorenewable eutectic mixtures in a sequential one-pot fashion using a commercially and easily available catalytic system, with excellent conversions (up to 99% yield), at room temperature and under air in the last step, with no concomitant reduction or enolisation processes, and with high atom economy, in agreement with the principles of the so-called green chemistry.

An Expeditious and Greener Synthesis of 2-Aminoimidazoles in Deep Eutectic Solvents

A high-yield one-pot two-step synthesis of 2-aminoimidazoles (2-AI), exploiting an under-air heterocyclodehydration process between α-chloroketones and guanidine derivatives, and using deep eutectic solvents (DESs) as nonconventional, “green” and “innocent” reaction media, has been accomplished successfully. The combination of either glycerol or urea with choline chloride (ChCl) proved to be effective for decreasing the reaction time to about 4–6 h in contrast to the 10–12 h usually required for the same reaction run in toxic and volatile organic solvents and under an argon atmosphere. In addition, the use of the ChCl–urea as a DES also enables the direct isolation of triaryl-substituted 2-AI derivatives by means of a simple work-up procedure consisting in filtration and crystallization, and allows the recycle of the DES mixture. A plausible mechanism highlighting the potential role played by hydrogen bonding catalysis has also been illustrated.