Armen Panossian

Recent advances in transition metal-catalyzed Csp2-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

Summary In the last few years, transition metal-mediated reactions have joined the toolbox of chemists working in the field of fluorination for Life-Science oriented research. The successful execution of transition metal-catalyzed carbon–fluorine bond formation has become a landmark achievement in fluorine chemistry. This rapidly growing research field has been the subject of some excellent reviews. Our approach focuses exclusively on transition metal-catalyzed reactions that allow the introduction of –CFH2, –CF2H, –CnF2 n +1 and –SCF3 groups onto sp² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups.

Trifluoromethyl Ethers and –Thioethers as Tools for Medicinal Chemistry and Drug Discovery

The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation.

Transition‐Metal‐Free Atropo‐Selective Synthesis of Biaryl Compounds Based on Arynes

A modular way towards biaryls: Highly enantioenriched biphenyls can be prepared based on a transition-metal-free aryl-aryl coupling followed by efficient desymmetrization or deracemization and chemoselective functionalization (see scheme).

In Situ Generated Fluorinated Iminium Salts for Difluoromethylation and Difluoroacetylation

The use of TFEDMA, a fluoroalkyl amino reagent, for the difluoromethylation and difluoroacylation of arenes, heteroarenes, and C-H acidic compounds is reported. This approach allows for an efficient access to difluoromethylated products of high added value in good to excellent yields and with scale-up possibilities.

Atroposelective synthesis of axially chiral P,S-ligands based on arynes

The first atropo-selective aryl–aryl coupling based on arynes in the presence of a tert-butylsulfinyl group as the chiral auxiliary on the aryllithium nucleophile is described. The approach allows for the efficient access to a novel family of atropo-enantiopure biphenyl-based phosphine–thioether ligands. The new P,S heterodonor ligands were assessed in model palladium-catalyzed allylic substitution reactions.

A Major Advance in the Synthesis of Fluoroalkyl Pyrazoles: Tuneable Regioselectivity and Broad Substitution Patterns

A novel approach towards highly functionalized fluoroalkyl pyrazoles was developed by using fluoroalkyl amino reagents in combination with a variety of fluorinated ketimines. Tuneable introduction of fluoroalkyl groups in the 3- and 5-positions was possible by using vinamidinium intermediates or the corresponding enamino ketones after hydrolysis. These high-value building blocks can give rise to a large number of analogues for bioactivity screening and discovering new heterocyclic bioactive ingredients in various life science fields.

Multi-nuclear NMR of axially chiral biaryls in polypeptide orienting solvents: spectral discriminations and enantiorecognition mechanisms

Due to the importance of axially chiral biaryl derivatives as chiral auxiliaries and/or ligands for asymmetric synthesis, as well as their structural role in bioactive natural products, continuous efforts have been undertaken to propose efficient methods for their atropo-selective synthesis. As a consequence, proposing robust and reliable analytical tools that are able to discriminate the spectral signal of atropisomeric enantiomers becomes crucial to evaluate the enantiomeric excesses of mixtures. In this work, we show how several multi-nuclear 1D/2D-NMR techniques using homopolypeptide chiral liquid crystals as aligning solvents can provide a panel of analytical possibilities (through differences of chemical shift anisotropies, dipolar and quadrupolar residual couplings) to spectrally discriminate enantiomers of a large collection of trisubstituted axially chiral biphenyls. Approaches involving 31P, 13C and 2H 1D- or 2D-NMR experiments at natural abundance levels are explored. Among noteworthy results, the first examples of spectral enantioseparations using 31P nuclei as nuclear probe are reported. Finally, the roles of electronic factors and shape anisotropy in the efficiency of chiral discrimination mechanisms are examined and discussed. Molecular modeling calculations were carried out to establish the electronic profile of these analytes in order to understand and rationalize the 13C–{1H} NMR results.

A new approach toward the synthesis of 2,4-bis(fluoroalkyl)-substituted quinoline derivatives using fluoroalkyl amino reagent chemistry

The present work describes the unprecedented use of Fluoroalkyl Amino Reagents (FARs) to afford 2,4-bis(fluoroalkyl)-substituted quinoline derivatives in two steps. In contrast to the Combes reaction, this approach allows for the synthesis of numerous quinoline derivatives bearing two identical or different fluoroalkyl substituents in the 2 and 4 positions, under mild reaction conditions, in good yields and with a very good regioselectivity. This reaction is easily scalable and suitable for an industrial process.

Fluoroalkyl Amino Reagents for the Introduction of the Fluoro(trifluoromethoxy)methyl Group onto Arenes and Heterocycles

Fluoroalkyl amino reagents 1a and 2a have been developed from commercially available trifluoromethyl trifluorovinyl ether via a hydroamination reaction with diethylamine or dimethylamine. These reagents can be activated by treatment with a Lewis acid and subsequently used as a mono- or dielectrophile for the introduction of the fluoro(trifluoromethoxy)methyl group, either in Vilsmeier-type acylations of aromatic substrates or in the synthesis of fluorinated pyrazoles from CH-acidic substrates and of bis-fluorinated pyrazoles, all being important building blocks for medicinal and agricultural chemistry.

Fluoroalkyl Amino Reagents (FARs): A General Approach towards the Synthesis of Heterocyclic Compounds Bearing Emergent Fluorinated Substituents

Fluorinated heterocycles are important building blocks in pharmaceutical, agrochemical and material sciences. Therefore, organofluorine chemistry has witnessed high interest in the development of efficient methods for the introduction of emergent fluorinated substituents (EFS) onto heterocycles. In this context, fluoroalkyl amino reagents (FARs)—a class of chemicals that was slightly forgotten over the last decades—has emerged again recently and proved to be a powerful tool for the introduction of various fluorinated groups onto (hetero)aromatic derivatives.