Solvent-Dependent Rhodium-Catalyzed Divergent Hydrofunctionalization of Trifluoromethylalkenes.

We report a rhodium-catalyzed anti-Markovnikov regioselective hydrosilylation of trifluoromethylalkenes with substituted silanes giving various α-trifluoromethyl-ß-silanes in good to excellent yields. The hydrogenation products were obtained via the same key intermediate treated with methanol as a protic solvent. Both transformations had a broad functional tolerance and were expected to facilitate the construction of complex α-trifluoromethyl compounds.

Organophotocatalysis Enables the Synthesis of gem-Fluorophosphonate Alkenes.

gem-Bromofluoroalkenes have been combined with phosphite under irradiation, in the presence of Fukuzumi's catalyst (9-mesityl-10-methylacridinium perchlorate) as an organic photocatalyst, to provide valuable gem-fluorophosphonate derivatives, known as stable mimics of phosphates. The desired products were obtained in good to excellent yields, and the reaction showed very good chemical tolerance.

Directed Palladium Catalyzed C-H (Ethoxycarbonyl)difluoromethylthiolation Reactions.

The unprecedented Pd-catalyzed (ethoxycarbonyl)difluoromethylthiolation reaction of various unsaturated derivatives was studied. In the presence of the (ethoxycarbonyl)difluoromethylsulfenamide reagent I and under mild reaction conditions (60 °C), both 2-(hetero)aryl and 2-(α-aryl-vinyl)pyridine derivatives were smoothly functionalized with this methodology (37 examples, up to 87 % yield). Moreover, the synthetic interest of this fluorinated moiety was further showcased by its conversion into various original fluorinated residues. Finally, a plausible mechanism for this transformation was suggested.

Phospha-Michael Addition on α-Fluorinated Acrylates: A Straightforward Access to Polyfunctionalized Fine Chemicals.

α-Fluorinated acrylates could act as Michael acceptors and become a platform toward the synthesis of relevant complex molecules. Very few conjugate additions have been developed in the literature with these specific substrates, and herein, we reported the first phospha-Michael addition (PMA) on α-trifluoromethylacrylates and α-fluoromethylacrylates. The reaction proved to be highly tolerant and gave original products containing contiguous C-P and C-CFY2 (Y = F or H) bonds in good to excellent yields and diastereoselectivities.

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor-Acceptor and Diacceptor Diazo Reagents.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh2 ((S)-TCPTAD)4 or Rh2 ((R)-BTPCP)4 catalysts (up to 95 % yield, >95 : 5 d.r. and 99 : 1 e.r.). This methodology gave a direct access to ACPs bearing multiple electron-deficient substituents and allows to further expand the availability of ACPs chemistry. Interestingly, during the examination of the scope of this reaction, the asymmetric intramolecular C-H insertion reaction into tert-butyl group was observed as a side reaction with up to 94 : 6 e.r.

Fluorocyclopropane-Containing Proline Analogue: Synthesis and Conformation of an Item in the Peptide Chemist's Toolbox.

Over the years, numerous modifications to the structure of proline have been made in order to tune its effects on bioactive compounds. Notably, the introduction of a cyclopropane ring or a fluorine atom has produced interesting results. Herein, we describe the synthesis of a proline containing fluorocyclopropane. This modified amino acid was inserted into a tripeptide, whose conformation was studied by nuclear magnetic resonance and density functional theory calculations.

gem-Heteroatom-Substituted Fluoroalkenes as Mimics of Amide Derivatives or Phosphates: A Comprehensive Review.

gem-Heteroatom-substituted fluoroalkenes have received little attention despite their great potential in medicinal chemistry or in fine chemistry. Indeed, due to the electronic and steric similarity between the fluoroalkene moiety and the amide bond as well as the high strength of the carbon-fluorine bond, these gem-heteroatom-substituted fluoroalkenes could be envisioned as stable mimics of various important organic functions, such as phosphates, carbamates, S-thiocarbamates and ureas. We present herein an overview describing the syntheses over the last decade of heteroatom-substituted fluoroalkenes in geminal position. This review will be divided into several sections covering each the common following heteroatom: oxygen-, nitrogen-, sulfur-, phosphorus-, boron- and silicon-substituted fluoroalkenes.

Wonderful fusion of organofluorine chemistry and decarboxylation strategy.

Decarboxylation strategy has been emerging as a powerful tool for the synthesis of fluorine-containing organic compounds that play important roles in various fields such as pharmaceuticals, agrochemicals, and materials science. Considerable progress in decarboxylation has been made over the past decade towards the construction of diverse valuable fluorinated fine chemicals for which the fluorinated part can be brought in two ways. The first way is described as the reaction of non-fluorinated carboxylic acids (and their derivatives) with fluorinating reagents, as well as fluorine-containing building blocks. The second way is dedicated to the exploration and the use of fluorine-containing carboxylic acids (and their derivatives) in decarboxylative transformations. This review aims to provide a comprehensive summary of the development and applications of decarboxylative radical, nucleophilic and cross-coupling strategies in organofluorine chemistry.

Biocatalytic Strategy for the Highly Stereoselective Synthesis of CHF2 -Containing Trisubstituted Cyclopropanes.

The difluoromethyl (CHF2 ) group has attracted significant attention in drug discovery and development efforts, owing to its ability to serve as fluorinated bioisostere of methyl, hydroxyl, and thiol groups. Herein, we report an efficient biocatalytic method for the highly diastereo- and enantioselective synthesis of CHF2 -containing trisubstituted cyclopropanes. Using engineered myoglobin catalysts, a broad range of α-difluoromethyl alkenes are cyclopropanated in the presence of ethyl diazoacetate to give CHF2 -containing cyclopropanes in high yield (up to >99 %, up to 3000 TON) and with excellent stereoselectivity (up to >99 % de and ee). Enantiodivergent selectivity and extension of the method to the stereoselective cyclopropanation of mono- and trifluoromethylated olefins was also achieved. This methodology represents a powerful strategy for the stereoselective synthesis of high-value fluorinated building blocks for medicinal chemistry, as exemplified by the formal total synthesis of a CHF2 isostere of a TRPV1 inhibitor.

Synthesis of Fluoro-, Monofluoromethyl-, Difluoromethyl-, and Trifluoromethyl-Substituted Three-Membered Rings.

This Minireview describes recent advances toward the synthesis of fluoro-, monofluoromethyl-, difluoromethyl-, and trifluoromethyl-substituted three-membered rings such as cyclopropanes, aziridines, epoxides, episulfides, cyclopropenes, and 2 H-azirines. The main synthetic methodologies since 2016 for cyclopropanes and since 2010 for the other three-membered rings are reported.

Organocatalyzed Sulfa-Michael Addition of Thiophenols on Trisubstituted α-Fluoroacrylates, a Straightforward Access to Chiral Fluorinated Compounds.

In this manuscript, a simple and efficient sulfa-Michael addition reaction of aryl thiols to trisubstituted α-fluoro-α,ß-unsaturated esters both in racemic and, for the first time, in enantioselective version is reported. The commercially available dimer of cinchona derivatives (DHQ)2PYR was used as a catalyst. This strategy showed a great tolerance for various substrates and substituents, providing fair to excellent yields, moderate to excellent diastereoselectivities (2:1 to >99:1), and low to good enantioselectivities (2 to 87%). The reaction has been applied to the synthesis of fluorinated analogues of diltiazem and tiazesim, both therapeutic agents.

Synthesis of α-Trifluoromethylacrylates by Ligand-Free Palladium-Catalyzed Mizoroki-Heck Reaction.

Efficient ligand-free palladium catalyzed Mizoroki-Heck reaction allowed the formation of trisubstituted α-trifluoromethylacrylates. The reaction showed good chemical tolerance and furnished moderate to excellent yields of reaction. Silver salt additive proved to be essential for the reaction. The reaction has been then applied to the formation of 3-trifluoromethyl coumarins and analogues of therapeutic agents.

Effect of Fluorination on Skin Sensitization Potential and Fragrant Properties of Cinnamyl Compounds.

A series of three α- and three ß-fluorinated representatives of the family of cinnamate-derived odorants (cinnamaldehyde (1), cinnamyl alcohol (2), and ethyl cinnamate (3)) as used as fragrance ingredients is described. Olfactive evaluation shows that the fluorinated compounds exhibit a similar odor profile to their parent compounds, but the olfactive detection thresholds are clearly higher. In vitro evaluation of the skin sensitizing properties with three different assays indicates that α-fluorination of Michael acceptor systems 1 and 3 slightly improves the skin sensitization profile. α-Fluorocinnamyl alcohol 2b is a weaker skin sensitizer than cinnamyl alcohol 2a by in vitro tests and the fluorinated product drops below the sensitization threshold of the KeratinoSens® assay. On the other hand, ß-fluorination of compounds 1 - 3 results in highly reactive products which display a worsened in vitro skin sensitization profile.

Transition metal-free stereospecific access to (E)-(1-fluoro-2-arylvinyl)phosphine borane complexes.

This work describes the first transition metal-free stereospecific synthesis of (E)-(1-fluoro-2-arylvinyl)phosphine boranes through the addition of diarylphosphine-boranes to gem-bromofluoroalkenes in the presence of a base at room temperature. The reaction proceeds well under very mild conditions and tolerates a variety of functionalities. Scope and limitations of the reaction are discussed. Mechanistic investigations have been undertaken and revealed that the reaction takes place through an SRN1 mechanism. The formation of the fluorinated vinyl radical has been evidenced by electron paramagnetic resonance (EPR) experiment.

Access to Constrained Fluoropseudopeptides via Ring-Closing Metathesis of Fluoroalkenes.

Bis-alkene substrates, containing one fluoroalkene and linked by an amide moiety, have been designed and synthesized to be subjected to ring-closing metathesis reactions. The substitution of fluoroalkene by a phenyl group enhanced the reactivity, and the resulting fluorinated lactams were obtained in high yields except when a hindered alkyl group was present in the molecule. The cycles were then subjected to ring opening in order to develop a new route to constrained fluoropseudopeptides bearing a fluoroalkene as a peptide bond mimic.

Stereospecific Synthesis of Tri- and Tetrasubstituted α-Fluoroacrylates by Mizoroki-Heck Reaction.

Ligand-free, efficient, palladium-catalyzed Mizoroki-Heck reaction between methyl α-fluoroacrylate and arene or hetarene iodides is reported for the first time. The reaction is stereospecific and provides fair to quantitative yields of fluoroalkenes. The Mizoroki-Heck reaction starting from more hindered and usually reluctant trisubstituted acrylate, to access tetrasubstituted fluoroalkenes, is also reported. Finally, the use of a three-step synthesis sequence, including Mizoroki-Heck reaction, allows the synthesis of fluorinated analogues of therapeutic agents with high yield.

Copper-catalyzed direct C-H fluoroalkenylation of heteroarenes.

Copper-catalyzed direct C-H fluoroalkenylation of heterocycles using various gem-bromofluoroalkenes as electrophiles is reported. This efficient method offers step-economical, low-cost and stereocontrolled access to relevant heteroarylated monofluoroalkenes. The synthesis of fluorinated analogues of biomolecules and therapeutic agents for the treatment of Duchenne muscular dystrophy as application is reported.

Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl α-Amino-ß-fluoro-ß-vinylcyclopropanecarboxylate as Key Intermediate.

Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl α-amino-ß-fluoro-ß-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor.

Pd- and Cu-catalyzed stereo- and regiocontrolled decarboxylative/C-H fluoroalkenylation of heteroarenes.

Pd/Cu-catalyzed decarboxylative/direct C-H alkenylations of heteroarenes with α-fluoroacrylic acid is reported. This method offers step-economical and stereocontrolled access to valuable heteroarylated monofluoroalkenes as both Z and E isomers, which are known to be useful in the synthesis of fluorinated biomolecules.

Indium-promoted diastereoselective addition of fluorinated haloallylic derivatives to imines.

We report herein the first general access to fluorinated homoallylic amines by means of an addition of fluorinated organoindium reagent. The corresponding amines were obtained in good to excellent yield with excellent diastereoisomeric ratio. A plausible mechanism is proposed to explain the stereochemical outcome of the reaction based on the X-ray structure of the products.