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.

Evaluation of ferrocenyl-containing γ-hydroxy-γ-lactam-derived tetramates as potential antiplasmodials.

A series of ferrocenyl-containing γ-hydroxy-γ-lactam tetramates were prepared in 2-3 steps through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of ferrocenyl alkylamines. The compounds were screened in vitro for their antiplasmodial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (W2) clones of P. falciparum, displaying activity in the range of 0.12-100 µM, with generally good resistance index. The most active ferrocene in these series exhibited IC50 equal to 0.09 µM (3D7) and 0.12 µM (W2). The low cytotoxicity of the ferrocenyl-containing γ-hydroxy-γ-lactam tetramates against Human Umbilical Vein Endothelial (HUVEC) cell line demonstrated selective antiparasitic activity. The redox properties of these ferrocene-derived tetramates were studied and physico-biochemical studies evidenced that these derivatives can exert potent antimalarial activities via a mechanism distinct from ferroquine.

Catalytic Enantioselective Synthesis of Functionalized Cyclopropanes from α-Substituted Allyl Sulfones with Donor-Acceptor or Diacceptor Diazo Reagents.

The catalytic asymmetric synthesis of highly functionalized cyclopropanes from α-substituted allyl sulfones and silanes is reported. The reaction, using α-aryl diazoacetates or diacceptor diazo reagents, catalyzed by a chiral rhodium complex (Rh2 ((S)-BTPCP)4 ), furnished the corresponding cyclopropanes in moderate to high yields (27-97 %), high diastereoselectivities (68 : 32 to 20 : 1 d.r.) and moderate to excellent ee (40-99 %). This methodology offers a privileged access to an underexplored class of enantioenriched cyclopropanes with a high level of functionality, an asset for further post-functionalization and their incorporation into more complex structure.

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.

Photocatalyzed E→Z Contra-thermodynamic Isomerization of Vinyl Boronates with Binaphthol.

The photocatalytic contra-thermodynamic E→Z isomerization of vinyl boronates by using a binaphthol catalyst is disclosed. The reaction, based on the transient formation of a suitable chromophore with a BINOL derivative as the catalyst, allowed geometrical isomerization in good-to-excellent Z/E ratio and excellent-to-quantitative yields. The mechanism of this E→Z contra-thermodynamic isomerization was studied, and the formation of a transient chromophore species is suggested.

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.

Copper-Photocatalyzed Contra-Thermodynamic Isomerization of Polarized Alkenes.

The contra-thermodynamic isomerization of α- and ß-substituted cinnamate derivatives catalyzed by the Cu(OAc)2/rac-BINAP complex under blue light irradiation is reported. The use of an oxazolidinone template, which favored the complexation of the copper catalyst to the substrate, allowed the E → Z isomerization of the catalytically formed chromophore under simple and robust reaction conditions in good to excellent ratios. The mechanism of this process based on the transient formation of a chromophore was also studied.

Gold(I)-Catalyzed Intramolecular Hydroamination and Hydroalkoxylation of Alkynes: Access to Original Heterospirocycles.

We report here a simple and robust gold-catalyzed annulation reaction, giving N- and O-spirocycles in good to excellent yields. We have prepared a library of protected amines and tertiary alcohols that give, upon cyclization with alkynes, a representative set of heterospirocycles and illustrate reaction compatibility with diverse functional groups. A change in catalytic activity is possible by modifying the solvent, and two original tricyclic spirocycles were synthesized in a tandem reaction.

Design of iodinated radioligands for SPECT imaging of central human 5-HT4R using a ligand lipophilicity efficiency approach.

A series of iodinated ligands for the SPECT imaging of 5-HT4 receptors was designed starting from the previously reported hit MR-26132. We focused on the modulation of the piperidine-containing lateral chain by introducing hydrophilic groups in order to decrease the liphophilicity of the new ligands. All the synthesized compounds were tested for their binding affinities on 5-HT4Rs and based on the Ligand Lipophilicity Efficiency approach, compound 13 was further selected for radioiodination with iodine-125 and imaging experiments. Compound 13 showed its ability to displace the specific signal of the reference compound [125I]SB-207710 but no significant detection of [125I]13 was observed in vivo in SPECT experiments.

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.

Palladium-Mediated Site-Selective C-H Radio-iodination.

The palladium-mediated C-H radio-iodination of arenes using sodium iodide as the primary isotopic source is reported and performed without chemical know-how in 30 min and applied to the synthesis of complex radio-iodinated compounds of biological interest.

Catalytic Enantioselective Synthesis of Highly Functionalized Pentafluorosulfanylated Pyrrolidines.

The first catalytic asymmetric synthesis of highly functionalized pentafluorosulfanylated pyrrolidines is described. The method, based on a 1,3-dipolar cycloaddition reaction of aryl and heteroaryl-substituted glycine Schiff bases with pentafluorosulfanyl acrylic esters, gave access to a broad range of pyrrolidines bearing aryl, naphtyl, and heteroaryl groups. By using Xing-Phos as a catalyst, the corresponding products were obtained in good yields, good to high regioselectivity, and excellent diastereo- and enantioselectivities (up to 98 % ee). This methodology allowed the preparation of enantioenriched SF5 compounds for the first time using an enantioselective approach.

Synthesis and biological evaluation of pyridazinone derivatives as potential anti-inflammatory agents.

Cyclic nucleotide phosphodiesterase type 4 (PDE4), that controls intracellular level of cyclic nucleotide cAMP, has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases. Here we describe the development of two families of pyridazinone derivatives as potential PDE4 inhibitors and their evaluation as anti-inflammatory agents. Among these derivatives, 4,5-dihydropyridazinone representatives possess promising activity, selectivity towards PDE4 isoenzymes and are able to reduce IL-8 production by human primary polymorphonuclear cells.

Pd-Catalyzed Diastereoselective Trifluoromethylthiolation of Functionalized Acrylamides.

The Pd-catalyzed diastereoselective trifluoromethylthiolation of acrylamides was developed to allow the formation of the Z-isomer as a single product. Using a C-H bond functionalization strategy, the method was applied to a broad range of α-aryl, α-alkyl, and α,ß-disubstituted acrylamides bearing the amide derived from the 8-aminoquinoline as a directing group. Mechanistic studies as well as postfunctionalization of the products were performed. This approach opens new routes to unprecedented SCF3-containing scaffolds.

Palladium-Catalyzed Synthesis of 3-Trifluoromethyl-Substituted 1,3-Butadienes by Means of Directed C-H Bond Functionalization.

A palladium-catalyzed C-H bond functionalization of acrylamides was developed to build up stereoselectively trifluoromethylated 1,3-butadienes. Using a tertiary amide as a directing group, olefins were selectively functionalized with 2-bromo-3,3,3-trifluoropropene to access these important fluorinated compounds. The methodology was extended to the construction of pentafluoroethyl-substituted 1,3-dienes. Mechanistic studies supported by density functional theory calculations suggested a redox neutral mechanism for this transformation.

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.

7-Chloro-4-aminoquinoline γ-hydroxy-γ-lactam derived-tetramates as a new family of antimalarial compounds.

In this Letter we report on an efficient and short 2-3 steps synthesis of γ-hydroxy-γ-lactam derived-tetramates bearing a 7-chloro-4-aminoquinoline skeleton and their evaluation as potent antimalarials. These molecules were obtained through ring opening-ring closure (RORC) process of γ-ylidene-tetronate derivatives in the presence of 7-chloro-4-aminoquinoline-derived amines. In vitro antimalarial activity of these new γ-lactams was evaluated against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) and they were found to be active in the range of 14-827nM with generally good resistance index. A preliminary SAR study is also presented to explain these results. Finally, the most active compounds did not show in vitro cytotoxicity when tested against Human Umbilical Vein Endothelial Cells (HUVEC) up to concentration of 50µM and they were stable at pH 7.4 for at least 48h.

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.