Synthesis of Cyclobutenoates From Photochemical Rearrangement of α-Diazo Cyclopropanes and Computational Studies.

The ring expansion of α-cyclopropyl diazoacetates into cyclobutenoates upon irradiation at 425 nm was reported. This method allowed an access to a large array of cyclobutenoates as a mixture of regioisomers. The products were isolated in moderate to excellent yields (17% to 75%) and moderate to good regioisomeric ratio (55:45 to 82:18).

Strain Release Cycloadditions of 2H-Azirines: Access to Polycyclic Heterocycles.

A strain release cycloaddition has been developed that exploits intermediate azirines formed via irradiation with blue LEDs. Subsequent cycloaddition with pyrones afforded novel aza-heterocycles (13 examples, 42%→66% yields). A variety of substituents were tolerated.

Electrochemical synthesis of allenyl silanes and allenyl boronic esters.

Allenyl silanes and boronates are pivotal building blocks in organic synthesis. Nevertheless, their synthesis requires the manipulation of transition metal or highly reactive species. Hence, the development of more sustainable protocol is highly sought after.

Excited-state configuration of nitroarenes enables oxidative cleavage of aromatics over alkenes.

The ozonolytic deconstruction of aromatics remains a challenge in organic chemistry. Ozone preferentially reacts with alkenes over arenes, meaning that once the initial aromatic cleavage occurs, the dearomatized products are inherently more reactive than the starting materials. Consequently, the process cannot be halted, resulting in full oxidation.

→-Thermodynamic isomerization of alkenes with SEGPHOS.

Herein we disclose a photosensitized →-thermodynamic isomerization of vinyl sulfones, employing SEGPHOS as a promoter. The reaction was performed successfully on 23 vinyl sulfones and was extended to three other olefins. Different mechanistic experiments were performed as well as photophysical studies.

Chemoenzymatic synthesis of optically active α-cyclopropyl-pyruvates and cyclobutenoates via enzyme-catalyzed carbene transfer with diazopyruvate.

Cyclopropanes are recurrent structural motifs in natural products and bioactive molecules. Recently, biocatalytic cyclopropanations have emerged as a powerful approach to access enantioenriched cyclopropanes, complementing chemocatalytic approaches developed over the last several decades. Here, we report the development of a first biocatalytic strategy for cyclopropanation using ethyl α-diazopyruvate as a novel enzyme-compatible carbene precursor.

Photocatalytic and Electrochemical Borylation and Silylation Reactions.

Due to their high versatility borylated and silylated compounds are inevitable synthons for organic chemists. To escape the classical hydroboration/hydrosilylation paradigm, chemists turned their attention to more modern and green methods such as photoredox chemistry and electrosynthesis. This account focuses on novel methods for the generation of boryl and silyl radicals to forge C-B and C-Si bonds from our group.

Photoinduced Minisci Reaction with Diazines: An Approach Toward Original Fused Heterocycles.

Herein, we developed a photoinduced Minisci reaction on a large panel of diazines with good to excellent yields (28 examples, 44 % to 89 %). The reaction using 4CzIPN (1 mol %) as photoinitiator was carried out under white LED irradiation and required a slight excess of the acid reagent (1.2 equiv.

Electrochemical Difluoromethylation of Electron-Rich Olefins.

The electrochemical difluoromethylation of electron-rich olefins (enamides and styrene derivatives) is disclosed. The addition of the electrogenerated difluoromethyl radical from the corresponding sodium sulfinate (i.e.

Electrochemical Hydrosilylation of Alkynes.

Herein, the electrochemical hydrosilylation of alkynes is reported. In the presence of the Suginome reagent (PhMeSi-Bpin), a large panel of terminal alkynes and internal alkynes was successfully converted into the hydrosilylated product in good to excellent yields and good selectivity in favor of the linear product. Preliminary mechanistic study supported the involvement of a silyl radical, which reacted on the alkyne.

The Light-Controlled Release of 2-fluoro-l-fucose, an Inhibitor of the Root Cell Elongation, from a nitrobenzyl-caged Derivative.

Glycan metabolic engineering is a powerful tool for studying the glycosylation in living plant cells. The use of modified monosaccharides such as deoxy or fluorine-containing glycosides has been reported as a powerful pharmacological approach for studying the carbohydrate metabolism. 1,3,4-tri--acetyl-2-fluoro-l-fucose (2F-Fuc) is a potent inhibitor of the plant cell elongation.

Continuous-Flow Divergent Lithiation of 2,3-Dihalopyridines: Deprotolithiation versus Halogen Dance.

We describe herein the first halogen dance (HD) in continuous flow on 2-chloro-3-bromopyridine by selectively trapping a (pyridin-4-yl)lithium species that is known to undergo the halogen-dance process. In addition, this lithiated intermediate was trapped at lower temperature before the HD occurs. The HD process was extended to fluoro-iodopyridines by using various electrophiles to afford 28 examples with yields ranging from 42 to 97 % with very short residence times.

Electrochemical Synthesis of gem-Difluoro- and γ-Fluoro-Allyl Boronates and Silanes.

The electrochemical synthesis of fluorinated allyl silanes and boronates was disclosed. The addition of electrogenerated boryl or silyl radicals onto many α-trifluoromethyl or α-difluoromethylstyrenes in an undivided cell allowed the formation of a large panel of synthetically useful gem-difluoro and γ-fluoroallyl boronates and silanes (64 examples, from 31 % to 95 % yield). In addition, a scale up of the reactions under continuous flow was showcased using an electrochemical reactor with promising volumetric productivity (688 g.

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.

Photocatalytic E→Z Contra-Thermodynamic Isomerization of Vinyl Silanes with Lewis Base.

Herein, we disclosed the contra-thermodynamic E→Z isomerization of alkenyl silanes, according to the in situ formation of a chromophoric species, in the presence of rac-BINAP as the catalyst. The reaction carried out in DMSO or CH CN under irradiation at 405 nm allowed the interconversion of the E-isomers into the Z-congeners in good to excellent yields and outstanding Z/E selectivities, on 18 examples. Finally, the mechanism of this E→Z isomerization was studied to get insight into the reaction mechanism.

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 Rh ((S)-TCPTAD) or Rh ((R)-BTPCP) catalysts (up to 95 % yield, >95 : 5 d.r.

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 (Rh ((S)-BTPCP) ), furnished the corresponding cyclopropanes in moderate to high yields (27-97 %), high diastereoselectivities (68 : 32 to 20 : 1 d.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.

Continuous Flow Synthesis of Propofol.

Herein, we report a continuous flow process for the synthesis of 2,6-diisopropylphenol-also known as Propofol-a short-acting intravenous anesthesia, widely used in intensive care medicine to provide sedation and hypnosis. The synthesis is based on a two-step procedure: a double Friedel-Crafts alkylation followed by a decarboxylation step, both under continuous flow.

Continuous flow synthesis of Celecoxib from 2-bromo-3,3,3-trifluoropropene.

Unlabelled: We describe the total flow synthesis of the widely prescribed anti-inflammatory COX-2 inhibitor Celecoxib from 2-bromo-3,3,3-trifluoropropene, as a convenient and available trifluoromethyl building block, to generate trifluoropropynyl lithium and to trap it immediately with an aldehyde. Oxidation of the obtained alcohol into ketone followed by condensation with 4-sulfamidophenylhydrazine afforded the targeted drug with full regioselectivity. It is noteworthy that the quality of these flow reactions (50% overall yield within 1 h cumulated residence time over 3 steps) directly furnished the target API and intermediates with excellent purity.

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.

Asymmetric Synthesis of Fluoro, Fluoromethyl, Difluoromethyl, and Trifluoromethylcyclopropanes.

Fluorine-containing cyclopropanes are a subclass of cyclopropane derivatives that have generated considerable interest in medicinal chemistry for several decades. The replacement of a cyclopropane C-H or C-CH bond with fluorine or a fluorinated group (such as CF or CFH) can lead sometimes to synergistic effects in terms of biological activity and improved metabolic profile of a cyclopropane containing bioactive compound. In this context, the preparation of fluoro-, difluoromethyl-, or trifluoromethyl-cyclopropane is particularly attractive and important but quite challenging considering the unique electronic properties that result from the incorporation of a fluorine atom into a substrate or a reagent.

-Selective Pd-catalyzed 2,2,2-trifluoroethylation of acrylamides at room temperature.

A straightforward 2,2,2-trifluoroethylation of acrylamides by Pd-catalyzed C-H bond activation was reported by using a fluorinated hypervalent iodine reagent as a coupling partner. At room temperature, this additive-free approach allowed the synthesis of Z-2,2,2-trifluoroethylated acrylamides (19 examples, up to 73% yield) in a stereoselective manner. Under these mild reaction conditions, the methodology turned out to be functional group tolerant and mechanistic studies gave us a better understanding of the transformation.

Copper-Photocatalyzed Hydrosilylation of Alkynes and Alkenes under Continuous Flow.

Herein, the photocatalytic hydrosilylation of alkynes and alkenes under continuous flow conditions is described. By using 0.2 mol % of the developed [Cu(dmp)(XantphosTEPD)]PF under blue LEDs irradiation, a large panel of alkenes and alkynes was hydrosilylated in good to excellent yields with a large functional group tolerance.

Electrochemical Hydroboration of Alkynes.

Herein we reported the electrochemical hydroboration of alkynes by using B Pin as the boron source. This unprecedented reaction manifold was applied to a broad range of alkynes, giving the hydroboration products in good to excellent yields without the need of a metal catalyst or a hydride source. This transformation relied on the possible electrochemical oxidation of an in situ formed borate.