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.). Cyclization reactions were then developed to access original N-heterocycles building blocks for drug discovery programs. An extension of the reaction to continuous flow was also reported. Finally, the mechanism of the transformation was studied suggesting a plausible radical chain mechanism.

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., HCF2SO2Na) to enamides and styrenes in an undivided cell allowed the formation of a large panel of difluoromethylated building blocks in good to excellent yields (42 examples, 23-87% yields). A plausible unified mechanism was suggested according to control experiments and cyclic voltammetry measurements.

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-O-acetyl-2-fluoro-l-fucose (2F-Fuc) is a potent inhibitor of the plant cell elongation. After feeding plant seedlings with 2F-Fuc, this monosaccharide derivative is deacetylated and converted by the endogenous metabolic machinery into the corresponding nucleotide-sugar, which then efficiently inhibits Golgi-localized fucosyltransferases. Among plant cell wall polymers, defects in the fucosylation of the pectic rhamnogalacturonan-II cause a decrease in RG-II dimerization, which in turn induce the arrest of the cell elongation. In order to perform the inhibition of the cell elongation process in a spatio-temporal manner, we synthesized a caged 3,4-di-O-acetyl-1-hydroxy-2-fluoro-l-fucose (1-OH-2F-Fuc) derivative carrying a photolabile ortho-nitrobenzyl alcohol function at the anomeric position: 3,4-di-O-acetyl-1-ortho-nitrobenzyl-2-fluoro-l-fucose (2F-Fuc-NB). The photorelease of the trapped 1-OH-2F-Fuc was performed under a 365 nm LED illumination. We demonstrated that the in planta elimination by photoexcitation of the photolabile group releases free 2F-Fuc in plant cells, which in turn inhibits in a dose-dependent manner and, reversibly, the root 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. Finally, scale up of the reaction was demonstrated, affording a promising space-time yield (STY) of 4.2 kg.h-1 .L-1 .

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.L-1 .h-1 and 496 g.L-1 .h-1 ). Moreover, the synthetic utility of these building blocks was highlighted through versatile transformations. Finally, plausible reaction mechanisms were suggested to explain the formation of the products.

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.

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 CH3 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 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.

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.

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

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. Supplementary Information: The online version contains supplementary material available at 10.1007/s41981-021-00205-x.

Electrochemical Hydrosilylation of Alkynes.

Herein, the electrochemical hydrosilylation of alkynes is reported. In the presence of the Suginome reagent (PhMe2Si-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.

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.

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-CH3 bond with fluorine or a fluorinated group (such as CF3 or CF2H) 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. In the past decade, we have sought to develop new routes for the stereoselective synthesis of these building blocks using the most reliable cyclopropanation methods and convenient and readily available starting materials. The challenge that had to be undertaken was how we could use the unique properties of the fluorine atom to improve upon the efficiency of a given process rather than shutting it down. This could be overcome by defining new substrate/reagent reactivity guidelines and carefully selecting whether the fluorinated group was introduced on the electrophilic or nucleophilic partner for a given reaction. In this Account, we describe our contributions in this area that take advantage of diazo-derived rhodium carbenes, zinc carbenoids, ring closure processes, and biocatalytic methods to access these important potential drug subunits. Our initial investigation relied on the development of a Michael-initiated ring closure reaction using the Reformatsky enolate derived from readily available ethyl dibromofluoroacetate and α,ß-unsaturated electrophiles. The reaction proceeded extremely well but with modest to good diastereoselectivities with ester acrylates. Further extension to various fluorinated nucleophiles such as oxazolidinone based and DABCO ylides led to similar selectivities.In order to access enantioenriched fluorocyclopropanes, we then investigated the chiral dioxaborolane mediated zinc carbenoid based approaches using the fluoroiodomethylzinc carbenoid/allylic alcohol combination or the iodomethylzinc carbenoid/fluoroallylic alcohol combination. Quite surprisingly, both approaches were equally successful at providing the corresponding fluorocyclopropanes with excellent diastereo- and enantioselectivities.To broaden the scope of fluorinated cyclopropane building blocks that could be prepared with good enantiocontrol, we then investigated the rhodium-catalyzed cyclopropanation of fluoro-, difluoromethyl-, and trifluoromethyl-substituted alkenes with acceptor-acceptor and donor-acceptor diazo reagents. Depending on the substrate/reagent combination, Hashimoto's Rh2((S)-TCPTTL)4 or Davies' Rh2((S)-BTPCP)4 catalyst proved be the most efficient catalysts providing the cyclopropane derivatives with the highest enantioselectivities.More recently, a collaboration with Fasan's group led to the use of engineered myoglobins to catalyze the reaction of ethyl diazoacetate and difluoromethyl-substituted alkenes. This biocatalyzed process led to high turnover number and high enantioselectivities.Although our work has significantly increased the number of tools in the organic chemist's toolbox, continuous efforts in this area would be beneficial to the development of diastereo- and enantioselective approaches to allow the preparation of any elusive isomers of these valuable chiral building blocks.

Z-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)]PF6 under blue LEDs irradiation, a large panel of alkenes and alkynes was hydrosilylated in good to excellent yields with a large functional group tolerance. The mechanism of the reaction was studied, and a plausible scenario was suggested.

Electrochemical Hydroboration of Alkynes.

Herein we reported the electrochemical hydroboration of alkynes by using B2 Pin2 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. This anodic oxidation performed in an undivided cell allowed the formation of a putative boryl radical, which reacted on the alkyne.

Copper-Photocatalyzed Hydroboration of Alkynes and Alkenes.

The photocatalytic hydroboration of alkenes and alkynes is reported. The use of newly-designed copper photocatalysts with B2 Pin2 permits the formation a boryl radical, which is used for hydroboration of a large panel of alkenes and alkynes. The hydroborated products were isolated in high yields, with excellent diastereoselectivities and a high functional group tolerance under mild conditions. The hydroboration reactions were developed under continuous flow conditions to demonstrate their synthetic utility. The reaction mechanism was studied and suggested an oxidation reaction between an in situ formed borate and the Cu-photocatalyst in its excited state for the boryl radical formation.