Développement de nouvelles réactions de trifluorométhylation photocatalysées : difonctionnalisation vicinale d'alcènes

Over the past decade, organic fluorine chemistry has attracted wide interest due to the unique nature of this halogen which modifies the physicochemical properties of molecules. Numerous fluorinated compounds are nowadays used in medicine and crop science. These features have stimulated the development of new strategies for the efficient introduction of fluorine, especially the trifluoromethyl group into organic molecules. Among the contemporary methods, visible-light photoredox trifluoromethylation of alkenes is an efficient and attractive strategy. This first aim was to develop a methodology giving rise to original β-trifluoromethylamines. We could efficiently perform a photocatalyzed α-β-difunctionalization of enecarbamates through a three-component reaction between enecarbamates, Togni reagent, and a nucleophile: alcohol, cyanide or azide. Another approach uses styrenes, which are commercially available compounds or easily accessible. The nitrogen atom was introduced by concomitant addition of a CF₃ group and an azido or amino function. The second project of my PhD was to extend this methodology to aromatic or heteroaromatic nucleophiles leading to the formation of 1,1 diarylalkane derivatives, which are present in many biologically active products. Changing the nucleophilic partner to halogen (chlorine, bromine or iodine) is also very effective. Finally, the photoredox-mediated process has been applied to the synthesis of 1,3-dihydroisobenzofurans, commonly named phthalans and their nitrogen analogs: 1,3-isoindolines.La chimie du fluor a connu un essor considérable ces dernières années en raison des caractéristiques remarquables de cet halogène et de l'influence qu'il exerce sur les propriétés physicochimiques des molécules organiques l'incorporant. De nombreuses molécules fluorées sont désormais utilisées comme médicaments ou en agriculture. Au laboratoire, nous nous sommes intéressés au développement de nouvelles stratégies directes et efficaces pour incorporer un groupement trifluorométhyle sur une double liaison carbone-carbone. Pour cela, des procédés faisant intervenir la catalyse photoinduite ont été employés.Tout d'abord, la synthèse d'amines β-trifluorométhylées a été mise au point en utilisant des enecarbamates comme substrats de départ. Une deuxième approche a consisté à utiliser des styrènes, commerciaux ou plus facile d'accès, et d'introduire l'atome d'azote par addition concomitante du nucléophile et du groupement CF₃. Cette stratégie a été ensuite étendue à d'autres nucléophiles carbonés ou halogénés de façon obtenir une grande diversité structurale. Enfin, la réactivité inattendue des 2-vinylbenzaldéhydes nous a permis d'appliquer nos méthodologies photocatalysées à la synthèse de phthalanes, composés présents dans un grand nombre de produits naturels ou biologiquement actifs

Development of photocatalytic trifluoromethylated reactions : Vicinal Difunctionalization of Alkenes

La chimie du fluor a connu un essor considérable ces dernières années en raison des caractéristiques remarquables de cet halogène et de l'influence qu'il exerce sur les propriétés physicochimiques des molécules organiques l'incorporant. De nombreuses molécules fluorées sont désormais utilisées comme médicaments ou en agriculture. Au laboratoire, nous nous sommes intéressés au développement de nouvelles stratégies directes et efficaces pour incorporer un groupement trifluorométhyle sur une double liaison carbone-carbone. Pour cela, des procédés faisant intervenir la catalyse photoinduite ont été employés.Tout d'abord, la synthèse d'amines β-trifluorométhylées a été mise au point en utilisant des enecarbamates comme substrats de départ. Une deuxième approche a consisté à utiliser des styrènes, commerciaux ou plus facile d'accès, et d'introduire l'atome d'azote par addition concomitante du nucléophile et du groupement CF₃. Cette stratégie a été ensuite étendue à d'autres nucléophiles carbonés ou halogénés de façon obtenir une grande diversité structurale. Enfin, la réactivité inattendue des 2-vinylbenzaldéhydes nous a permis d'appliquer nos méthodologies photocatalysées à la synthèse de phthalanes, composés présents dans un grand nombre de produits naturels ou biologiquement actifs.Over the past decade, organic fluorine chemistry has attracted wide interest due to the unique nature of this halogen which modifies the physicochemical properties of molecules. Numerous fluorinated compounds are nowadays used in medicine and crop science. These features have stimulated the development of new strategies for the efficient introduction of fluorine, especially the trifluoromethyl group into organic molecules. Among the contemporary methods, visible-light photoredox trifluoromethylation of alkenes is an efficient and attractive strategy. This first aim was to develop a methodology giving rise to original β-trifluoromethylamines. We could efficiently perform a photocatalyzed α-β-difunctionalization of enecarbamates through a three-component reaction between enecarbamates, Togni reagent, and a nucleophile: alcohol, cyanide or azide. Another approach uses styrenes, which are commercially available compounds or easily accessible. The nitrogen atom was introduced by concomitant addition of a CF₃ group and an azido or amino function. The second project of my PhD was to extend this methodology to aromatic or heteroaromatic nucleophiles leading to the formation of 1,1 diarylalkane derivatives, which are present in many biologically active products. Changing the nucleophilic partner to halogen (chlorine, bromine or iodine) is also very effective. Finally, the photoredox-mediated process has been applied to the synthesis of 1,3-dihydroisobenzofurans, commonly named phthalans and their nitrogen analogs: 1,3-isoindolines

Photoredox-induced three-component azido- and aminotrifluoromethylation of alkenes.

International audienceWe report herein a photoredox-catalyzed azidotrifluoromethylation of alkenes. Under the optimized conditions using [Ru(bpy)3(PF6)2] as the photocatalyst and Umemoto's reagent as the CF3 source, a wide range of substituted styrenes as well as various activated and nonactivated alkenes can readily be difunctionalized, affording β-trifluoromethylated azides or amines in good yields

One pot and selective intermolecular aryl- and heteroaryl-trifluoromethylation of alkenes by photoredox catalysis.

International audienceWe report herein the first photoredox-catalyzed intermolecular aryl- and heteroaryltrifluoromethylation of alkenes. Under the optimized conditions using Umemoto's reagent as a CF3 source, a wide range of styrenes can be readily difunctionalized, affording the corresponding trifluoromethylated adducts in up to 99% yield

Photoredox-Catalyzed Three-Component Tandem Process: An Assembly of Complex Trifluoromethylated Phthalans and Isoindolines

International audienc

Photoredox-Induced Three-Component Azido- and Amino­tri­fluoro­methyla­tion of Alkenes

We report herein a photoredox-catalyzed azido­trifluoro­methyla­tion of alkenes. Under the optimized conditions using [Ru­(bpy)₃(PF₆)₂] as the photocatalyst and Umemoto’s reagent as the CF₃ source, a wide range of substituted styrenes as well as various activated and nonactivated alkenes can readily be difunctionalized, affording β-trifluoromethylated azides or amines in good yields

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants