Synthesis of pentafluorosulfanylated heterocycles and stereoselective hydrometallation reactions on polarized alkynes

Cette thèse traite de la synthèse d’hétérocycles pentafluorosulfanylés ainsi que des réactions d’hydrométallation stéréosélectives d’alcynes polarisés. Dans un premier temps, nous avons mis au point une méthode de synthèse de pyrimidines 4- et 5-SF5 par fluoration oxydante. Cette méthode repose sur l’utilisation de pyrimidines (benzylthio)pyrimidines comme précurseurs qui sont plus faciles d’accès et suffisamment réactifs en fluoration oxydante. Dans un deuxième temps, nous avons développé une voie de synthèse des indoles et aza-indoles 2-SF5 grâce à l’utilisation du gaz SF5-Cl. Différentes réactions de fonctionnalisation et des études physico-chimiques ont été réalisées sur ces hétérocycles apportant des informations uniques sur ce groupement fluoré. En parallèle, nous avons étudié les réactions stéréosélectives d’hydrométallation d’alcynes polarisés. Une méthode palladocatalysée d’hydrogermylation régiodivergente d’ynamide a été mise en place, tandis qu’une étude mécanistique par calcul DFT a permis d’appuyer l’importance des ligands phosphine dans le contrôle de la régiosélectivité de la réaction. Enfin, des résultats préliminaires sur la réaction d’hydrostannylation d’alcynes pentafluorosulfanylés sont aussi décrits.This thesis deals with the synthesis of pentafluorosulfanyl heterocycles as well as the hydrometallation reactions of polarized alkynes. First, we developed a method for the synthesis of pyrimidines 4- and 5-SF5 by oxidative fluorination. This method is based on the use of (benzylthio)pyrimidines as precursors which are easier to access and sufficiently reactive in oxidative fluorination. In a second part, we developed the synthesis of indoles and aza-indoles 2-SF5 thanks to the use of SF5-Cl gas. Different functionalization reactions and physicochemical studies have been carried out on these heterocycles providing unique information on this fluorinated group. In parallel, we have studied stereoselective hydrometallation reactions of polarized alkynes. A palladium catalyzed regiodivergent hydrogermylation of ynamide was implemented, while a mechanistic study by DFT calculation supported the importance of phosphine ligands in controlling the regioselectivity of the reaction. Finally, preliminary results on the hydrostannylation reaction of pentafluorosulfanylated alkynes are also described

Synthesis of pentafluorosulfanylated heterocycles and stereoselective hydrometallation reactions on polarized alkynes

Cette thèse traite de la synthèse d’hétérocycles pentafluorosulfanylés ainsi que des réactions d’hydrométallation stéréosélectives d’alcynes polarisés. Dans un premier temps, nous avons mis au point une méthode de synthèse de pyrimidines 4- et 5-SF5 par fluoration oxydante. Cette méthode repose sur l’utilisation de pyrimidines (benzylthio)pyrimidines comme précurseurs qui sont plus faciles d’accès et suffisamment réactifs en fluoration oxydante. Dans un deuxième temps, nous avons développé une voie de synthèse des indoles et aza-indoles 2-SF5 grâce à l’utilisation du gaz SF5-Cl. Différentes réactions de fonctionnalisation et des études physico-chimiques ont été réalisées sur ces hétérocycles apportant des informations uniques sur ce groupement fluoré. En parallèle, nous avons étudié les réactions stéréosélectives d’hydrométallation d’alcynes polarisés. Une méthode palladocatalysée d’hydrogermylation régiodivergente d’ynamide a été mise en place, tandis qu’une étude mécanistique par calcul DFT a permis d’appuyer l’importance des ligands phosphine dans le contrôle de la régiosélectivité de la réaction. Enfin, des résultats préliminaires sur la réaction d’hydrostannylation d’alcynes pentafluorosulfanylés sont aussi décrits.This thesis deals with the synthesis of pentafluorosulfanyl heterocycles as well as the hydrometallation reactions of polarized alkynes. First, we developed a method for the synthesis of pyrimidines 4- and 5-SF5 by oxidative fluorination. This method is based on the use of (benzylthio)pyrimidines as precursors which are easier to access and sufficiently reactive in oxidative fluorination. In a second part, we developed the synthesis of indoles and aza-indoles 2-SF5 thanks to the use of SF5-Cl gas. Different functionalization reactions and physicochemical studies have been carried out on these heterocycles providing unique information on this fluorinated group. In parallel, we have studied stereoselective hydrometallation reactions of polarized alkynes. A palladium catalyzed regiodivergent hydrogermylation of ynamide was implemented, while a mechanistic study by DFT calculation supported the importance of phosphine ligands in controlling the regioselectivity of the reaction. Finally, preliminary results on the hydrostannylation reaction of pentafluorosulfanylated alkynes are also described

Exploring the Reactivity of Trifluoromethyl Tolueneselenosulfonate with Alkynes under Copper Catalysis

International audienc

Ligand-Controlled Regiodivergent Palladium-Catalyzed Hydrogermylation of Ynamides

International audienceYnamides are fascinating small molecules with complementary reactivities under radical, ionic, and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydrometalation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent α,E- or β,E-selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metalated enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans-geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, these calculations support the prevalence of a hydro-palladation pathway over a metal palladation of the π system of the ynamide

Synthesis and Physico-Chemical Properties of 2-SF5-(Aza)Indoles, A New Family of SF5-Heterocycles

Structural diversity in heterocyclic chemistry is key to unlock new properties and modes of action. In this regard, heterocycles embedding emerging fluorinated substituents hold great promises. Herein is described a strategy to access 2-SF5- (aza)indoles for the first time. The sequence relies on the radical addition of SF5Cl to the alkynyl p-system of 2-ethynyl anilines followed by a cyclization reaction. A telescoped sequence is proposed making this strategy very appealing and reproducible on gram scale. Downstream functionalizations are also demonstrated, allowing an easy diversification of N- and C3-positions. Ames test, pKa, logP and DSC measurements of several fluorinated 2-Rfindoles are also disclosed. These studies highlight the strategic advantages that a C2-pentafluorosulfanylated motif impart to a privileged scaffold such as indole

Ligand-Controlled Regiodivergent Palladium-Catalyzed Hydrogermylation of Ynamides

Ynamides are fascinating small molecules with complementary reactivities under radical, ionic and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydro-metallation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent alpha,E- or beta,E-selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metallated-enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans-geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, the prevalence of a hydro-palladation pathway over a metal-palladation of the pi system of the ynamide was demonstrated

Visible-Light-Mediated Metal-Free Synthesis of Trifluoromethylselenolated Arenes

International audienc

Sex-related exacerbation of injury-induced mechanical hypersensitivity in GAD67 haplodeficient mice

International audienceAbstract Decreased GABA levels in injury-induced loss of spinal inhibition are still under intense interest and debate. Here, we show that GAD67 haplodeficient mice exhibited a prolonged injury-induced mechanical hypersensitivity in postoperative, inflammatory, and neuropathic pain models. In line with this, we found that loss of 1 copy of the GAD67-encoding gene Gad1 causes a significant decrease in GABA contents in spinal GABAergic neuronal profiles. Consequently, GAD67 haplodeficient males and females were unresponsive to the analgesic effect of diazepam. Remarkably, all these phenotypes were more pronounced in GAD67 haplodeficient females. These mice had significantly much lower amount of spinal GABA content, exhibited an exacerbated pain phenotype during the second phase of the formalin test, developed a longer lasting mechanical hypersensitivity in the chronic constriction injury of the sciatic nerve model, and were unresponsive to the pain relief effect of the GABA-transaminase inhibitor phenylethylidenehydrazine. Our study provides strong evidence for a role of GABA levels in the modulation of injury-induced mechanical pain and suggests a potential role of the GABAergic system in the prevalence of some painful diseases among females

Metabolism and estrogenicity of benzophenone-2 and bisphenol-S in zebrafish in vitro and in vivo models

Among endocrine disruptors, benzophenones and bisphenols detected in human, in the aquatic environment and in fish, are of major concerns to human and wildlife health. Among benzophenones (UV filters) and bisphenols, benzophenone-2 (BP2) and bisphenos S (BPS, bisphenol A substitute) are hormonally active compounds that have been shown to be estrogenic and to disrupt the hormonal regulation in rat and/or fish. Several human and aquatic vertebrate bioassays have been designed over the last years with the aim to characterize the estrogeno-mimetic potential of chemicals. However, the characterization of the biotransformation capability of these biological models, which allows taking into account bioactivation/detoxification processes in effect assessment, is rarely reported. We have recently developed novel zebrafish assays used to assess the estrogenic potency of chemicals. They included ZELH zfERs cell lines based on the expression of zebrafish estrogen receptors in the hepatic cell line ZFL (ZELH zfERs), and the EASZY assay based on the expression of the Green Fluorescent Protein under the control of the cyp19a1b promoter in the zebrafish larva. They were used to investigate in a global approach, the fate and the estrogenic potency of BP2 and BPS. Metabolism of tritium-labeled chemicals was explored using radio-HPLC (metabolic profiling), and metabolite identification was investigated using biochemical tools and high resolution mass spectrometry. Whereas BP2 and BPS were found to be estrogenic in ZELH zfERs cells and in adult zebrafish, no disruption of expression of estrogeno-regulated genes specific of brain and liver in larva was observed. Regarding the BP2 and the BPS metabolism, similar metabolic profiles were shared by zebrafish in vitro and in vivo models suggesting a well conservation of metabolic capabilities. Overall, this study provides new and relevant data concerning the fate and the estrogenic activity of BP2 and BPS in novel zebrafish assays, allowing a better characterization of their respective biotransformation capabilities which is required for their use in the context of endocrine disruptors testing