Comprehensive Study and Development of a Metal-Free and Mild Nucleophilic Trifluoromethoxylation.

Among the general interest in fluorinated compounds, trifluoromethoxylated molecules play a specific role. However, despite this interest, the development of efficient reagents to perform trifluoromethoxylation reactions remains a challenge. Here, 2,4-dinitro-trifluoromethoxybenzene (DNTFB) is used as a trifluoromethoxylating reagent to perform nucleophilic substitution under mild metal-free conditions with different leaving groups, including direct dehydroxytrifluoromethoxylation. A mechanistic study rationalized the reaction and subsequently proposed only three reaction conditions, depending on the reactivity of the starting substrates.

Perfluoroalkyl Selenoxides, Selenones and Selenoximines: General Preparation and Properties.

A selective access to perfluoroalkyl selenoxides, via Oxone® as oxidant or to selenones by using a Polyoxometalate-based Ionic Liquid (POM-IL) as a catalyst for the oxidation step is described. The reaction works with various perfluoralkyl chains and substituents with satisfactory to excellent yields. A two-step one-pot reaction from selenocyanates was performed to gain access to perfluoroalkyl selenoxides. The previously unknown perfluoroalkyl selenoximines family was also prepared with good yields. Having unlocked two strategies for the synthesis of fluoroalkylated SeIV and SeVI compounds, we then evaluated the Hansch-Leo lipophilicity parameters of these groups. Finally, asymmetric aryl perfluoroalkyl selenoximines were resolved to determine their absolute configurations.

Study of Carbamoyl Fluoride: Synthesis, Properties and Applications.

Carbamoyl fluoride is a fluorinated group that, to this date, remains underexplored, probably due to the lack of data concerning its properties. In this paper, a study of carbamoyl fluoride is presented. Stability studies, in particular under physiological conditions, and lipophilicity measurement were performed. A new easy, safe, inexpensive, and metal-free synthesis method is also described. Finally, a potential use in radiochemistry through a 18 F/19 F isotopic exchange is demonstrated.

Vinylic Trifluoromethylselenolation via Pd-Catalyzed C-H Activation.

Trifluorometylselenolation via C-H activation is barely described in literature. In particular, no such vinylic functionalization has been yet described. Herein, a palladium-catalyzed trifluoromethylselenolation of vinylic C-H bonds is described. The 5-methoxy-8-aminoquinoline has been used as auxiliary directing group to perform this reaction. The reaction gives excellent yields with α-substituted compounds whatever the substituents and a microwave activation can be used to accelerate the reaction. With ß-substituted substrates lower yields, but still satisfactory, are obtained. This methodology was also successfully extended to other fluoroalkylselenyl groups.

Aromatic Trifluoromethylselenolation via Pd-catalyzed C-H functionalization.

The synthesis of trifluoromethylselenolated aromatic molecules via an auxiliary-assisted, palladium catalyzed, C-H bonds functionalization with trifluoromethyl tolueneselenosulfonate as reagent is described. The mono- or bis-products can be preferentially formed. Some mechanistic investigations were realized to better understand the reaction. This methodology was also extended to fluoroalkylselenyl groups.

(Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity.

The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch-Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.

Study of a Stable "Trifluoromethoxide Anion Solution" Arising from 2,4-Dinitro-Trifluoromethoxybenzene.

Despite recent advances, trifluoromethoxylation remains a challenging reaction. Here we describe an efficient trifluoromethoxylative substitution, using an inexpensive and easy-to-handle reagent. By mixing DMAP with a slight excess of 1,4-dinitro-trifluoromethoxybenzene (DNTFB), a stable solution of trifluoromethoxide anion is obtained and can be used to perform a SN 2 reaction without any silver additives. A precise study of the properties and behavior of this unusual stable solution of CF3 O- species is also performed.

Metal-free nucleophilic trifluoromethylselenolation via an iodide-mediated umpolung reactivity of trifluoromethylselenotoluenesulfonate.

We report herein a practical method to generate CF3Se- (and RFSe-) anions from shelf-stable reagents under iodide activation. Metal-free nucleophilic trifluoromethylselenolations have been then performed with this in situ-generated anion. Perfluoroalkylselenolations have also been described.

Merging Visible-Light Catalysis for the Direct Late-Stage Group-16-Trifluoromethyl Bond Formation.

The use of visible light activation/photoredox chemistry for the generation of radical-centered chalcogen-CF3 has gained widespread interest in the last past three years. Its subsequent reactivity for the synthesis of new chalcogen-CF3 -containing building blocks gained much attention. To date several methodologies have been developed addressing several challenges in modern organofluorine chemistry and enabled substantial progress in substrates scope and reaction conditions. This review describes these advancements with a particular focus on the reaction mechanisms.

Evaluation of [18 F]2FP3 in pigs and non-human primates.

So far, no suitable 5-HT7 R radioligand exists for clinical positron emission tomography (PET) imaging. [18 F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs). Furthermore, we investigate species differences in 5-HT7 R binding with [3 H]SB-269970 autoradiography in post-mortem pig, NHP, and human brain tissue. Specific binding of [18 F]2FP3 was investigated by intravenous administration of the 5-HT7 R specific antagonist SB-269970. [3 H]SB-269970 autoradiography was performed as previously described. [18 F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB-269970 only resulted in decreased binding of 20% in the thalamus, a 5-HT7 R-rich region. Autoradiography on post-mortem pig, NHP, and human tissues revealed that specific binding of [3 H]SB-269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [18 F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5-HT7 R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5-HT7 Rs in vivo and that part of the PET signal arises from targets other than the 5-HT7 R.

Difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and Selanes: Missing Links of Trichloroisocyanuric Acid/Potassium Fluoride Chemistry.

The TCICA/KF approach to oxidative fluorination of heteroatoms has emerged as a surprisingly simple, safe, and versatile surrogate to classically challenging fluorination reactions. Although polyfluorination (or chlorofluorination) of diaryl disulfides, diaryl diselenides, diaryl ditellurides, aryl iodides, and aryl(perfluoroalkyl)tellanes has been described, the application of this TCICA/KF methodology to aryl(perfluoroalkyl)sulfanes and selanes remains an area of unexplored chemical space. Accordingly, to address the "missing links" in the developing series of chalcogen-based substrate reactivity, we report mild syntheses of metastable difluoro(aryl)(perfluoroalkyl)-λ4 -sulfanes and selanes. As only limited examples of these species exist in the current literature (accessible only by using F2 or XeF2 /HF), we have carried out detailed structural analyses, primarily using NMR and SC-XRD data. In addition, we investigate the effect of the perfluoroalkyl chain on the outcome of oxidative fluorination, and, finally, we provide preliminary evidence that difluoro(aryl)(trifluoro-methyl)-λ4 -sulfanes may act as fluorinating reagents.

Synthetic Approaches to Trifluoromethylselenolated Compounds.

The association of trifluoromethyl group to chalcogens gives new fluorinated substituents with specific properties, mainly in term of lipophilicity. The trifluoromethylselenyl group is the last of the series that has been studied and despite pioneering approaches in the late 1960s, CF3 Se chemistry has been scarcely developed over the last decades. Some modern and efficient methods to obtain trifluoromethylselenolated molecules have recently emerged. This Review describes the advancements that have been reported.

Exploring the Reactivity of Trifluoromethyl Tolueneselenosulfonate with Alkynes under Copper Catalysis.

The direct fluoroalkylselenolation of terminal alkynes is reported herein involving shelf stable electrophilic reagents TsSeRF . The use of these reagents allows for the first time performing the reaction under catalytic conditions (copper/ligand). Moreover, the presence of oxygen directing groups allows the selective addition of the reagents to alkynes, therefore yielding a new family of vinyl sulfones.

In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging.

Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aß fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.

Fluorous l-Carbidopa Precursors: Highly Enantioselective Synthesis and Computational Prediction of Bioactivity.

New fluorous enantiopure (S)-α-aminated ß-keto esters were prepared through a highly enantioselective electrophilic α-amination step in the presence of europium triflate and (R,R)-phenyl-pybox. These compounds are precursors of fluorinated analogues of l-carbidopa, which is known to inhibit DOPA decarboxylase (DDC), a key protein in Parkinson's disease. Fluorination provides better stability for biological applications, which could possibly lead to DDC inhibitors better than l-carbidopa itself. Induced fit docking computational simulations performed on the new structures interacting with DDC highlight that for an efficient binding at the DDC site, at least one hydroxyl substituent must be present at the aromatic ring of the l-carbidopa analogues and show that the presence of fluorine can further fix the position of the ligand in the active site.

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

The first visible-light-mediated synthesis of trifluoromethylselenolated arenes under metal-free conditions is reported. The use of an organic photocatalyst enables the trifluoromethylselenolation of arene diazonium salts using the shelf-stable reagent trifluoromethyl tolueneselenosulfonate at room temperature. The reaction does not require the presence of any additives and shows high functional-group tolerance, covering a very broad range of starting materials. Mechanistic investigations, including EPR spectroscopy, luminescence investigations, and cyclic voltammetry allow rationalization of the reaction mechanism.

Trifluoromethyl- and Fluoroalkylselenolations of Alkynyl Copper(I) Compounds.

The successful perfluoroalkylselenolation of alkynyl copper(I) compounds is described herein. The reaction occurs under oxidant free conditions at room temperature. This convenient one-pot procedure is based on the in situ generation of trifluoromethylselenyl chlorides. The developed system shows high functional group tolerance and also promotes the employment of fluoroalkyl derivatives.

Generation of the SCF3 Radical by Photoredox Catalysis: Intra- and Intermolecular Carbotrifluoromethylthiolation of Alkenes.

We report the first use of N-trifluoromethylthiosaccharin as the source of SCF3 radical under photoredox catalysis. This allowed an efficient and general visible-light-mediated carbotrifluoromethylthiolation of alkenes. Under the optimized conditions using fac-[Ir(ppy)3 ] as the photocatalyst, various N-aryl acrylamides as well as a wide range of substituted styrenes can readily be difunctionalized in an intra- or intermolecular fashion, affording the corresponding SCF3 -containing products in good to excellent yield. Importantly, the formation of this SCF3 radical along with other key radical intermediates was unambiguously demonstrated thanks to spin trapping/electron paramagnetic resonance (ST/EPR) experiments, which enabled a clear understanding of the reaction mechanism.

Electrophilic Trifluoromethylselenolation of Boronic Acids.

Trifluoromethylselenylated compounds are emergent compounds with interesting physicochemical properties that still suffer from a lack of efficient synthetic methods. We recently developed an efficient one-pot strategy to generate in situ CF3SeCl and use it in various reactions. Herein, we continue our study of the reactivity scope of this preformed reagent. Cross-coupling reactions with aromatic and heteroaromatic boronic acids have been investigated. The expected products have been obtained, using a stoichiometric amount of copper, with moderate yields.

Superacid-Catalyzed Trifluoromethylthiolation of Aromatic Amines.

Upon activation under superacid conditions, functionalized tailor-made N-SCF3 sulfenamides served as reagents for the trifluoromethylthiolation of aromatic amines. This method has a broad substrate scope and can be used for the late-stage functionalization of complex molecules such as alkaloids or steroids. Mechanistic studies based on in situ low-temperature NMR spectroscopy revealed the involvement of dicationic superelectrophilic intermediates.