Dearomatization of Pyridines: Photochemical Skeletal Enlargement for the Synthesis of 1,2-Diazepines.

In this report, we developed a unified and standardized one-pot sequence that converts pyridine derivatives into 1,2-diazepines by inserting a nitrogen atom. This skeletal transformation capitalizes on the in situ generation of 1-aminopyridinium ylides, which rearrange under UV light irradiation. A thorough evaluation of the key parameters (wavelength, reaction conditions, activating agent) allowed us to elaborate on a simple, mild, and user-friendly protocol. The model reaction was extrapolated to more than 40 examples, including drug derivatives, affording unique 7-membered structures. Mechanistic evidence supports the transient presence of a diazanorcaradiene species. Finally, pertinent transformations of the products, including ring contraction reactions to form pyrazoles, were conducted and paved the way to a broad application of the developed protocol.

Bio-Inspired Deaminative Hydroxylation of Aminoheterocycles and Electron-Deficient Anilines.

Among the tools available to chemists for drug design of bioactive compounds, the bioisosteric replacement of atoms or groups of atoms is the cornerstone of modern strategies. Despite the undeniable interest in amino-to-hydroxyl interchange, enzymatic deaminative hydroxylation remains unmatched. Herein, we report a user friendly and safe procedure to selectively convert aminoheterocycles to their hydroxylated analogues by means of a simple pyrylium tetrafluoroborate salt. The hydroxylation step relies on a Lossen-type rearrangement under mild conditions thus avoiding the use of strong hydroxide bases. In addition to biorelevant heterocycles, the deaminative hydroxylation of electron-deficient anilines was also demonstrated. Finally, mechanistic experiments allowed the identification of the key intermediates, thus unveiling a rather unusual mechanism for this formal aromatic substitution.

Strain-Release Pentafluorosulfanylation and Tetrafluoro(aryl)sulfanylation of [1.1.1]Propellane: Reactivity and Structural Insight.

We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding C⋅⋅⋅C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.

Forging C-SeCF3 Bonds with Trifluoromethyl Tolueneselenosulfonate under Visible-Light.

This account highlights some of our recent work on photoinduced trifluoromethylselenolation reactions. This research program relies primarily on the design of a new key shelf-stable selenating reagent that can be involved in various radical processes In particular, we demonstrated that trifluoromethylselenolation of arenes, alkenes, alkynes as well as aliphatic organic building blocks can be readily achieved under visible-light irradiation. Mechanistic investigations based on 19 F NMR studies, EPR spectroscopy, cyclic voltammetry and luminescence studies allowed us to shed the light on the different proposed mechanisms in the designed methodologies. The applicative potential of these strategies was further demonstrated through the synthesis of bioactive analogue containing SeCF3 motif.

Copper-promoted/copper-catalyzed trifluoromethylselenolation reactions.

Copper catalysis and, more generally, copper chemistry are pivotal for modern organofluorine chemistry. Major advances have been made in the field of trifluoromethylselenolations of organic compounds where copper catalysis played a crucial role. Recent developments in this field are highlighted in this minireview.

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.

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.

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.

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.

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.

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.

Electrophilic trifluoromethylselenolation of terminal alkynes with Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate.

Herein the nucleophilic addition of Se-(trifluoromethyl) 4-methylbenzenesulfonoselenoate, a stable and easy-to-handle reagent, to alkynes is described. This reaction provides trifluoromethylselenylated vinyl sulfones with good results and the method was extended also to higher fluorinated homologs. The obtained compounds are valuable building blocks for further syntheses of fluoroalkylselenolated molecules.

Atroposelective Construction of Axially Chiral 2-Aryl-Pyrroloquinolones.

A two-step protocol including an enantioselective organocatalyzed synthesis of pyrroloquinolines followed by an oxidation reaction allowed the formation of axially chiral 2-aryl-pyrroloquinolones. Thorough optimization of the experimental conditions for the second step allowed the oxygenation reaction to take place and ensured, in most cases, a central-to-axial chirality conversion with complete retention of the enantiomeric excess.

Deaminative chlorination of aminoheterocycles.

Selective modification of heteroatom-containing aromatic structures is in high demand as it permits rapid evaluation of molecular complexity in advanced intermediates. Inspired by the selectivity of deaminases in nature, herein we present a simple methodology that enables the NH2 groups in aminoheterocycles to be conceived as masked modification handles. With the aid of a simple pyrylium reagent and a cheap chloride source, C(sp2)‒NH2 can be converted into C(sp2)‒Cl bonds. The method is characterized by its wide functional group tolerance and substrate scope, allowing the modification of >20 different classes of heteroaromatic motifs (five- and six-membered heterocycles), bearing numerous sensitive motifs. The facile conversion of NH2 into Cl in a late-stage fashion enables practitioners to apply Sandmeyer- and Vilsmeier-type transforms without the burden of explosive and unsafe diazonium salts, stoichiometric transition metals or highly oxidizing and unselective chlorinating agents.

Chalcogen OCF3 Isosteres Modulate Drug Properties without Introducing Inherent Liabilities.

The synthesis of SCF3 as well as SeCF3 isosteres of two OCF3 -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF3 and SeCF3 groups are more lipophilic than their oxygen counterpart; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for in vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF3 groups as potential key players for future fluorinated pharmaceuticals.

Visible-light promoted fluoroalkylselenolation: toward the reactivity of unsaturated compounds.

The reactivity of fluoroalkylselenotoluenesulfonates with unsaturated substrates is explored herein. The direct activation of these shelf-stable reagents under visible light allows the double functionalisation of alkenes or alkynes efficiently, leading to a wide range of ß-fluoroalkylselenolated sulfones. Mechanistic investigations have been undertaken supporting the formation of radical intermediates.