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.

Novel N(SCF)(CF)-amines: synthesis, scalability and stability.

We disclosed herein a straightforward strategy for the synthesis of unprecedented -((trifluoromethyl)thio), -(trifluoromethyl) amines using a combination of isothiocyanates with a fluoride source and an electrophilic trifluoromethylthiolation reagent. More interestingly, the scalability of the methodology has been demonstrated and the stability of the new motif has been studied.

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.

Ketenimines as Intermediates To Access Difluoromethoxylated Scaffolds.

We report herein the generation of difluoromethoxylated ketenimines. This novel intermediate is readily obtained from the corresponding oxime through a Beckmann rearrangement. The reactivity potential of this species is demonstrated as it easily undergoes addition of various nucleophiles, with a great modularity of the starting oxime.

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.

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.

Metal-Free SF Activation: A New SF -Based Reagent Enables Deoxyfluorination and Pentafluorosulfanylation Reactions.

The activation of SF , a potent greenhouse gas, under metal-free and visible light conditions is reported. Herein, mechanistic investigations including EPR spectroscopy, NMR studies and cyclic voltammetry allowed the rational design of a new fluorinating reagent which was synthesized from the 2-electron activation of SF with commercially available TDAE. This new SF -based reagent was efficiently employed for the deoxyfluorination of CO and the fluorinative desulfurization of CS allowing the formation of useful fluorinated amines.

From Academia to the Market - Air-stable Ni()/Josiphos Catalysts.

The design, synthesis, commercialization and application of air-stable Ni(II)/Josiphos complexes has been realized in a collaboration between Solvias and ICBMS (University Lyon 1). The Ni-complexes are utilized as versatile precatalysts for diverse cross-coupling reactions. Apart from being active in established C-C and C-N couplings at low catalyst loadings, the novel Ni-precatalysts enabled the development of the challenging monoarylation of ammonia, ammonia surrogates and even alkylammonium chlorides with aryl carbamates.

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 S 2 reaction without any silver additives.

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.

Acridinium Salts and Cyanoarenes as Powerful Photocatalysts: Opportunities in Organic Synthesis.

The use of organic photocatalysts has revolutionized the field of photoredox catalysis, as it allows access to reactivities that were traditionally restricted to transition-metal photocatalysts. This Minireview reports recent developments in the use of acridinium ions and cyanoarene derivatives in organic synthesis. The activation of inert chemical bonds as well as the late-stage functionalization of biorelevant molecules are discussed, with a special focus on their mechanistic aspects.

Metal-Free Visible-Light Synthesis of Arylsulfonyl Fluorides: Scope and Mechanism.

The first metal-free procedure for the synthesis of arylsulfonyl fluorides is reported. Under organo-photoredox conditions, aryl diazonium salts react with a readily available SO source (DABSO) to afford the desired product through simple nucleophilic fluorination. The reaction tolerates the presence of both electron-rich and -poor aryls and demonstrated a broad functional group tolerance.

Forging C-SeCF 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 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.

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

We report herein a practical method to generate CFSe (and RSe) 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.

Nickel-Catalyzed Mono-Selective α-Arylation of Acetone with Aryl Chlorides and Phenol Derivatives.

The challenging nickel-catalyzed mono-α-arylation of acetone with aryl chlorides, pivalates, and carbamates has been achieved for the first time. A nickel/Josiphos-based catalytic system is shown to feature unique catalytic behavior, allowing the highly selective formation of the desired mono-α-arylated acetone. The developed methodology was applied to a variety of (hetero)aryl chlorides including biologically relevant derivatives.

Chalcogen OCF Isosteres Modulate Drug Properties without Introducing Inherent Liabilities.

The synthesis of SCF as well as SeCF isosteres of two OCF -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 SCF and SeCF 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.

Direct Synthesis of Carbamoyl Fluorides by CO Deoxyfluorination.

Herein, a new concept for the direct synthesis of carbamoyl fluoride derivatives is disclosed. The developed method makes use of CO as an inexpensive and abundant C source; a variety of amines were successfully converted in the presence of a deoxyfluorinating reagent. The corresponding products were often obtained in excellent yields under mild reaction conditions (1 atm and room temperature).

Transition-Metal-Free Synthesis of Biarylmethanes from Aryl Iodides and Benzylic Ketones.

An original metal-free procedure for the synthesis of biarylmethanes is disclosed herein. The reactions occur with high selectivity starting from aryl iodides and benzylic ketones in the presence of superbasic media (CsOH/DMSO). This procedure allows a straightforward access to a wide range of biarylmethane derivatives substituted with electron-withdrawing and -donating substituents.

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 β-fluoroalkylselenolated sulfones. Mechanistic investigations have been undertaken supporting the formation of radical intermediates.

A Metal-Free Route to Heterocyclic Trifluoromethyl- and Fluoroalkylselenolated Molecules.

A metal-free methodology to easily synthesize various CFSe-containing heterocyclic compounds has been developed through intramolecular ring closures of alkynes promoted with CFSeCl. Moreover, this strategy has also been extended to other fluoroalkylselenyl groups.

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

New fluorous enantiopure (S)-α-aminated β-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.

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, CF Se chemistry has been scarcely developed over the last decades. Some modern and efficient methods to obtain trifluoromethylselenolated molecules have recently emerged.

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.

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.

Superacid-Catalyzed Trifluoromethylthiolation of Aromatic Amines.

Upon activation under superacid conditions, functionalized tailor-made N-SCF 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.