Electrophilic Fluorination of Silyl Dienol Ethers: a General and Selective Access to γ-Fluoro Enals.

We describe the direct synthesis of γ-fluoro enals from the corresponding silyl dienol ethers. This simple process operates under mild conditions and is compatible with a wide range of functionalities. The high γ regioselectivity of this protocol was rationalized by means of theoretical calculations.

Light-Driven Synthesis and Functionalization of Bicycloalkanes, Cubanes and Related Bioisosteres.

Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora of novel synthetic methods. In this review, we assess the progress made in the field of light-driven construction and functionalization of such relevant molecules. We have focused on diverse structural targets, as well as on reaction processes giving access to: (i) [1.1.1]-bicyclopentanes (BCPs); (ii) [2.2.1]-bicyclohexanes (BCHs); (iii) [3.1.1]-bicycloheptanes (BCHeps); and (iv) cubanes; as well as other structurally related scaffolds. Finally, future perspectives dealing with the identification of novel reaction manifolds to access new functionalized bioisosteric units are discussed.

The Revival of Enantioselective Perfluoroalkylation - Update of New Synthetic Approaches from 2015-2022.

Over the last years, methods devoted to the synthesis of asymmetric molecules bearing a perfluoroalkylated chain have been limited in number. Among them, only a few can be used on a large variety of scaffolds. This microreview aims at summarizing these recent advances in enantioselective perfluoroalkylation (-CF3 , -CF2 H, -Cn F2n+1 ) and highlights the need for new enantioselective methods to easily synthesize chiral fluorinated molecules which would be useful for the pharmaceutical and agrochemical industries. Some perspectives are also mentioned.

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.

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.

(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.

Photoredox-Catalyzed Selective Synthesis of Allylic Perfluoroalkanes from Alkenes.

We report herein a novel photoredox-catalyzed synthesis of allylic trifluoromethanes. The use of sulfilimino iminium as a source of trifluoromethyl radicals proves crucial to achieving high selectivity. Importantly, both styrene derivatives and unactivated alkenes are for the first time suitable partners for this process. The mild reaction conditions are compatible with a variety of functional groups. Remarkably, this method is readily broadened to other perfluoroalkyl groups (RF =CFCl2 , CF2 Br, C4 F9 ). An extensive mechanistic study is also provided.

Pyridinium Salts as Redox-Active Functional Group Transfer Reagents.

In this Review, we highlight recent advances in the understanding and design of N-functionalized pyridinium scaffolds as redox-active, single-electron, functional group transfer reagents. We provide a selection of representative methods that demonstrate reactivity and fundamental advances in this emerging field. The reactivity of these reagents can be divided into two divergent pathways: homolytic fragmentation to liberate the N-bound substituent as the corresponding radical or an alternative heterolytic fragmentation that liberates an N-centered pyridinium radical. A short description of the elementary steps involved in fragmentation induced by single-electron transfer is also critically discussed to guide readers towards fundamental processes thought to occur under these conditions.

One-Pot Synthesis of Aryl- and Alkyl S-Perfluoroalkylated NH-Sulfoximines from Sulfides.

A general efficient one-pot synthesis of S-perfluoroalkylated NH-sulfoximines from sulfides has been developed using phenyliodine diacetate (PIDA) and ammonium carbamate. Remarkable rate enhancement with trifluoroethanol was observed, presumably due to H-bonding effects. These mild and metal-free conditions are compatible with -CH2 F, -CFCl2 , -CF2 H, -CF2 Br, -C4 F9 , and -CF3 groups, in both the alkyl- and aryl series. Based on a 19 F NMR analysis, a λ6 -acetoxysulfanenitrile intermediate was proposed.

Alkoxyl Radicals Generated under Photoredox Catalysis: A Strategy for anti-Markovnikov Alkoxylation Reactions.

Reported herein is a novel photoredox-catalyzed approach for ether synthesis and it involves alkoxyl radicals generated from N-alkoxypyridinium salts. A wide range of alkenes are smoothly difunctionalized in an anti-Markovnikov fashion, affording various functionalized alkyl alkyl ethers. Notably, this mild process tolerates a number of functional groups and is efficiently carried out under both batch and flow conditions. Importantly, electron paramagnetic resonance (EPR) experiments by spin trapping were carried out to characterize the radical intermediates involved in this radical/cationic process.

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.

Dichlorotrifluoromethoxyacetic Acid: Preparation and Reactivity.

We describe the first gram scale preparation of the reagent dichlorotrifluoromethoxyacetic acid. This stable compound is obtained in five steps starting from the cheap diethylene glycol. The reactivity of the sodium salt of this fluorinated acid was also tested and allowed the preparation of new amides.

Fluorinated Sulfilimino Iminiums: Efficient and Versatile Sources of Perfluoroalkyl Radicals under Photoredox Catalysis.

Reported herein is the use of S-perfluoroalkyl sulfilimino iminiums as a new source of RF radicals under visible-light photoredox catalysis (RF =CF3 , C4 F9 , CF2 Br, CFCl2 ). These shelf-stable perfluoroalkyl reagents, readily prepared on gram scale from the corresponding sulfoxide using a one-pot procedure, allow the efficient photoredox-induced oxyperfluoroalkylation of various alkenes using fac-Ir(ppy)3 as the photocatalyst. Importantly, spin-trapping/electron paramagnetic resonance experiments were carried out to characterize all the radical intermediates involved in this radical/cationic process.

Catalytic enantioselective [4 + 2]-cycloaddition: a strategy to access aza-hexacycles.

The aza-Diels Alder reaction has become one of the most widely used synthetic tools for the preparation of N-containing 6-membered heterocycles. Numerous important developments have been reported to render this reaction catalytic and enantioselective. This tutorial review highlights strategies and recent advances to achieve high efficiency and selectivity through the use of organocatalysts and transition metal complexes, allowing also the extension of this transformation substrate scope.

Diastereoselective synthesis of open-chain secondary alkyllithium compounds and trapping reactions with electrophiles.

A practical stereoselective iodide-lithium exchange was used in the first general preparation of functionalized stereodefined acyclic secondary nonstabilized lithium reagents from the corresponding secondary alkyl iodides. These lithium reagents react with various electrophiles including carbon electrophiles with high retention of configuration. Kinetic data on the configurational stability of these acyclic alkyllithium reagents are given. This methodology offers a new entry to chiral synthons for the stereoselective synthesis of open-chain molecules.

Preparation of stereodefined secondary alkyllithium compounds.

We have developed a practical stereoretentive iodine/lithium-exchange process that allows the stereodefined preparation of cis- and trans-cycloalkyllithium compounds from their corresponding stereodefined iodides. Quenching with electrophiles offers stereospecific access to both cis- (up to 96% cis) and trans-cycloalkyl derivatives (up to 99% trans). A detailed study of the thermodynamic stabilities, stereochemical behavior, and reactivities of axially and equatorially substituted cyclohexyllithium reagents is reported. Ab initio calculations demonstrate that the formation of oligomeric cyclohexyllithium structures is pivotal for explaining the observed stereochemical preference.

Highly selective γ-alkoxylation, γ-amination and γ-alkylation of unbiased enals by means of photoredox catalysis.

We report herein a general and highly selective γ-functionalization protocol under visible light irradiation. This mild radical approach enables the expansion of the scope of application to unbiased enals and the introduction of a wide variety of alkoxy, amino and alkyl functionalities in the γ position with complete regioselectivity.

Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using cyclic enethioureas as dienophiles: stereocontrolled access to enantioenriched hexahydropyrroloquinolines.

Three become one: Phosphoric acid-catalyzed enantioselective three-component Povarov reactions of aldehydes, anilines, and endocyclic enethioureas have been developed (see scheme). This process afforded hexahydropyrroloquinolines in high yields with excellent diastereo- and enantioselectivities. The presence of the thiourea functionality is crucial for the enantioselectivity of the reaction.

Remote Radical Trifluoromethylation: A Unified Approach to the Selective Synthesis of γ-Trifluoromethyl α,ß-Unsaturated Carbonyl Compounds.

Site-selective trifluoromethylation of silyl dienol ethers derived from α,ß-unsaturated aldehydes, ketones, and amides was achieved for the first time in the remote γ position. This photoredox catalyzed process is quite general to compounds bearing many functionalities and is applicable to the late-stage functionalization of biorelevant molecules. The use of S-perfluoroalkyl sulfoximines as ·RF radical sources enables the generalization of the reaction to other perfluoroalkyl groups (RF = CF2H, C4F9). Importantly, an unprecedented enantioselective C(sp3)-H perfluoroalkylation process is disclosed.

Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using enecarbamates as dienophiles: highly diastereo- and enantioselective synthesis of substituted 4-aminotetrahydroquinolines.

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF(3), NO(2)) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With ß-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst-substrate interaction as well as a linear correlation between catalyst and product ee's were also documented.