C-F Bond Insertion: An Emerging Strategy for Constructing Fluorinated Molecules.

C-F Insertion reactions, where an organic fragment formally inserts into a carbon-fluorine bond in a substrate, are highly attractive, yet largely unexplored, methods to prepare valuable fluorinated molecules. The inherent strength of C-F bonds and the resulting need for a large thermodynamic driving force to initiate C-F cleavage often leads to sequestering of the released fluoride in an unreactive by-product. Recently, however, several groups have succeeded in overcoming this challenge, opening up the study of C-F insertion as an efficient and highly atom-economical approach to prepare fluorinated compounds. In this article, the recent breakthroughs are discussed focusing on the key conceptual advances that allowed for both C-F bond cleavage and subsequent incorporation of the released fluoride into the product.

Catalyst-Free Trifluoromethoxylation of Silyl Enol Ethers and Allyl Silanes with Bis(trifluoromethyl)peroxide.

Radical trifluoromethoxylation is an attractive approach to prepare compounds featuring the important OCF3 group, however most existing methods have focused on aromatic substrates. Here, we report novel methodologies with alkenyl substrates employing bis(trifluoromethyl)peroxide (BTMP) as a practical and comparatively atom economical trifluoromethoxylating reagent. With silyl enol ether substrates, switching reaction solvent allows for the synthesis of either α-(trifluoromethoxy)ketone products or unprecedented alkenyl-OCF3 species. Furthermore, allyl silanes have been employed as substrates for the first time, affording allyl(trifluoromethyl)ether products in good yields. In each case, the methods operate at room temperature without large excesses of the alkene substrate while, in contrast to previous radical trifluoromethoxylation reactions, no catalyst, light or other activators are required.

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents.

2-(Trifluoromethylthio)benzothiazolium triflate (BT-SCF3) was used as deoxyfluorinating reagent for the synthesis of versatile acyl fluorides directly from the corresponding carboxylic acids. These acyl fluorides were reacted with amines in a one-pot protocol to form different amides, including dipeptides, under mild and operationally simple conditions in high yields. Mechanistic studies suggest that BT-SCF3 can generate acyl fluorides from carboxylic acids via two distinct pathways, which allows the deoxyfluorinating reagent to be employed in sub-stoichiometric amounts.

Formal Insertion of Alkenes Into C(sp3 )-F Bonds Mediated by Fluorine-Hydrogen Bonding.

C-F Insertion reactions represent an attractive approach to prepare valuable fluorinated compounds. The high strength of C-F bonds and the low reactivity of the fluoride released upon C-F bond cleavage, however, mean that examples of such processes are extremely scarce in the literature. Here we report a reaction system that overcomes these challenges using hydrogen bond donors that both activate C-F bonds and allow for downstream reactions with fluoride. In the presence of hexafluoroisopropanol, benzyl and propargyl fluorides undergo efficient formal C-F bond insertion across α-fluorinated styrenes. This process, which does not require any additional fluorinating reagent, occurs under mild conditions and delivers products featuring the gem-difluoro motif, which is attracting increasing interest in medicinal chemistry. Moreover, readily available organic bromides can be engaged directly in a one-pot process that avoids the isolation of organic fluorides.

Radical C-H Trifluoromethoxylation of (Hetero)arenes with Bis(trifluoromethyl)peroxide.

Trifluoromethoxylated (hetero)arenes are of great interest for several disciplines, especially in agro- and medicinal chemistry. Radical C-H trifluoromethoxylation of (hetero)arenes represents an attractive approach to prepare such compounds, but the high cost and low atom economy of existing . OCF3 radical sources make them unsuitable for the large-scale synthesis of trifluoromethoxylated building blocks. Herein, we introduce bis(trifluoromethyl)peroxide (BTMP, CF3 OOCF3 ) as a practical and efficient trifluoromethoxylating reagent that is easily accessible from inexpensive bulk chemicals. Using either visible light photoredox or TEMPO catalysis, trifluoromethoxylated arenes could be prepared in good yields under mild conditions directly from unactivated aromatics. Moreover, TEMPO catalysis allowed for the one-step synthesis of valuable pyridine derivatives, which have been previously prepared via multi-step approaches.

Benzothiazolium salts as reagents for the deoxygenative perfluoroalkylthiolation of alcohols.

A series of 2-(perfluoroalkylthio)benzothiazolium (BT-SRF) salts have been synthesized that serve as convenient sources of hitherto underexplored perfluoroalkylthiolate anions. An investigation of their reactivity in a deoxygenative nucleophilic substitution reaction led to the development of an unprecedented process that provides pentafluoroethyl and heptafluoropropyl thioethers directly from readily available alcohols.

An overview of N-heterocyclic carbenes.

The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

N-Heterocyclic Carbene Catalyzed Photoenolization/Diels-Alder Reaction of Acid Fluorides.

The combination of light activation and N-heterocyclic carbene (NHC) organocatalysis has enabled the use of acid fluorides as substrates in a UVA-light-mediated photochemical transformation previously observed only with aromatic aldehydes and ketones. Stoichiometric studies and TD-DFT calculations support a mechanism involving the photoactivation of an ortho-toluoyl azolium intermediate, which exhibits "ketone-like" photochemical reactivity under UVA irradiation. Using this photo-NHC catalysis approach, a novel photoenolization/Diels-Alder (PEDA) process was developed that leads to diverse isochroman-1-one derivatives.

Deoxytrifluoromethylthiolation and Selenylation of Alcohols by Using Benzothiazolium Reagents.

Aliphatic compounds substituted with medicinally important trifluoromethylthio (SCF3 ) and trifluoromethylselenyl (SeCF3 ) groups were synthesized directly from alcohols by using the new benzothiazolium salts BT-SCF3 and BT-SeCF3 . These bench-stable fluorine-containing reagents are facile to use and can be prepared in two steps from non-fluorinated heteroaromatic starting materials. The metal-free deoxytrifluoromethylthiolation process using BT-SCF3 proceeds under mild conditions and the similarly efficient trifluoromethylselenylation reactions using BT-SeCF3 are, to the best of our knowledge, the first reported examples of this transformation.

A Radical Revolution for Trifluoromethoxylation.

The study of OCF3 -substituted molecules is somewhat hampered by a lack of diverse synthetic methods to access them. By introducing a new mild and practical reaction system for accessing the . OCF3 radical, a recent study by Liu, Ngai, and co-workers has the potential to dramatically expand the scope of direct trifluoromethoxylation. The features of this ground-breaking system are discussed and placed into context with other recent advances on nucleophilic trifluoromethoxylation.

Merging Visible Light Photoredox and Gold Catalysis.

Since the beginning of this century, π-Lewis acidic gold complexes have become the catalysts of choice for a wide range of organic reactions, especially those involving nucleophilic addition to carbon-carbon multiple bonds. For the most part, however, the gold catalyst does not change oxidation state during the course of these processes and two-electron redox cycles of the kind implicated in cross-coupling chemistry are not easily accessible. In order to address this limitation and expand the scope of gold catalysis beyond conventional hydrofunctionalization, extensive efforts have been made to develop new oxidative reactions using strong external oxidants capable of overcoming the high potential of the AuI/AuIII redox couple. However, these processes typically require superstoichiometric amounts of the oxidant and proceed under relatively harsh conditions. Moreover, to date, gold-catalyzed oxidative coupling reactions have remained somewhat limited in scope because, for many systems, the desired cross-coupling does not favorably compete with homodimerization or conventional hydrofunctionalization. In 2013, we disclosed a new concept for gold-catalyzed coupling reactions that, rather than involving external oxidants, employs aryl radicals that act as both the oxidant and the coupling partner in overall redox-neutral transformations. For this, we developed a dual catalytic system combining homogeneous gold catalysis with the emerging field of visible light photoredox catalysis. Using aryldiazonium salts, which are known to act as sources of aryl radicals upon activation with reducing photocatalysts, we could achieve intramolecular oxy- and aminoarylations of alkenes upon irradiating the reaction mixtures with visible light. Further studies on this transformation, in which nucleophilic addition onto a gold-activated alkene is followed by C(sp3)-C(sp2) bond formation, expanded the scope of the process to intermolecular, three-component oxyarylation, while inexpensive organic dyes and user-friendly diaryliodonium salts could be employed as alternative photocatalysts and aryl radical sources, respectively. The potential of dual gold/photoredox catalysis was quickly realized by several research groups and a range of diverse new coupling reactions involving nucleophilic addition to π-systems and even P-H and C(sp)-H functionalization have been developed. In addition to the ambient reaction conditions and the simple setup using household light sources or even sunlight, a key advantage of dual gold/photoredox catalysis results from the simultaneous oxidation of gold(I) and coordination of the coupling partner, which results in high levels of selectivity for the cross-coupled products over homodimers. Furthermore, when gold complexes that are not catalytically active prior to oxidation by the aryl radical are employed, background reactions not involving coupling can be suppressed. Notably, this feature has allowed for the successful use of allenes and alkynes, for which conventional hydrofunctionalization pathways are highly favored, opening the door to new transformations involving the most common substrate classes for gold catalysis. In this Account, we provide an overview of dual gold/photoredox catalysis and highlight the potential of this concept to greatly expand the scope of homogeneous gold catalysis and enable the efficient construction of complex organic molecules. Moreover, recent studies on the visible light-promoted synthesis of novel gold(III) complexes suggest that photoredox activation could yet find further applications in gold chemistry beyond coupling.

Diverse Visible-Light-Promoted Functionalizations of Benzotriazoles Inspired by Mechanism-Based Luminescence Screening.

Three new visible-light-promoted functionalizations of benzotriazole substrates were discovered using a mechanism-based screening method. ortho-Thiolated, borylated, and alkylated N-arylbenzamide products were obtained under mild reaction conditions in a new denitrogenative synthetic approach to functionalized aniline derivatives. The functional group tolerance of the borylation reaction was further analyzed in the first application of an additive-based robustness screen in a photocatalytic transformation. All the functionalizations proceed via photocatalytically initiated chain mechanisms as indicated by determination of the reaction quantum yields and Stern-Volmer analyses.

Oxidative Addition to Gold(I) by Photoredox Catalysis: Straightforward Access to Diverse (C,N)-Cyclometalated Gold(III) Complexes.

Herein, we report the oxidative addition of aryldiazonium salts to ligand-supported gold(I) complexes under visible light photoredox conditions. This method provides experimental evidence for the involvement of such a process in dual gold/photoredox-catalyzed reactions and delivers well-defined (C,N)-cyclometalated gold(III) species. The remarkably mild reaction conditions and the ability to widely vary the ancillary ligand make this method a potentially powerful synthetic tool to access diverse gold(III) complexes for systematic studies into their properties and reactivity. Initial studies show that these species can undergo chloride abstraction to afford Lewis acidic dicationic gold(III) species.

Alkyne Difunctionalization by Dual Gold/Photoredox Catalysis.

Highly selective tandem nucleophilic addition/cross-coupling reactions of alkynes have been developed using visible-light-promoted dual gold/photoredox catalysis. The simultaneous oxidation of Au(I) and coordination of the coupling partner by photo-generated aryl radicals, and the use of catalytically inactive gold precatalysts allows for high levels of selectivity for the cross-coupled products without competing hydrofunctionalization or homocoupling. As demonstrated in representative arylative Meyer-Schuster and hydration reactions, this work expands the scope of dual gold/photoredox catalysis to the largest class of substrates for gold catalysts and benefits from the mild and environmentally attractive nature of visible-light activation.

Visible-Light-Promoted Trifluoromethylthiolation of Styrenes by Dual Photoredox/Halide Catalysis.

Herein, we report a new visible-light-promoted strategy to access radical trifluoromethylthiolation reactions by combining halide and photoredox catalysis. This approach allows for the synthesis of vinyl-SCF3 compounds of relevance in pharmaceutical chemistry directly from alkenes under mild conditions with irradiation from household light sources. Furthermore, alkyl-SCF3-containing cyclic ketone and oxindole derivatives can be accessed by radical-polar crossover semi-pinacol and cyclization processes. Inexpensive halide salts play a crucial role in activating the trifluoromethylthiolating reagent towards photoredox catalysis and aid the formation of the SCF3 radical.

Accelerated Discovery in Photocatalysis using a Mechanism-Based Screening Method.

Herein, we report a conceptually novel mechanism-based screening approach to accelerate discovery in photocatalysis. In contrast to most screening methods, which consider reactions as discrete entities, this approach instead focuses on a single constituent mechanistic step of a catalytic reaction. Using luminescence spectroscopy to investigate the key quenching step in photocatalytic reactions, an initial screen of 100 compounds led to the discovery of two promising substrate classes. Moreover, a second, more focused screen provided mechanistic insights useful in developing proof-of-concept reactions. Overall, this fast and straightforward approach both facilitated the discovery and aided the development of new light-promoted reactions and suggests that mechanism-based screening strategies could become useful tools in the hunt for new reactivity.

External-Photocatalyst-Free Visible-Light-Mediated Synthesis of Indolizines.

A visible-light-mediated synthesis of valuable polycyclic indolizine heterocycles from easily accessed brominated pyridine and enol carbamate derivatives has been developed. This process, which operates at room temperature under irradiation from readily available light sources, does not require the addition of an external photocatalyst. Instead, an investigation into the reaction mechanism indicates that the indolizine products themselves may be in some way involved in mediating and accelerating their own formation. Preliminary studies also show that these simple heterocyclic compounds may be capable of facilitating other visible-light-mediated transformations.

Dual catalysis sees the light: combining photoredox with organo-, acid, and transition-metal catalysis.

The photoredox activation of organic substrates with visible light is a powerful methodology that generates reactive radical species under very mild conditions. When combined with another catalytic process in a dual catalytic system, novel, visible-light-promoted transformations have been realized that do not proceed using either catalyst in isolation. In this minireview, the state of the art in organic reactions mediated by dual catalytic systems merging photoredox activation with organo-, acid or metal catalysis is discussed.

Combining gold and photoredox catalysis: visible light-mediated oxy- and aminoarylation of alkenes.

A room-temperature intramolecular oxy- and aminoarylation of alkenes with aryldiazonium salts has been developed using a novel gold and photoredox dual-catalytic system. The compatibility of these two catalytic modes has been established for the first time and demonstrates the potential of this system as a method to expand the scope of nucleophilic addition reactions to carbon-carbon multiple bonds.

A (TD-)DFT study on photo-NHC catalysis: photoenolization/Diels-Alder reaction of acid fluorides catalyzed by N-heterocyclic carbenes.

A comprehensive mechanistic study on the N-heterocyclic carbene (NHC) catalyzed photoenolization/Diels-Alder (PEDA) reaction of acid fluorides was performed in the framework of (time-dependent) density functional theory ((TD)-DFT). The 1,5-hydrogen atom transfer (1,5-HAT) during photoenolization of an ortho-toluoyl azolium salt was found to be feasible via, first, singlet excitation and photoenolization, and then, after crossing to the triplet manifold, populating a biradical dienol which allows for the formation of two ortho-quinodimethane (o-QDM) isomers due to a low rotational barrier. The (Z)-isomer is mostly unproductive through sigmatropic rearrangement back to the starting material while the (E)-isomer reacts in a subsequent concerted Diels-Alder reaction likely as the deprotonated dienolate. The experimentally observed diastereoselectivity is correctly predicted by theory and is determined by a more favorable endo trajectory in the cycloaddition step. These findings demonstrate that ortho-toluoyl azolium species exhibit similar photophysical properties as structurally related benzophenones, highlighting the unique ability of the NHC organocatalyst to transiently alter the excited state properties of an otherwise photoinactive carboxylic acid derivative, thereby expanding the scope of classical carbonyl photochemistry.