Photocatalytic Perfluoroalkylation of Disulfides and Diselenides. Syntheses of Perfluoroalkyl Thio- and Seleno-ethers.

The synthesis of alkyl(aryl)-fluoroalkyl sulfanyl [R(Ar)-S-RF] and aryl-fluoroalkyl selenolyl (Ar-Se-RF) ethers through visible-light photocatalysis has been successfully carried out. This process involves disulfides, and diselenides [R(Ar)-X-X-R(Ar), where X = S or Se], and fluoroalkyl iodides (RF-I) in the presence of a base as an additive under photocatalysis. The photocatalyst Eosin Y and green light-emitting diodes are utilized for irradiation of R(Ar)-S-RF and Ar-Se-RF syntheses. Our method integrates low-energy visible-light photocatalysis, commercially available perfluoroalkylating reagents (RF-I), and easily obtainable disulfides and diselenides as starting materials. Mechanistic studies and a detailed synthetic procedure for (Ar)-S-RF on a large scale are presented.

Perfluoroalkylation of Triarylamines by EDA Complexes and Ulterior Sensitized [6π]-Electrocyclization to Perfluoroalkylated Endo-Carbazoles. Mechanistic and Photophysical Studies.

Blue LEDs-irradiation of a mixture of N,N,N',N'-tetramethylethylenediamine (TMEDA) and perfluoroalkyl iodides (RF-I) - Electron Donor Acceptor (EDA)-complex - in the presence of triphenylamines (TPAs) in an aqueous solvent mixture afforded mono-perfluoroalkylated triphenylamines (RF-TPA) in good yields. These RF-TPA were further subjected to acetone-sensitized [6π]-electrocyclization at 315 nm-irradiation affording exclusively perfluoroalkylated endo-carbazole derivatives (RF-CBz) in quantitative yields. Mechanistic studies and photophysical properties of products are studied.

Trifluoromethoxylation Reactions of (Hetero) arenes, Olefinic Systems and Aliphatic Saturated Substrates.

Direct fluoroalkoxylation reactions of (hetero)arenes, carbon-carbon multiple bonds, and substitution reactions at Csp3 carbon centers by CF3 O, CHF2 O, and (CF3 )2 CFO groups are discussed. Emphasis on thermal radical, electron transfer, photocatalytic, electrochemical and redox-neutral radical methods are placed to accomplish fluoroalkoxylation reactions. All these methods employ either radical fluoroalkoxylating reagents or some nucleophilic trifluoromethoxylating sources of CF3 O. A summary of all these methods is provided in Table 2.

Rose Bengal-photocatalyzed perfluorohexylation reactions of organic substrates in water. Applications to late-stage syntheses.

The Rose Bengal-photocatalyzed perfluorohexylation of olefins, alkynes, and electron-rich aromatic compounds in water was achieved employing perfluorohexyl iodide as fluoroalkyl source and TMEDA as sacrificial donor under green LED irradiation. Alkenes and alkynes rendered products derived from the atom transfer radical addition (ATRA) pathway, and in the case of alkynes, exclusively as E-stereoisomers. These are the first examples of photocatalyzed ATRA reactions carried out excursively in water alone. The reactions of aromatic compounds under the current protocol in water present the advantage of employing a perfluoroalkyl iodide (C6F13-I) as source of perfluorohexyl radicals. Examples of photocatalytic late-stage incorporations of fluoroalkyl moieties into two commercial drugs of widespread use are reported.

Visible light-catalyzed fluoroalkylation reactions of free aniline derivatives.

The electron-rich nature of aminoaromatic compounds and the electrophilic character of fluoroalkyl RF radicals allow for a special match in substitution reactions. We herein present visible light photocatalyzed fluoroalkylation reactions of aniline derivatives, with a study of the reaction mechanisms. The examples evaluated make use of different photocatalysts, such as polypyridyl complexes of Ir or Ru transition metals, organic dyes such as Rose Bengal, phthalocyanine-metal organocatalysts, or visible-light activated complexes. Different visible light sources that span from the blue region of the electromagnetic spectrum to low power red light irradiation sources deliver the excited photocatalysts that ensue into the production of fluoroalkyl RF radicals. In turn, many sources of RF radicals can be employed, such as fluoroalkyl halides, Togni's reagents, Umemoto's reagent, etc. All these protocol variants demonstrate the expansion of the methodology and the versatility of photocatalytic techniques applied to a special family of organic compounds such as aminoaromatic substrates, which has been studied by different groups. Contributions from our own laboratory will be given.

New Visible-Light-Triggered Photocatalytic Trifluoromethylation Reactions of Carbon-Carbon Multiple Bonds and (Hetero)Aromatic Compounds.

Visible-light-photocatalyzed methods employed in synthetic transformations present attractive properties such as environmentally friendly, safety, availability and excellent functional group tolerance. In this regard, research on the visible-light photocatalytic incorporation of the trifluoromethyl CF3 moiety into organic substrates, in particular, has contributed to a clear evolution of the field of photocatalysis. Although this particular area is constantly evolving and has been reviewed, the last five years have experienced an outburst of seminal and significant photocatalytic trifluoromethylation examples that are leading the way and opening new synthetic avenues. Recent review articles on Ru- and Ir-based photocatalytic trifluoromethylation reactions have borne witness of this evolution. Although this account will show the new Ru- and Ir-based photocatalytic trifluoromethylations, Sections 2 and 3 will also illustrate other photocatalytic systems, such as organic dyes, organic semiconductors and newly-developed all-organic photocatalysts. All the known and reviewed strategies for photocatalytic trifluoromethylation reactions of olefins and (hetero)aromatic compounds will not be discussed but will be summarized in two figures (Figures 4 and 5), and new examples (2015-present) will be presented and discussed.

Photocatalytic Difluoromethylation Reactions of Aromatic Compounds and Aliphatic Multiple C-C Bonds.

Among the realm of visible light photocatalytic transformations, late-stage difluoromethylation reactions (introduction of difluoromethyl groups in the last stages of synthetic protocols) have played relevant roles as the CF2X group substitutions exert positive impacts on the physical properties of organic compounds including solubility, metabolic stability, and lipophilicity, which are tenets of considerable importance in pharmaceutical, agrochemical, and materials science. Visible-light-photocatalyzed difluoromethylation reactions are shown to be accomplished on (hetero)aromatic and carbon-carbon unsaturated aliphatic substrates under mild and environmentally benign conditions.

Organic dye-photocatalyzed fluoroalkylation of heteroarene-N-oxide derivatives.

The first direct CHet-H perfluoroalkylation reaction of heteroaromatic-N-oxides has been achieved through a visible light-photocatalyzed reaction in the presence of commercially available perfluoroalkyl iodides RF-I and base in DMF as solvent and Rose Bengal as organic photocatalyst. The reactions proceed in the absence of transition metals and can be scaled up. Through an acid-catalyzed transformation of the perfluoroalkylated-N-oxides thus obtained, the first direct syntheses of 2-(perfluoroalkyl)benzo[f][1,3]oxazepines are achieved. De-oxygenation of the resulting perfluoroalkylated heteroaromatic-N-oxides leads to high yielding and regioselective radical perfluoroalkylation protocols of heteroaromatic compounds. To the best of our knowledge, this is the first report on a direct method for perfluoroalkylation of pyridine-, quinoline-, and diazine-N-oxide derivatives.

Difluoromethylation Reactions of Organic Compounds.

The relevance of the -CF2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF2 H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2 H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF2 H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF2 -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF2 -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF2 H or CF2 Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

Late stage trifluoromethylthiolation strategies for organic compounds.

Substitution by the CF3S group allows for an increase in lipophilicity and electron-withdrawing properties along with an improvement in the bioavailability of medicinal targets; consequently, the late stage introduction of CF3S moieties into medicinal scaffolds is a sought-after strategy in synthetic organic chemistry. Different newly-developed electrophilic and nucleophilic reagents are used to effect the trifluoromethylthiolation of (hetero)aromatic compounds, aliphatic compounds (alkyl, alkenyl, alkynyl substrates), the trifluoromethylthiolation at the α- and ß-carbonyl positions, and heteroatoms (N- and S-). Such reactions can involve homolytic substitutions, or functional-group substitutions (ipso). Addition reactions of electrophilic reagents to double and triple bonds followed by ring-cyclizations will be shown to yield relevant CF3S-substituted heteroaromatic compounds with relevant pharmacological action.

Photocatalytic fluoroalkylation reactions of organic compounds.

Photocatalytic methods for fluoroalkyl-radical generation provide more convenient alternatives to the classical perfluoroalkyl-radical (Rf) production through chemical initiators, such as azo or peroxide compounds or the employment of transition metals through a thermal electron transfer (ET) initiation process. The mild photocatalytic reaction conditions tolerate a variety of functional groups and, thus, are handy to the late-stage modification of bioactive molecules. Transition metal-photocatalytic reactions for Rf radical generation profit from the redox properties of coordinatively saturated Ru or Ir organocomplexes to act as both electron donor and reductive species, thus allowing for the utilization of electron accepting and donating fluoroalkylating agents for Rf radical production. On the other hand, laboratory-available and inexpensive photoorgano catalysts (POC), in the absence of transition metals, can also act as electron exchange species upon excitation, resulting in ET reactions that produce Rf radicals. In this work, a critical account of transition metal and transition metal-free Rf radical production will be described with photoorgano catalysts, studying classical examples and the most recent investigations in the field.

(Me3Si)3SiH-mediated intermolecular radical perfluoroalkylation reactions of olefins in water.

Perfluoroalkyl-substituted compounds are regarded as important components of fluorophors and for the introduction of fluorous tags into organic substrates. Their syntheses in organic solvents are achieved through different methods, among which, the addition of perfluoroalkyl radicals to unsaturated bonds represents a convenient choice. On the other hand, intermolecular radical reactions in water have attracted the attention of synthetic chemists as a strategic route to carbon-carbon bond formation reactions. In this paper we undertook the intermolecular addition of perfluoroalkyl radicals on electron rich alkenes and alkenes with electron withdrawing groups in water, mediated by silyl radicals, and obtained perfluoroalkyl-substituted compounds in fairly good yields. The radical triggering events employed consist of the thermal decomposition of an azo compound and the dioxygen initiation. Our results indicate that for intermolecular carbon-carbon bond formation reactions mediated by (Me(3)Si)(3)SiH, the decomposition of the azo compound 1,1'-azobis(cyclohexanecarbonitrile) (ACCN) is the best radical initiator. We also found that water exerts a relevant solvent effect on the rates of perfluoroalkyl radical additions onto double bonds and the H atom abstraction from the silane. Our account provides a versatile and convenient method to achieve perfluoroalkylation reactions of alkenes in water to render perfluoroalkylated alkanes as key intermediates in the synthesis of fluorophors and other fluorinated materials. This is the first report where perfluoroalkyl-substituted alkanes are synthesized through intermolecular radical carbon-carbon bond formation reactions in water, mediated by silyl radicals.