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.

Preparation of Carbazoles Involving 6π-Electrocyclization, Photoredox-, Electrochemical-, and Thermal Cyclization Reactions: Mechanistic Insights.

Carbazole is a heterocyclic motif that can be found in a diverse array of natural and unnatural products displaying a wide range of biological and physiological properties. Furthermore, this heterocycle is part of electronic materials like photoconducting polymers and organic optoelectronic materials owing to its excellent photophysical characteristics. Consequently, the development of synthetic strategies for carbazole scaffolds holds potential significance in biological and material fields. In this regard, a variety of preparation methods has been developed to exploit their efficient and distinct formation of new C-C and C-heteroatom bonds under mild conditions and enabling broad substrate diversity and functional group tolerance. Therefore, this review focuses on the synthesis of a set of carbazole derivatives describing a variety of methodologies that involve direct irradiation, photosensitization, photoredox, electrochemical and thermal cyclization reactions.

Photocatalyzed Perfluoroalkylation of Endoglycals.

The visible light-induced perfluoroalkyl (RF) radical reactions on peracetylglycals derived from hexoses and pentoses (galactal, glucal, arabinal, and xylal derivatives) were investigated. Various photocatalysts and perfluoroalkyl iodides (RF-I) were employed as sources of RF radicals with LEDs as the irradiation source. Particularly noteworthy was the use of an Iridium photocatalyst, Ir[dF(CF3)ppy]2(dtbpy))PF6, which yielded two distinct product types when applied to glucal. On the one hand, the 2-RF-substituted glucal was formed, a trend observed even when utilizing organic dyes as photocatalysts. On the other hand, the unexpected addition product, namely the 1-RF-2-iodo-α-manno-configured C-glycosyl derivative, was also obtained, as a result of a highly regioselective addition reaction of the RF moiety into the anomeric carbon, followed by attachment of the iodine atom on C-2 in axial disposition. This result contrasted with other radical reactions carried out on 2-unsubstituted glycals, where the incipient radical adds to C-2, generating a stabilized 1-glycosyl radical. The photocatalyzed radical perfluoroalkylations of peracetyl glycals derived from galactose, arabinose, and xylose all afforded the 2-RF-substituted glycals in good yields as a result of the expected vinylic substitution reaction. Mechanistic studies revealed that the 1-RF-2-iodo-α-manno-configured C-glycosyl derivatives arise from a radical chain reaction, whereas the 2-RF-substituted glycals proceed from inefficient chain processes.

Solvent Effects on the Photoinduced [6π]-Electrocyclization Reactions of Mono-, Di-, and Trisubstituted Arylamines: Photophysical, Preparative Photochemistry, and Mechanistic Investigations.

The substituent and solvent effects on the spectroscopic behavior and on the photoinduced [6π]-electrocyclization reaction of substituted triphenylamine derivatives have been investigated. Direct irradiation of triphenylamines bearing electron-donor substituents in different solvents has provided for the first time the substituted exo/endo carbazole derivatives from modest to good yields, whereas triphenylamines bearing electron-withdrawing substituents did not provide the carbazoles due to the formation of charge transfer complexes (CTCs). A corollary of the experiments purports that the photoreaction is favored with weak electron-acceptor groups in polar solvents. The lowest-frequency absorption bands of the triarylamines (π,π* electronic transitions) displayed bathochromic shifts as the solvent polarity is increased. The fluorescence emission spectra of triarylamines bearing electron-donor substituents behave as mirror images of the lowest absorption bands, showing dependence on the solvent polarity. Conversely, triarylamines bearing formyl, acetyl, and nitro groups formed CTCs behaving as good fluorescence chromophores in polar solvents. Hammett correlations on the ΔE(0,0) energies of monosubstituted amines showed a bell-shape behavior where the ρ values depended on the solvent polarity. The physical quenching of the photoreaction of triarylamines has demonstrated for the first time that the triplet excited state is univocally the photoreactive state leading to exo/endo carbazole derivatives.

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.

Photoinduced [6π]-Electrocyclic Reaction of Mono-, Di-, and Trisubstituted Triphenylamines in Acetonitrile. A Steady-State Investigation.

Direct irradiation of mono-, di-, and trisubstituted triphenylamine derivatives in acetonitrile as solvent with light of 254 nm has been systematically investigated, revealing that the exo/endo carbazole derivatives were formed as the main photoproducts from modest to good yields for triphenylamines substituted with electron-donor and neutral substituents. The kinetic profiles of the photoreaction were also recorded, and the consumption rate constants (k) were measured. These kinetic parameters show dependence on the nature of the substituents, and linear Hammett correlations were carried out to showcase the substituent effect. On the other hand, the spectroscopic behavior of the electron-rich substituted triphenylamines has been analyzed, suggesting that the fluorescence emission spectra display a mirror image of the lower energy absorption bands, while for those amines bearing electron-acceptor groups the formation of charge-transfer complexes and their fluorescence emissions constitute the main deactivation pathway of the photoreaction.

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.

Approaches to the Synthesis of Perfluoroalkyl-Modified Carbohydrates and Derivatives: Thiosugars, Iminosugars, and Tetrahydro(thio)pyrans.

Fluoroalkyl-substituted carbohydrates play relevant roles in diverse areas such as supramolecular chemistry, glycoconjugation, liquid crystals, and surfactants, with direct applications as wetting, antifreeze, and coating agents. In light of these promising applications, new methodologies for the late-stage incorporation of fluoroalkyl RF groups into carbohydrates and derivatives are herein presented as they are relevant to the synthetic carbohydrate community. Previously reviewed protocols for the installation of RF groups onto carbohydrates and derivatives will be succinctly summarized in the light of the new achievements. Fluoroalkyl-substituted iminosugars, on the other hand, are also interesting glycomimetic derivatives with prominent roles as glycosidases and glycosyltransferases inhibitors, as has recently been demonstrated. Also, they positively contribute to the study of sugar-protein interactions and enzyme mechanisms. New advances in the syntheses of fluoroalkyl-substituted iminosugars will also be presented here.

Photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals towards the stereoselective synthesis of α-1-fluoroalkyl-C-glycosyl derivatives.

A benign, efficient, regio- and stereoselective protocol for the syntheses of α-1-fluoroalkyl-C-glycosyl compounds bearing CF3, C4F9, and C6F13 substituents on the anomeric carbon has been developed by a new methodology starting from 2-acetoxyglycals for the first time. Remarkably, the reactions proceeded in only one step, through the visible light-photocatalyzed reductive fluoroalkylation of 2-acetoxyglycals by means of an Ir photocatalyst and employed commercially available fluoroalkyl iodides n-CnF2n+1-I (n = 1, 4, 6) as a source of fluoroalkyl radicals.

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.

Synthetic strategies for fluorination of carbohydrates.

This review article discusses different synthetic strategies for accomplishing regio- and stereoselective fluorinations of the sugar moiety, discussing the reaction mechanisms and some biological implications arising from such substitutions.

Radical fluoroalkylation reactions of (hetero)arenes and sulfides under red light photocatalysis.

Fluoroalkylation reactions of (hetero)aromatics have been accomplished through the low-power illumination from red LEDs (λmax = 635 nm) of commercially available perfluoroalkyl iodides RF-I and phthalocyanine zinc salt as photocatalyst in MeCN : DMF solvent mixture. This methodology has been extended to the perfluorobutylation of sulfides. As far as we are concerned, this is the first report on a perfluoroalkylation reaction of (hetero)aromatics and sulfides under red-light photocatalysis.

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.

Radical fluorination reactions by thermal and photoinduced methods.

The radical or radical ion-based fluorination reactions of organic compounds will be presented. These methodologies include fluorination processes accomplished through thermal or photoinduced radical/electron transfer methods. In doing so, the fluorination reactions of diverse families of organic compounds such as aliphatic and aromatic substrates will be presented. Recently summarized or reviewed articles will be mentioned but not discussed.

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.

Fluorination methods in drug discovery.

Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that a fluorine atom can impart to targets of medicinal importance, such as modulation of lipophilicity, electronegativity, basicity and bioavailability, the latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, either of nucleophilic or electrophilic, and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp(3), sp(2), and sp carbon atoms) will be studied in late-stage fluorination reaction 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.