Atom Transfer Radical Addition Research Articles

Bundling Fluorine and Iodine on Unactivated Alkenes

Key words alkene functionalization - perfluorinated compounds - atom-transfer radical addition

Fast Heating‐Assisted One‐Pot Copper‐Catalyzed Sulfonylation and Sulfochlorination of Styrenes

AbstractHere, a strategy for the synthesis under fast‐heating conditions of vinyl sulfones and β‐chlorosulfones from styrene derivatives, tosyl chloride (TsCl) as sulfonyl and chlorine source, and CuBr‐neocuproine as the catalytic system is reported. The reaction occurs through an atom transfer radical addition (ATRA) mechanism to generate the sulfochlorinated adducts followed by E2 elimination to generate the vinyl sulfones. This methodology allows a wide range of vinyl sulfones and β‐chlorosulfones to be obtained using inexpensive reagents in one and five minutes respectively. These reactions appear as an interesting fast and easy‐to‐handle alternative to obtain these compounds.

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.

Photoactive Metal Carbonyl Complexes Bearing N-Heterocyclic Carbene Ligands: Synthesis, Characterization, and Viability as Photoredox Catalysts.

This report details the synthesis and characterization of a small family of previously unreported, structurally related chromium, molybdenum, tungsten, manganese, and iron complexes bearing N-heterocyclic carbene and carbonyl supporting ligands. These complexes have the general form [ML(CO)3X] or [ML(CO)3], where X = CO or Br and L = 1-phenyl-3-(2-pyridyl)imidazolin-2-ylidene. Where possible, the solid-state, spectroscopic, electrochemical, and photophysical properties of these molecules were studied using a combination of experiment and theory. Photophysical studies reveal that decarbonylation occurs when these complexes are exposed to ultraviolet light, with the CO ligand being replaced with a labile acetonitrile solvent molecule. To obtain insights into the potential utility, scope, and applications of these complexes in visible-light-mediated photoredox catalysis, their capacity to facilitate a range of photoinduced reactions via the reductive or oxidative functionalization of organic molecules was investigated. These chromium, molybdenum, and manganese catalysts efficiently facilitated atom-transfer radical addition processes. In light of their photolability, these types of catalysts may potentially allow for the development of photoinduced reactions involving less conventional inner-sphere electron-transfer pathways.

Periodically Functionalized Sequence‐Regulated Vinyl Polymers via Iterative Atom Transfer Radical Additions and Acyclic Diene Metathesis Polymerization

AbstractSequence‐regulated vinyl polymers with functional groups, such as aliphatic, aromatic, hydroxy, amino, and carboxylic acid groups, as found in natural macromolecules such as proteins, are one of the ultimate targets in synthetic polymers. This study is directed toward the synthesis of periodically functionalized sequence‐regulated vinyl polymers using a series of reactions consisting of iterative atom transfer radical additions (ATRAs) of vinyl monomers, allylation, functionalization, protection, acyclic diene metathesis (ADMET) polymerization, hydrogenation, and deprotection. The functionalized sequence‐regulated telechelic diene oligomers, possessing protected hydroxy, carboxylic acid, and amino groups in the pendant of the acrylate unit between two styrene units, are prepared by iterative ATRAs of two styrene molecules to methyl dichloroacetate followed by allylation of both C–Cl termini and substitution of methyl ester with the protected functionalized groups. The protected functionalized sequence‐regulated telechelic diene oligomers are then polymerized by ADMET polymerization to afford polymers with main‐chain internal olefins and protected functionalized side chains in the acryl units between the two styrene units. The subsequent hydrogenation and deprotection reactions produce a series of sequence‐regulated vinyl polymers with periodic polar functional groups such as –OH, –CO2H, and –NH3+Cl–. These functional groups affect the thermal properties and solubility of the polymers.

Co-Catalyzed atom transfer radical addition of bromodifluoroacetamides, expanding the scope of radical difluoroalkylation.

The atom transfer radical addition (ATRA) of bromodifluoroacetamides to arylalkynes and terminal alkenes was conducted using von Wangelin's Co catalyst system (CoBr2/1,2-bis(diphenylphosphino)benzene/Zn) in acetone/H2O at 30 °C to afford the corresponding functionalized difluoroacetamides in 33-89% yields. Moreover, the Co catalyst was successfully applied to the tandem addition/cyclization of 1,6-diene and -enyne substrates and intramolecular ATRA of N-allyl and N-propargyl bromodifluoroacetamides, significantly expanding the scope of radical difluoroalkylation.

Iodoperfluoroalkylation of unactivated alkenes via pyridine-boryl radical initiated atom-transfer radical addition.

The pyridine/bis(pinacolate)diboron combination has been found to be able to initiate the iodoperfluoroalkylation of unactivated alkenes with perfluoroalkyl iodides. Theoretical calculations and control experiments indicate that the atom transfer radical addition mechanism is responsible for the formation of iodoperfluoroalkylation products. This metal-free and photo-free strategy is applicable to a wide range of perfluoroalkyl iodides and unactivated alkenes with good functional group tolerance. Further applications in iodoperfluoroalkylation of organic semiconductor-relevant or bioactive molecules demonstrate the synthetic potential of this method.

Copper(ii) complexes of quinoline-based ligands for efficient photoredox catalysis of atom transfer radical addition (ATRA) reaction

Cu(ii)·1Q is efficient in ATRA reactions with perhaloalkanes, revealing the role of common additives (AIBN or inorganic base).

In situ generation of radical initiators using amine-borane complexes for carbohalogenation of alkenes

Atom transfer radical addition of alkyl halides to alkenes was developed using a low amount of a stable initiator, amine borane complexes. Thanks to a slow hydroboration step, the overall carbohalogenation process leads to good isolated yields.

Organocopper(ii) complexes: new catalysts for carbon-carbon bond formation via electrochemical atom transfer radical addition (eATRA).

Organocopper(ii) complexes are a rarity while organocopper(i) complexes are commonplace in chemical synthesis. In the course of building a strategy to generate organocopper(ii) species utilizing electrochemistry, a method to form compounds with CuII–C bonds was discovered, that demonstrated remarkably potent reactivity towards different functionalized alkenes under catalytic control. The role of the organocopper(ii) complex is to act as a source of masked radicals (in this case ˙CH2CN) that react with an alkene to generate the corresponding γ-halonitrile in good yields through atom transfer radical addition (ATRA) to various alkenes. The organocopper(ii) complexes can be continuously regenerated electrochemically for ATRA (eATRA), which proceeds at room temperature, under low Cu loadings (1–10 mol%) and with the possibility of Cu-catalyst recovery.

Engineered myoglobin as a catalyst for atom transfer radical cyclisation.

Myoglobin was subjected to site-directed mutagenesis and transformed into a catalyst able to perform atom transfer radical cyclisation reactions, i.e. intramolecular atom transfer radical additions. Replacing the iron-coordinating histidine with serine, or introducing small changes inside or at the entrance of the active site, transformed the completely inactive wild-type myoglobin into an artificial metalloenzyme able to catalyse the 5-exo cyclisation of halogenated unsaturated compounds for the synthesis of γ-lactams. This new-to-nature activity was achieved not only with purified protein but also in crude cell lysate and in whole cells.

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions-Synthesis and Antibacterial Studies.

Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19–C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.

Meso-Antracenyl-BODIPY Dyad as a New Photocatalyst in Atom-Transfer Radical Addition Reactions.

We demonstrate that because of the efficient generation of triplet excited state under UV or visible-light irradiation, meso-antracenyl-BODIPY donor–acceptor dyad can catalyze atom-transfer radical addition (ATRA) reactions between bromomalonate and alkenes. This finding paves the way for the design and application of the new type of heavy atom-free organic chromophores for photocatalysis.

Photocatalytic Atom‐Transfer Radical Addition of Activated Chlorides to Alkenes

AbstractA protocol for performing atom transfer radical addition of activated alkyl chlorides to alkenes is described. The reaction is promoted by blue light in the presence of an organic photocatalyst (3DPA2FBN), serving to generate free radicals, and a copper complex (IMesCuCl), which facilitates the chlorine transfer step. The reaction works efficiently with fluorinated and non‐fluorinated α‐chloroesters.magnified image

Radical Relay Trichloromethylacylation of Alkenes through N-Heterocyclic Carbene Catalysis.

N-Heterocyclic carbene catalysis enabling vicinal trichloromethylacylation of alkenes using tetrachloromethane and aldehydes has been developed. The reaction involves single electron transfer from the enolate form of the Breslow intermediate to tetrachloromethane to generate the persistent Breslow intermediate-derived ketyl radical and a transient trichloromethyl radical. After radical addition of the trichloromethyl radical to an alkene, the prolonged alkyl radical is preferentially captured by the ketyl radical over tetrachloromethane leading to the atom transfer radical addition product.

Versatile Heteroleptic Cu(I) Complexes Based on Quino(xa)‐line‐Triazole Ligands: from Visible‐Light Absorption and Cooperativity to Luminescence and Photoredox Catalysis

AbstractFour new heteroleptic Cu(I) complexes based on 1, 2, 3‐triazolyl‐quinoline or quinoxaline and a chelating diphosphine were prepared and fully characterised. The mononuclear derivatives absorb in the visible region, up to 600 nm, while the dinuclear complex has a long‐tail absorption up to 800 nm, showing an additional electronic state corroborated by theoretical calculations. Although a methylene group between the triazole and the quino(xa)line moiety increases the bite angle and decreases the luminescence in solution, all complexes emit brightly in the solid‐state. Their redox properties in the excited state were determined, proving their ability in serving as photoredox catalysts in atom transfer radical addition successfully.

The serendipitous effect of KF in Ritter reaction: Photo-induced amino-alkylation of alkenes

SummaryRitter reaction has been recognized as an elegant strategy to construct the C−N bond. Its key feature is forming the carbocation for nucleophilic attack by nitriles. Herein, we report a complementary visible-light-induced three-component Ritter reaction of alkenes, nitriles, and α-bromo nitriles/esters, thereby providing mild and rapid access to various γ-amino nitriles/acids. Mechanistic studies indicated that traceless fluoride relay, transforming KF into imidoyl fluoride intermediate, is critical for the efficient reaction switch from atom transfer radical addition (ATRA) to the Ritter reaction. This approach to amino-alkylation of alkenes is chemoselective and operationally simple.

Photoinduced Atom Transfer Radical Addition Reaction of Olefins with α-Bromo Carbonyls.

The irradiation of halogen-bonded complexes with light leads to the homolysis of carbon-halogen bonds and the formation of the corresponding carbon radical species. However, the only methodology reported for these halogen-bonding complexes is using CBr4 as the halogen-bond donor and its applicability is of great interest. In this study, the atom transfer radical addition (ATRA) reaction of olefins using bromomalonates as halogen-bonding donors was developed. Using 4-phenylpyridine as the halogen-bonding acceptor, the desired reaction proceeded well under external irradiation of 380 nm light to furnish the corresponding ATRA reaction product. The ATRA reaction was effective in generating the corresponding products for a variety of olefins. Furthermore, the ATRA reaction was applicable to bulky ketones, substrates, and malonate esters. The intermediates of the reaction were identified and a plausible reaction mechanism was proposed.

Preparation of Antiproliferative Terpene-Alkaloid Hybrids by Free Radical-Mediated Modification of ent-Kauranic Derivatives.

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C–C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.

Synthesis of ruthenium–dithiocarbamate chelates bearing diphosphine ligands and their use as latent initiators for atom transfer radical additions

Nine representative [Ru(S 2 CNEt 2 ) 2 (diphos)] complexes were prepared in almost quantitative yields (91–97%) from [RuCl 2 ( p -cymene)] 2 , sodium diethyldithiocarbamate trihydrate, and a diphosphine (dppm, dppe, dppp, dppb, dpppe, dppen, dppbz, dppf, or DPEphos), using a novel, straightforward, one-pot procedure. The recourse to a monomodal microwave reactor was instrumental in reaching the thermodynamic equilibria favoring the targeted monometallic trichelates. All the products were fully characterized by using various analytical techniques and the molecular structures of seven of them were determined by X-ray crystallography. NMR, XRD, and IR spectroscopies evidenced a significant contribution of the thioureide resonance form Et 2 N + =CS 2 2– to the electronic structure of the 1,1-dithiolate ligand. MS/MS spectrometry showed the formation of phosphine-free [Ru(S 2 CNEt 2 ) 2 ] + cations in the gas phase, except when starting from [Ru(S 2 CNEt 2 ) 2 (dppbz)]. The activity of the nine complexes was probed in three different catalytic processes, viz. , the cyclopropanation of styrene with ethyl diazoacetate, the synthesis of vinyl esters from benzoic acid and 1-hexyne, and the atom transfer radical addition (ATRA) of carbon tetrachloride and methyl methacrylate. In the first two reactions, the saturated trichelates were poorly efficient. This was most likely due to their high stability, which prevented the formation of coordinatively unsaturated species. Contrastingly, with a turnover number of 2000 and an initial turnover frequency of 2080 h –1 for a 0.05 mol% catalyst loading, the [Ru(S 2 CNEt 2 ) 2 (dppm)] complex emerged as a very robust, latent ATRA initiator, whose activity matched or outperformed those displayed by the most efficient ruthenium catalysts described so far.