Photoredox Activation of Organozinc Reagents: Barbier-Type Reaction of Alkyl Halides with α-(Trifluoromethyl)styrenes.

Organozinc reagents may be activated under blue light irradiation using an organic photocatalyst to generate alkyl radicals. The radicals are trapped by α-(trifluoromethyl)styrenes leading to gem-difluorinated products after elimination of fluoride. The reaction can be conveniently performed under Barbier conditions starting from organic iodides and bromides and elemental zinc.

Electrooxidation Is a Promising Approach to Functionalization of Pyrazole-Type Compounds.

The review summarizes for the first time the poorly studied electrooxidative functionalization of pyrazole derivatives leading to the C-Cl, C-Br, C-I, C-S and N-N coupling products with applied properties. The introduction discusses some aspects of aromatic hydrogen substitution. Further, we mainly consider our works on effective synthesis of the corresponding halogeno, thiocyanato and azo compounds using cheap, affordable and environmentally promising electric currents.

Atom-transfer radical addition of fluoroalkyl bromides to alkenes via a photoredox/copper catalytic system.

A method for the addition of fluorinated alkyl bromides to alkenes is described. The reaction proceeds under visible light irradiation in the presence of two catalysts: Ir(ppy)3 and N-heterocyclic carbene ligated copper bromide (IMesCuBr). The role of the iridium photocatalyst is to generate the fluoralkyl radical, while the copper promotes formation of the carbon-bromine bond.

Using the Thiyl Radical for Aliphatic Hydrogen-Atom Transfer: Thiolation of Unactivated C-H Bonds.

A metal- and catalyst-free thiyl-radical-mediated activation of alkanes is described. Tetrafluoropyridinyl disulfide is used to perform thiolation of the C-H bonds under irradiation with 400 nm light-emitting diodes. The key C-H activation step is believed to proceed via hydrogen-atom abstraction effected by the fluorinated thiyl radical. Secondary, tertiary, and heteroatom-substituted C-H bonds can be involved in the thiolation reaction. The resulting sulfides have wide potential as photoredox-active radical precursors in reactions with alkenes and heteroarenes.

A New Method for the Synthesis of 3-Thiocyanatopyrazolo[1,5-a]pyrimidines.

In this article, we demonstrate how an original effective "metal-free" and "chromatography-free" route for the synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines has been developed. It is based on electrooxidative (anodic) C-H thiocyanation of 5-aminopyrazoles by thiocyanate ion leading to 4-thiocyanato-5-aminopyrazoles (stage 1, yields up to 87%) following by their chemical condensation with 1,3-dicarbonyl compounds or their derivatives (stage 2, yields up to 96%). This method is equally effective for the synthesis of 3-thiocyanatopyrazolo[1,5-a]pyrimidines, both without substituents and with various donor (acceptor) substituents in the pyrimidine ring.

Fluoroalkyl sulfides as photoredox-active coupling reagents for alkene difunctionalization.

A visible-light-promoted fluoroalkylation-thiolation of alkenes is described. A 4-tetrafluoropyridinylthio fragment serves as a photoredox-active group in the initiation step and undergoes a radical group transfer, which is important for the reaction efficiency. In the primary products, the pyridinylthio substituent may be further functionalized via radical processes or an aromatic substitution reaction.

Synthesis and Facile Dearomatization of Highly Electrophilic Nitroisoxazolo[4,3-b]pyridines.

A number of novel 6-R-isoxazolo[4,3-b]pyridines were synthesized and their reactions with neutral C-nucleophiles (1,3-dicarbonyl compounds, π-excessive (het)arenes, dienes) were studied. The reaction rate was found to be dependent on the nature of the substituent 6-R. The most reactive 6-nitroisoxazolo[4,3-b]pyridines are able to add C-nucleophiles in the absence of a base under mild conditions. In addition, these compounds readily undergo [4+2]-cycloaddition reactions on aromatic bonds C=C(NO2) of the pyridine ring, thus indicating the superelectrophilic nature of 6-NO2-isoxazolo[4,3-b]pyridines.

Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P-Glycoprotein ABCB5.

This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5-tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively). In some cases, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin, and artesunic acid. Annexin V flow-cytometry analysis revealed that the active ozonides 22 a and 23 a induced cell death of HepG2 by apoptosis. Further study showed that compounds 22 a and 23 a exhibited a strong inhibitory effect on P-glycoprotein (P-gp/ABCB5)-overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug-resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine-sensitive 3D7 strain of Plasmodium falciparum. Stereoisomeric ozonide 12 b is 11 times more active than stereoisomeric ozonide 12 a (IC50 =5.81 vs 65.18 µm). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug-resistant hepatocellular carcinoma.

Visible-Light-Promoted Iododifluoromethylation of Alkenes via (Phosphonio)difluoromethyl Radical Cation.

A reaction of an iododifluoromethylphosphonium salt with unactivated alkenes mediated by peri-xanthenoxanthene under blue-light irradiation is described. The reaction proceeds via activation of the carbon-iodine bond to generate (phosphonio)difluoromethyl radical cation, which attacks the double bond with subsequent quenching by the iodine. The intermediate phosphonium salts are easily hydrolyzed, furnishing products of iododifluoromethylation of alkenes.

Photoredox Reaction of 2-Mercaptothiazolinium Salts with Silyl Enol Ethers.

A method for the generation of free radicals from thiazolinium salts upon photocatalytic reduction is described. The thiazolinium salts are generated by treatment with methyl triflate of 2-mercaptothiazolines, which can be readily obtained from alkyl bromides and tosylates via a nucleophilic substitution reaction or by hydrothiolation of alkenes. Silyl enol ethers were used to trap the radicals, furnishing ketones after successive single-electron oxidation and elimination of the silyl cation.

Electrochemically induced oxidative S-O coupling: synthesis of sulfonates from sulfonyl hydrazides and N-hydroxyimides or N-hydroxybenzotriazoles.

The process of oxidative S-O coupling under the action of electric current was developed. Aryl, hetaryl and alkyl sulfonyl hydrazides and N-hydroxy compounds (N-hydroxyimides and N-hydroxybenzotriazoles) are applied as starting reagents for the preparation of sulfonates. The reaction is carried out under constant current conditions in an experimentally convenient undivided electrochemical cell equipped with a graphite anode and a stainless steel cathode under a high current density (60 mA cm-2). NH4Br in this process acts as a supporting electrolyte and participates in the oxidation of the starting compounds to form a coupling product. The developed strategy represents a quite atom-efficient approach: one partner loses two nitrogen and three hydrogen atoms, while another one loses only one hydrogen atom. Cyclic voltammetry and the control experiment allowed us to propose possible reaction pathways: generated through anodic oxidation molecular bromine or its higher oxidation state derivatives oxidize the starting compounds to form reactive species, which couple to form the S-O bond.

Electrochemically Induced Intermolecular Cross-Dehydrogenative C-O Coupling of ß-Diketones and ß-Ketoesters with Carboxylic Acids.

The electrochemically induced cross-dehydrogenative C-O coupling of ß-diketones and ß-ketoesters (C-H reagents) with carboxylic acids (O-H reagents) was developed. An important feature of this reaction lies in the selective formation of intermolecular C-O coupling products in high yields, up to 92%, using DMSO as a solvent with a broad substrate scope in an undivided cell equipped with carbon and platinum electrodes at high current density. Electric current acts as a stoichiometric oxidant.

A novel photoredox-active group for the generation of fluorinated radicals from difluorostyrenes.

A 4-tetrafluoropyridinylthio group was suggested as a new photoredox-active moiety. The group can be directly installed on difluorostyrenes in a single step by the thiolene click reaction. It proceeds upon visible light catalysis with 9-phenylacridine providing various difluorinated sulfides as radical precursors. Single electron reduction of the C-S bond with the formation of fluoroalkyl radicals is enabled by the electron-poor azine ring. The intermediate difluorinated sulfides were involved in a series of photoredox reactions with silyl enol ethers, alkenes, nitrones and an alkenyl trifluoroborate.

Photoredox generation of the trifluoromethyl radical from borate complexes via single electron reduction.

A method for the generation of the CF3 radical from CF3-substituted borate complexes bearing a pyridine-N-oxide ligand is described. Cleavage of the C-B bond occurs via single electron reduction by a Cu(i) photocatalyst activated by visible light.

Synthesis of 3-Fluoropyridines via Photoredox-Mediated Coupling of α,α-Difluoro-ß-iodoketones with Silyl Enol Ethers.

A method for the synthesis of diversely substituted 3-fluoropyridines from two ketone components is described. The reaction involves photoredox coupling of α,α-difluoro-ß-iodoketones with silyl enol ethers catalyzed by fac-Ir(ppy)3 under blue LED irradiation with subsequent one-pot condensation with ammonium acetate. Based on cyclic voltammetry studies, it was determined that α,α-difluoro-ß-iodoketones are reduced notably easier compared to 2,2,2-trifluoro-1-iodoethane, which may be ascribed to the influence of the carbonyl group.

Synthesis of 3-Fluoroindoles via Photoredox Catalysis.

A method for the synthesis of 3-fluoroindoles from N-arylamines substituted with the CF2I group is described. The reaction is mediated by a ruthenium photocatalyst in the presence of a substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting N-arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions.