On the Redox Properties of the Dimers of Thiazol-2-ylidenes That Are Relevant for Radical Catalysis.

We report the isolation and study of dimers stemming from popular thiazol-2-ylidene organocatalysts. The model featuring 2,6-di(isopropyl)phenyl (Dipp) N-substituents was found to be a stronger reducing agent (Eox = -0.8 V vs SCE) than bis(thiazol-2-ylidenes) previously studied in the literature. In addition, a remarkable potential gap between the first and second oxidation of the dimer also allows for the isolation of the corresponding air-persistent radical cation. The latter is an unexpected efficient promoter of the radical transformation of α-bromoamides into oxindoles.

Sequential Formation of Heteroternary Cucurbit[10]uril (CB[10]) Complexes.

The globular and monocationic guest molecule trimethyl-azaphosphatrane (AZAP, a protonated Verkade superbase) was shown to form a host:guest 1 : 1 complex with the cucurbit[10]uril (CB[10]) macrocycle in water. Molecular dynamics calculations showed that CB[10] adopts an 8-shape with AZAP occupying the majority of the internal space, CB[10] contracting around AZAP and leaving a significant part of the cavity unoccupied. This residual space was used to co-include planar and monocationic co-guest (CG) molecules, affording heteroternary CB[10]⋅AZAP⋅CG complexes potentially opening new perspectives in supramolecular chemistry.

Metal-Free SF6 Activation: A New SF5 -Based Reagent Enables Deoxyfluorination and Pentafluorosulfanylation Reactions.

The activation of SF6 , a potent greenhouse gas, under metal-free and visible light conditions is reported. Herein, mechanistic investigations including EPR spectroscopy, NMR studies and cyclic voltammetry allowed the rational design of a new fluorinating reagent which was synthesized from the 2-electron activation of SF6 with commercially available TDAE. This new SF5 -based reagent was efficiently employed for the deoxyfluorination of CO2 and the fluorinative desulfurization of CS2 allowing the formation of useful fluorinated amines. Moreover, for the first time we demonstrated that our SF5 -based reagent could afford the mild generation of Cl-SF5 gas. This finding was exploited for the chloro-pentafluorosulfanylation of alkynes and alkenes.

Beyond-Use Dates Assignment for Pharmaceutical Preparations: Example of Low-Dose Amiodarone Capsules.

Background: Beyond-use dates (BUDs) in compounding practice are assigned from stability studies. The United States Pharmacopoeia (USP 42 NF 37) suggested to assign a 6 months BUD for dry oral forms. A new pediatric formula of amiodarone capsules was implemented in our hospital, with 3 dosages (5 mg, 20 mg, and 50 mg). Objective: BUD of these new formulas had to be determined by stability study. Methods: The method for the determination of amiodarone content was validated to be stability indicating, and a stability study was performed. Different excipients commonly used for capsule compounding were compared. Results: We found that, with microcrystalline cellulose as excipient, 50 mg amiodarone capsules were stable for 1 year, whereas 5 mg and 20 mg capsules were not. This difference was studied, and lactose or mannitol were found to be better excipients for 5 mg amiodarone capsules, despite their potential side effects. A potential drug-excipient interaction between microcrystalline cellulose and amiodarone hydrochloride is described. Conclusion: Amiodarone hydrochloride/microcrystalline cellulose capsules have a BUD of 1 month for 5 mg capsules, 6 months for 20 mg, and 1 year for 50 mg.

Critical Assessment of the Reducing Ability of Breslow-type Derivatives and Implications for Carbene-Catalyzed Radical Reactions*.

We report the synthesis of acyl azolium salts stemming from thiazolylidenes CNS , triazolylidenes CTN, mesoionic carbenes CMIC and the generation of their corresponding radicals and enolates, covering about 60 Breslow-type derivatives. This study highlights the role of additives in the redox behavior of these compounds and unveils several critical misconceptions about radical transformations of aldehyde derivatives under N-heterocyclic carbene catalysis. In particular, the reducing ability of enolates has been dramatically underestimated in the case of biomimetic CNS . In contrast with previous electrochemical studies, we show that these catalytic intermediates can transfer electrons to iodobenzene within minutes at room temperature. Enols derived from CMIC are not the previously claimed super electron donors, although enolate derivatives of CNS and CMIC are powerful reducing agents.

Switching from Single to Simultaneous Free-Radical and Anionic Polymerization with Enamine-Based Organic Electron Donors.

Although most monomers can polymerize through different propagation pathways, polymerization-initiating systems that can switch from one mode to another are rare. In this study, we demonstrate that enamine-based organic electron donors (OEDs) constitute the first systems able to initiate either free-radical or anionic polymerization under simple, mild, and safe conditions. While direct electron-transfer reduction of monomers by OEDs results in the initiation of anionic chain-growth polymerization, introduction of a competing oxidant with a higher reduction potential than the monomer switches the former anionic propagation to a clean radical-propagation process. The benefit of this dual-mode activator is highlighted in the synthesis of an interpenetrating polymer network through simultaneous initiation of radical and anionic propagation processes.

Metal-Free Addition of Benzyl Halides to Aldehydes Using Super Electron Donors: Access to 3,4-Dihydroisocoumarins and 1,2-Diarylethanols.

We report here the intermolecular metal-free addition reaction of functionalized benzyl halides to aldehydes using a super electron donor (SED). The metal-free and mild conditions allowed the formation of 3,4-dihydroisocoumarins and 1,2-diarylethanols with unprecedented functional group tolerance.

Sequential Regioselective Diorganochalcogenations of Imidazo[1,2-a]pyrimidines Using I2/H3PO4 in Dimethylsulfoxide.

The dichalcogenation of imidazoheterocycles led to the first functionalization of imidazo[1,2-a]pyrimidine cores on the C6-position. The methodology, involving iodine/dimethylsulfoxide oxidation of diaryldichalcogenides, started with C3-chalcogenation, followed by C6 selanylation, activated in acidic medium. This novel sequential dichalcogenation strategy proceeded efficiently with excellent regioselectivity and yields.

Base-Free Generation of Organic Electron Donors from Air-Stable Precursors.

Organic electron donors (OEDs) are powerful reducing agents recognized for their potential in the reduction of challenging substrates and in original applications. Nonetheless, their low stability in atmospheric oxygen or over time complicates their manipulation and storage. To overcome these constraints and enhance OED practicality, new air- and moisture-stable aminopyridinium carboxylate and carbonate precursors were synthesized and thermally activated to generate the potent electron donor in situ. Carboxylate adducts proved to be excellent latent OED systems, enabling the facile and efficient reduction of challenging substrates. Their reduction properties were correlated to their structural characteristics by thermogravimetric and spectroscopic analysis.

Polymerization Initiated by Organic Electron Donors.

Polymerization reactions with organic electron donors (OED) as initiators are presented herein. The metal-free polymerization of various activated alkene and cyclic ester monomers was performed in short reaction times, under mild conditions, with small amounts of organic reducing agents, and without the need for co-initiators or activation by photochemical, electrochemical, or other methods. Hence, OED initiators enabled the development of an efficient, rapid, room-temperature process that meets the technical standards expected for industrial processes, such as energy savings, cost-effectiveness and safety. Mechanistic investigations support an electron-transfer initiation pathway that leads to the reduction of the monomer.

Studies toward the oxidative and reductive activation of C-S bonds in 2'-S-aryl-2'-thiouridine derivatives.

Studies directed toward the oxidative and reductive desulfurization of readily available 2'-S-aryl-2'-thiouridine derivatives were investigated with the prospect to functionalize the C2'-position of nucleosides. The oxidative desulfurization-difluorination strategy was successful on 2-(arylthio)alkanoate surrogates, while extension of the combination of oxidants and fluoride sources was not an efficient fluorination protocol when applied to 2'-S-aryl-2'-thiouridine derivatives, resulting mainly in C5-halogenation of the pyrimidine ring and C2'-monofluorination without desulfurization. Cyclic voltammetry of 2'-arylsulfonyl-2'-deoxyuridines and their 2'-fluorinated analogues showed that cleavage of the arylsulfone moiety could occur, although at relatively high cathodic potentials. While reductive-desulfonylation of 2'-arylsulfonyl-2'-deoxyuridines with organic electron donors (OEDs) gave predominantly base-induced furan type products, chemical (OED) and electrochemical reductive-desulfonylation of the α-fluorosulfone derivatives yielded the 2'-deoxy-2'-fluorouridine and 2',3'-didehydro-2',3'-dideoxy-2'-fluorouridine derivatives. These results provided good evidence of the generation of a C2'-anion through carbon-sulfur bond cleavage, opening new horizons for the reductive-functionalization approaches in nucleosides.

Synthesis and in vitro evaluation of 4-trichloromethylpyrrolo[1,2-a]quinoxalines as new antiplasmodial agents.

Thanks to a preliminary in vitro screening of several CCl3-substituted-nitrogen containing heterocycles belonging to our chemical library, the 2-trichloromethylquinoxaline scaffold appeared to be of potential interest for developing new antiplasmodial agents. Then, combining these experimental results to the antimalarial properties reported for various pyrrolo[1,2-a]quinoxaline derivatives, an original series of fifteen 7-substituted-4-trichoromethylpyrrolo[1,2-a]quinoxalines was synthesized in a 4 to 5 reaction steps pathway. All molecules were evaluated in vitro toward both their antiplasmodial activity on the K1 multi-resistant Plasmodium falciparum strain and their cytotoxicity on the HepG2 human cell line. Thus, 3 hit molecules were identified, displaying IC50 values in the micromolar range and low cytotoxicity values, reaching good selectivity indexes, in comparison with the reference drugs chloroquine and doxycycline. Structure-activity relationship studies showed that the pyrrolo[1,2-a]quinoxaline scaffold can support selective antiplasmodial activity when substituted at position 4 by a CCl3 group. However, substitution at position 7 of the same scaffold is neither beneficial for cytotoxicity nor favourable for the solubility in the biological media.

Organic electron donors as powerful single-electron reducing agents in organic synthesis.

One-electron reduction is commonly used in organic chemistry for the formation of radicals by the stepwise transfer of one or two electrons from a donor to an organic substrate. Besides metallic reagents, single-electron reducers based on neutral organic molecules have emerged as an attractive novel source of reducing electrons. The past 20 years have seen the blossoming of a particular class of organic reducing agents, the electron-rich olefins, and their application in organic synthesis. This Review gives an overview of the different types of organic donors and their specific characteristics in organic transformations.

The isolation of [Pd{OC(O)H}(H)(NHC)(PR3)] (NHC = N-heterocyclic carbene) and its role in alkene and alkyne reductions using formic acid.

The [Pd(SIPr)(PCy3)] complex efficiently promotes a tandem process involving dehydrogenation of formic acid and hydrogenation of C-C multiple bonds using H2 formed in situ. The isolation of a key catalytic hydridoformatopalladium species, [Pd{OC(O)H}(H)(IPr)(PCy3)], is reported. The complex plays a key role in the Pd(0)-mediated formation of hydrogen from formic acid. Mechanistic and computational studies delineate the operational role of the palladium complex in this efficient tandem sequence.

Novel antiviral C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates.

Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 µM) and against varicella zoster virus in vitro (IC(50) = 0.19 µM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.

The influence of phosphane ligands on the versatility of ruthenium-indenylidene complexes in metathesis.

The aim of the present study is to develop readily available and stable pre-catalysts that could be easily prepared on large scale from simple starting materials. Based on the hypothesis that substitution of classical PCy(3) with phosphanes of varying electron-donating properties could be a straightforward manner to improve catalytic activity, a methodical study dealing with the effect of phosphane fine-tuning in ruthenium-indenylidene catalysts was performed. Challenged to establish how the electronic properties of para-substituted phosphane ligands translate into catalyst activity, the versatile behaviour of these new ruthenium-indenylidene complexes was investigated for a number of metathesis reactions.

Alkyne-azide click chemistry mediated carbanucleosides synthesis.

Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a significant antiviral activity.

Study of different copper (I) catalysts for the "click chemistry" approach to carbanucleosides.

We compare herein the scope of three copper (I) catalysts on the synthesis of various 1,4-disubstitued-1,2,3-triazolo-carbanucleosides through a microwave (and thermic) assisted Huisgen 1,3-dipolar cycloaddition. The tetrakis(acetonitrile)copper hexafluorophosphate ([Cu(CH3CN)4]PF6), the imidazoline(mesythyl)copper bromide (Imes)CuBr, and the copper/copper sulfate Cu(0)/CuSO4 (II) mixture have been chosen for this study. Their influence in a catalytic amount will be analyzed according to the substituent of the alkyne, the solvent, or the heating method.