Modular Synthesis of Azines Bearing a Guanidine Core from N-Heterocyclic Carbene (NHC)-Derived Selenoureas and Diazo Reagents.

N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.

PtII -N-Heterocyclic Carbene Complexes in Solvent-Free Alkene Hydrosilylation.

Herein, we report the catalytic activity of a series of platinum(II) pre-catalysts, bearing N-heterocyclic carbene (NHC) ligands, in the alkene hydrosilylation reaction. Their structural and electronic properties are fully investigated using X-ray diffraction analysis and nuclear magnetic resonance spectroscopy (NMR). Next, our study presents a structure-activity relationship within this group of pre-catalysts and gives mechanistic insights into the catalyst activation step. An exceptional catalytic performance of one of the complexes is observed, reaching a turnover number (TON) of 970 000 and a turnover frequency (TOF) of 40 417 h-1 at 1 ppm catalyst loading. Finally, an attractive solvent-free and open-to-air alkene hydrosilylation protocol, featuring efficient platinum removal (reduction of residual Pt from 582 ppm to 5.8 ppm), is disclosed.

Unveiling the Potential of Innovative Gold(I) and Silver(I) Selenourea Complexes as Anticancer Agents Targeting TrxR and Cellular Redox Homeostasis.

A series of NHC-based selenourea Ag(I) and Au(I) complexes were evaluated for their anticancer potential in vitro, on 2D and 3D human cancer cell systems. All NHC-based selenourea complexes possess an outstanding cytotoxic potency, which was comparable or even better than that of the reference metallodrug auranofin, and were also able to overcome both platinum-based and multi-drug resistances. Intriguingly, their cytotoxic potency did not correlate with solution stability, partition coefficient or cellular uptake. On the other hand, mechanistic studies in cancer cells revealed their ability to strongly and selectively inhibit the redox-regulating enzyme Thioredoxin Reductase (TrxR), being even more effective than auranofin, a well-known TrxR inhibitor, without affecting other redox enzymes such as Glutathione Reductase (GR). The inhibition of TrxR in H157 human cancer cells caused, in turn, the disruption of cellular thiol-redox homeostasis and of mitochondria pathophysiology, ultimately leading to cancer cell death through apoptosis.

Sustainability in Ru- and Pd-based catalytic systems using N-heterocyclic carbenes as ligands.

This review is a critical presentation of catalysts based on palladium and ruthenium bearing N-heterocyclic carbene ligands that have enabled a more sustainable approach to catalysis and to catalyst uses. Aspects of sustainability associated with these in terms of catalytic uses or synthetic access are reviewed.

Synthetic Access to Aromatic α-Haloketones.

α-Haloketones play an essential role in the synthesis of complex N-, S-, O-heterocycles; of which some exhibit a remarkable biological activity. Research further illustrated that α-bromo-, α-chloro-, and α-iodoketones are key precursors for blockbuster pharmacological compounds. Over the past twenty years, substantial advances have been made in the synthesis of these industrially relevant building blocks. Efforts have focused on rendering the synthetic protocols greener, more effective and versatile. In this survey, we summarised and thoroughly evaluated the progress of the field, established in the past two decades, in terms of generality, efficacy and sustainability.

Synthesis of Gold(I)-Trifluoromethyl Complexes and their Role in Generating Spectroscopic Evidence for a Gold(I)-Difluorocarbene Species.

Readily prepared and bench-stable [Au(CF3 )(NHC)] compounds were synthesized by using new methods, starting from [Au(OH)(NHC)], [Au(Cl)(NHC)] or [Au(L)(NHC)]HF2 precursors (NHC=N-heterocyclic carbene). The mechanism of formation of these species was investigated. Consequently, a new and straightforward strategy for the mild and selective cleavage of a single carbon/fluorine bond from [Au(CF3 )(NHC)] complexes was attempted and found to be reversible in the presence of an additional nucleophilic fluoride source. This straightforward technique has led to the unprecedented spectroscopic observation of a gold(I)-NHC difluorocarbene species.

Simple Synthetic Routes to N-Heterocyclic Carbene Gold(I)-Aryl Complexes: Expanded Scope and Reactivity.

The discovery of sustainable and scalable synthetic protocols leading to gold-aryl compounds bearing N-heterocyclic carbene (NHC) ligands sparked an investigation of their reactivity and potential utility as organometallic synthons. The use of a mild base and green solvents provide access to these compounds, starting from widely available boronic acids and various [Au(NHC)Cl] complexes, with reactions taking place under air, at room temperature and leading to high yields with unprecedented ease. One compound, (N,N'-bis[2,6-(di-isopropyl)phenyl]imidazol-2-ylidene)(4-methoxyphenyl)gold, ([Au(IPr)(4-MeOC6 H4 )]), was synthesized on a multigram scale and used to gauge the reactivity of this class of compounds towards C-H/N-H bonds and with various acids, revealing simple pathways to gold-based species that possess attractive properties as materials, reagents and/or catalysts.

A Mechanistically and Operationally Simple Route to Metal-N-Heterocyclic Carbene (NHC) Complexes.

We have been puzzled by the involvement of weak organic and inorganic bases in the synthesis of metal-N-heterocyclic carbene (NHC) complexes. Such bases are insufficiently strong to permit the presumed required deprotonation of the azolium salt (the carbene precursor) prior to metal binding. Experimental and computational studies provide support for a base-assisted concerted process that does not require free NHC formation. The synthetic protocol was found applicable to a number of transition-metal- and main-group-centered NHC compounds and could become the synthetic route of choice to form M-NHC bonds.

Gold(i) catalysed regio- and stereoselective intermolecular hydroamination of internal alkynes: towards functionalised azoles.

Gold(i) catalysed regio- and stereoselective intermolecular hydroamination of internal alkynes was developed for the effective synthesis of a series of (Z)-functionalised vinylazoles under solvent free conditions. The catalytic hydrogenation of the resulting enamines leads to substituted saturated azoles in good yields.

PMO-Immobilized AuI -NHC Complexes: Heterogeneous Catalysts for Sustainable Processes.

A stable periodic mesoporous organosilica (PMO) with accessible sulfonic acid functionalities is prepared via a one-pot-synthesis and is used as solid support for highly active catalysts, consisting of gold(I)-N-heterocyclic carbene (NHC) complexes. The gold complexes are successfully immobilized on the nanoporous hybrid material via a straightforward acid-base reaction with the corresponding [Au(OH)(NHC)] synthon. This catalyst design strategy results in a boomerang-type catalyst, allowing the active species to detach from the surface to perform the catalysis and then to recombine with the solid after all the starting material is consumed. This boomerang behavior is assessed in the hydration of alkynes. The tested catalysts were found to be active in the latter reaction, and after an acidic work-up, the IPr*-based gold catalyst can be recovered and then reused several times without any loss in efficiency.

A new initiating system based on [(SiMes)Ru(PPh3)(Ind)Cl2] combined with azo-bis-isobutyronitrile in the polymerization and copolymerization of styrene and methyl methacrylate.

The homopolymerization and copolymerization of styrene and methyl methacrylate, initiated for the first time by the combination of azo-bis-isobutyronitrile (AIBN) with [(SiMes)Ru(PPh3)(Ind)Cl2] complex. The reactions were successfully carried out, on a large scale, in presence this complex at 80 °C. It was concluded from the data obtained that the association of AIBN with the ruthenium complex reduces considerably the transfer reactions and leads to the controlled radical polymerization and the well-defined polymers.

Olefin metathesis in air.

Since the discovery and now widespread use of olefin metathesis, the evolution of metathesis catalysts towards air stability has become an area of significant interest. In this fascinating area of study, beginning with early systems making use of high oxidation state early transition metal centers that required strict exclusion of water and air, advances have been made to render catalysts more stable and yet more functional group tolerant. This review summarizes the major developments concerning catalytic systems directed towards water and air tolerance.

Ruthenium indenylidene "1(st) generation" olefin metathesis catalysts containing triisopropyl phosphite.

The reaction of triisopropyl phosphite with phosphine-based indenylidene pre-catalysts affords "1(st) generation" cis-complexes. These have been used in olefin metathesis reactions. The cis-Ru species exhibit noticeable differences with the trans-Ru parent complexes in terms of structure, thermal stability and reactivity. Experimental data underline the importance of synergistic effects between phosphites and L-type ligands.

CuI/Pd0 cooperative dual catalysis: tunable stereoselective construction of tetra-substituted alkenes.

This paper describes a tunable and stereoselective dual catalytic system that uses copper and palladium reagents. This cooperative silylcupration and palladium-catalyzed allylation readily affords trisubstituted alkenylsilanes. Fine-tuning the reaction conditions allows selective access to one stereoisomer over the other. This new methodology tolerates different substituents on both coupling partners with high levels of stereoselectivity. The one-pot reaction involving a Cu(I)/Pd(0) cooperative dual catalyst directly addresses the need to develop more time-efficient and less-wasteful synthetic pathways.

Versatile Cu(I)/Pd(0) dual catalysis for the synthesis of quaternary α-allylated carbonyl compounds: development, mechanistic investigations and scope.

We report herein a versatile cooperative dual catalysis reaction based on a Cu(I)/Pd(0) system. Mechanistic investigation shows that every component plays a crucial role in determining the reaction outcome. The reaction is successfully extended to various substrates; such as α,ß-unsaturated ketones, malonates and coumarins. The strategy tolerates different substitution patterns and affords good yields for each family of substrates.

Synthesis and reactivity of N-heterocyclic carbene (NHC) gold-fluoroalkoxide complexes.

We disclose a novel series of N-heterocyclic carbene (NHC) gold complexes with varied steric and electronic properties, bearing fluorinated alkoxide anions. Early reactivity studies involving these synthons, lead to the synthesis of various complexes of relevance to gold chemistry and catalysis.

Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells.

Under hypoxia, cancer cells consume glucose and release lactate at a high rate. Lactate was recently documented to be recaptured by oxygenated cancer cells to fuel the TCA cycle and thereby to support tumor growth. Monocarboxylate transporters (MCT) are the main lactate carriers and therefore represent potential therapeutic targets to limit cancer progression. In this study, we have developed and implemented a stepwise in vitro screening procedure on human cancer cells to identify new potent MCT inhibitors. Various 7-substituted carboxycoumarins and quinolinone derivatives were synthesized and pharmacologically evaluated. Most active compounds were obtained using a palladium-catalyzed Buchwald-Hartwig type coupling reaction, which proved to be a quick and efficient method to obtain aminocarboxycoumarin derivatives. Inhibition of lactate flux revealed that the most active compound 19 (IC50 11 nM) was three log orders more active than the CHC reference compound. Comparison with warfarin, a conventional anticoagulant coumarin, further showed that compound 19 did not influence the prothrombin time which, together with a good in vitro ADME profile, supports the potential of this new family of compounds to act as anticancer drugs through inhibition of lactate flux.

Simply accessible platinum(II) complexes enabling alkene hydrosilylation at ppm catalyst loadings.

An efficient olefin hydrosilylation protocol utilising Pt(II)-thioether-based pre-catalysts is reported. These simple and readily available complexes exhibit excellent catalytic performance and offer significant advantages over existing alternatives, enabling rapid and high conversions at ppm-level catalyst loadings.

Site selective gold(i)-catalysed benzylic C-H amination via an intermolecular hydride transfer to triazolinediones.

Triazolinediones are known as highly reactive dienophiles that can also act as electrophilic amination reagents towards enolisable C-H bonds (ionic pathway) or weak C-H bonds (free radical pathway). Here, we report that this C-H amination reactivity can be significantly extended and enhanced via gold(i)-catalysis. Under mild conditions, several alkyl-substituted aryls successfully undergo benzylic C-H aminations at room temperature. The remarkable site selectivity that is observed points towards strong electronic activation and deactivation effects, that go beyond a simple weakening of the C-H bond. The observed catalytic C-H aminations do not follow the expected trends for a free radical-type C-H amination and show complementarity to existing methods. Density functional theory (DFT) calculations and distinct experimental trends provide a clear mechanistic rationale for observed selectivity patterns, postulating a novel pathway for triazolinedione-induced aminations via a carbon-to-nitrogen hydride transfer.

Unprecedented copper(I) bifluoride complexes: synthesis, characterization and reactivity.

To be or not to bifluoride: Two synthetic pathways to unprecedented N-heterocyclic carbene copper(I) bifluoride complexes have been developed. Catalytic tests demonstrated that copper(I) bifluorides are very efficient catalysts, which do not require any additional activating agent. The first Cu-catalyzed diastereoselective allylation of (R)-N-tert-butanesulfinyl aldimines was also established. The method enables efficient, simple and general synthesis of enantiomerically enriched homoallylic amines at room temperature in high yields.