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An operationally simple, user and eco-friendly synthetic protocol for the synthesis of [Rh(acac)(CO)(NHC)] complexes is described. Insights into the mechanism are provided using operando spectroscopy. The spectroscopic fingerprints of these complexes are correlated to NHCs reported electron-donating descriptor values, highlighting a new strategy to evaluate carbenes' electronic properties. An assessment of these complexes in catalytic applications is also reported, showing promising results in the catalytic hydrogenation of aromatic ketones.

The use of weak and inexpensive bases has recently opened promising perspectives towards the simpler and more sustainable synthesis of Au(I)-aryl complexes with valuable applications in catalysis, medicinal chemistry, and materials science. In recent years, continuous manufacturing has shown to be a reliable partner in establishing sustainable and controlled process scalability. Herein, the first continuous flow synthesis of a range of Au(I)-aryl starting from widely available boronic acids and various [Au(NHC)Cl] (NHC=N-heterocyclic carbene) complexes in unprecedentedly short reaction times and high yields is reported. Successful synthesis of previously non- or poorly accessible complexes exposed fascinating reactivity patterns. Via a gram-scale synthesis, convenient process scalability of the developed protocol was showcased.

The modularity and ease of synthesis of carbene-metal-amide (CMA) complexes based on the coinage metals (Au, Ag, Cu) and N-heterocyclic carbenes (NHCs) as ancillary ligands pave the way for the expansion of their applications beyond photochemistry and catalysis. Herein, we further improve the synthesis of such compounds by circumventing the use of toxic organic solvents which were previously required for their purification, and we expand their scope to include complexes incorporating carbolines as the amido fragments. The novel complexes are screened both in vitro and ex vivo, against several cancer cell lines and high-grade serous ovarian cancer (HGSOC) tumoroids, respectively. Excellent cytotoxicity values are obtained for most complexes, while the structural variety of the CMA library screened thus far, provides promising leads for future developments. Variations of all three components (NHC, metal, amido ligand), enable the establishment of trends regarding cytotoxicity and selectivity towards cancerous over normal cells.

We report herein the biological activities of several imidazolium aurate(I) salts. The cytotoxicity on three cell-lines (i. e. Hela, H460 and 3T3), enzyme inhibition on a panel of five enzymes (i. e. prolyl endopeptidase, butyrylcholinesterase, tyrosinase, dipeptidyl peptidase and carbonic anhydrase), iron chelation and in vitro Leishmanicidal assay for promastigotes are described. A comparison with other data found in the literature using similar standards to our control experiment is also discussed. Finally, all these data lead us to establish some structure-activity correlations and to determine the potential importance of the gold moiety in these salts.

A straightforward methodology for the decarboxylative cross-coupling of aryl bromides and phenylpropiolic acid using a Pd(II)-NHC catalyst has been developed. Various aryl bromides have been successfully transformed into the corresponding di-substituted alkynes using environmentally benign conditions (weak base and ethanol as solvent). This efficient catalytic system also proved useful for the copper-free Sonogashira coupling of aryl and alkenyl bromides with various terminal alkynes. The synthetic utility of these methodologies was highlighted in the synthesis of a polyaromatic compound and various fluoroenynes.

The functionalization of alkynes by Au (N-heterocyclic carbene, NHC) complexes via the hydrophenoxylation reaction is a paradigm for the discussion between mono and dual metal catalysis. With the aim of mimicking the framework containing two gold units, achieved with molecular boxes, two NHC ligands were joined here with a chelated chain and this motif was examined in the hydrophenoxylation/hydroalkoxylation reactions through DFT calculations. This synthetic motif transforms the standard hydrophenoxylation intermolecular reaction from an inter- into an intra-molecular nucleophilic attack, when forming the C–O bond. Various chain lengths were tested with regard to the coordination of the alkyne to the cationic NHC-gold(I) center Institucio Catalana de Recerca i Estudis Avançats (ICREA), Grant/Award Number: ICREA Academia 2019; Generalitat de Catalunya, Grant/Award Numbers: 2017SGR348, 2017SGR39; Ministerio de Economía y Competitividad (MINECO) of Spain, Grant/Award Numbers: CTQ2017-85341-P, MDM-2017-0767, PGC2018-097722-B-I00, PID-2019-106830GB-I00, PID2020-113711GB-I00 Open Access funding provided thanks to the CRUE-CSIC agreement with Wiley

We report a combined experimental and computational investigation of the Suzuki-Miyaura cross-coupling of amides enabled by [Pd(NHC)(allyl)Cl] precatalysts. Most crucially, mechanistic details pertaining to the Pd-0/NHC catalytic cycle were elucidated by computational methods. Mechanistic insights shed light on the role of each ligand about the metal. Sterics play a key role in the initial activation of the catalyst. As a key insight, we have shown that water participates in the activation of the Pd-NHC catalytic system. Easier activation has led to effect room temperature cross-coupling of a broad range of amides through selective N-C bond scission under the mildest conditions reported to date. The use of sterically hindered [Pd(IPr*)(cin)Cl] reported herein for the first time in the amide cross-coupling indicates that increasing flexible steric bulk of the isopropyl wingtip groups of the NHC ligand provides a modular scaffold for promoting amide cross-coupling in high yields. The precatalytic pathway involving both NHC ligands as well as the catalytic cycle beginning from the Pd-0 species are discussed. The mechanistic details provide insight into the amide bond twist (distortion) that leads to N-C cross-coupling reactions and is required for the efficient N-C bond activation.

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.

The authors gratefully acknowledge the European Commission (EC) for funding through the seventh framework program SYNFLOW, the European Research Council (ERC) (Advanced Investigator Award “FUNCAT” to S. P. N.), The Engineering and Physical Sciences Research Council (EPSRC) and AstraZeneca (Studentship to C. M. Z.). The influence of C4,5-halogenation on palladium N-heterocyclic carbene complexes and their activity in the Suzuki-Miyaura reaction have been investigated. Two [Pd(NHC)(cin)Cl] complexes bearing IPrCl and IPrBr ligands were synthesized. After determining electronic and steric properties of these ligands, their properties were compared to those of [Pd(IPr)(cin)Cl]. The three palladium complexes were studied using DFT calculations to delineate their behaviour in the activation step leading to the putative 12-electron active catalyst. Experimentally, their catalytic activity in the Suzuki-Miyaura reaction involving a wide range of coupling partners (30 entries) at low catalyst loading was studied. Postprint

The authors acknowledge FAPERJ for providing research grants and financial support. MB thanks the School of Chemistry and EaStCHEM for support and for access to a computer cluster maintained by Dr H. Früchtl. JWMC acknowledges CNPq for a research grant. The experimental work was supported via our membership of the UK Catalysis Hub consortium funded by EPSRC (grants EP/K014706/2, EP/K014668/1, EP/K014854/1 and EP/K014714/1). SPN gratefully acknowledges the European Commission for support in the form of an ERC Advanced Researcher grant (227817-FUNCAT). A new mechanism is proposed for the Ni-catalysed carboxylation of organoboronates with CO2. DFT investigations at the PBE0-D3 level have shown that direct CO2 addition to the catalysts [Ni(NHC)(Allyl)Cl] (1NHC, NHC = IMe, IPr, SIPr and IPr*) is kinetically disfavored and formation of the Aresta-type intermediate is unlikely to occur. According to the mechanism proposed here, the carboxylation process starts with addition of the borate species to 1NHC, followed by transmetalation, CO2 cycloaddition and carboxylation. The rate-determining step was identified as being the transmetalation process, with computed relative free energy barriers of 34.8, 36.8 and 33.5 kcal mol-1 for 1IPr, 1SIPr and 1IPr*, respectively Postprint

The aim of this research is to evaluate for the first time the in vitro leishmanicidal activity and inhibition of α-glucosidase and β-glucuronidase of new gold(I) and gold(III) complexes involving N-heterocyclic carbene (NHC) ligands, with the general formula [Au(X)n(NHC)R2][BF4] (X=Cl, OAc, R=various aromatic and aliphatic substituents). The Au(III) complexes were shown to have a significant antileishmanial activity, and were also found to be more potent inhibitors of α-glucosidase and β-glucuronidase enzymes than the standard drugs. Some complexes were also identified as potent anti-inflammatory agents with activity comparable to that of tested standard drugs, allopurinol and ibuprofen. These gold complexes were also evaluated for their in vitro cytotoxic activity against HeLa (cervical cancer), MCF-3 (breast cancer), and 3T3 (mouse fibroblast) cell lines.

We have synthesized and characterized new gold-N-heterocyclic carbene (NHC) complexes derived from the deprotonation of mineral acids. The use of sulfuric acid was a particularly interesting case. These complexes were tested in known gold-catalyzed reactions, such as the hydration of alkynes and the Meyer–Schuster rearrangement. They proved to be highly efficient in both reactions.

The improved synthesis of γ-, δ- and ϵ-lactones using a dinuclear N-heterocyclic carbene (NHC)-gold(I) catalyst is reported. This solvent-free process provides access to γ- and δ-lactones in high regio- and stereoselectivity. Reactions were performed at low catalyst loadings and without the need for any additives. The use of a digold pre-catalyst provides a new synthetic route to functionalised ϵ-lactones, poorly accessible using previous methodologies.

Several hitherto unknown acyclic 2-methyl-but-2-enyl nucleoside phosphonate analogs (ANPs) and their bis-(pivaloyloxymethyl) prodrug forms were prepared by a challenging ultrasonic-assisted olefin cross metathesis and further modifications under microwaves, giving rise to a small library of title compounds. These ANPs were evaluated against a wide spectrum of DNA/RNA viruses. Among them, the most active compound exhibited a micromolar anti-HIV-1 activity with an EC50 of 1.1 µM and an EC90 of 4.2 µM.

This report describes the evaluation of the biological activities of 13 gold-NHC complexes. These complexes were evaluated in vitro for their antioxidant properties, α-glucosidase, thymidine phosphorylase, β-glucuronidase and xanthine oxidase enzyme inhibition activities. Among the tested complexes, those bearing chloride ligands were found to be potent antioxidant, α-glucosidase, thymidine phosphorylase, β-glucuronidase and xanthine oxidase enzyme inhibitors, showing several hundred fold higher activity than the standard drugs. Some of these complexes were found to be potent antileishmanial agents, which were superior to standard antileishmanil drugs. These gold complexes were also evaluated for their in vitro cytotoxic activity against PC-3 (normal cells), HeLa (cervical cancer), MCF-3 (breast cancer) and 3T3 (mouse fibroblast) cell lines.

KGaA, Weinheim.Herein, we present a detailed investigation of the mechanistic aspects of the dual gold-catalysed hydrophenoxylation of alkynes by both experimental and computational methods. The dissociation of [{Au(NHC)}2(μ-OH)][BF4] is essential to enter the catalytic cycle, and this step is favoured by the presence of bulky, non-coordinating counter ions. Moreover, in silico studies confirmed that phenol does not only act as a reactant, but also as a co-catalyst, lowering the energy barriers of several transition states. A gem-diaurated species might form during the reaction, but this lies deep within a potential energy well, and is likely to be an "off-cycle" rather than an "in-cycle" intermediate A.P. thanks the Spanish MINECO (project CTQ2014-59832-JIN and FEDER grant UNGI10-4E-801 and the European Commission for a Career Integration Grant (CIG09-GA-2011-293900)

The use of the ITent-based series of Pd-N-heterocyclic carbenes precatalysts (Tent= Tentacular) enables the Buchwald–Hartwig amine arylation reaction in apolar alkane solvents. The use of such solvents is rare because of their poor solvation properties. Nonetheless, they could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. The excellent solubility of the precatalysts permitted the desired products to be obtained in yields ranging from 75 to 96 %, even with deactivated and functionalized coupling partners.

We gratefully acknowledge the EC for funding through the seventh framework program SYNFLOW, the ERC (Advanced Investigator Award ‘FUNCAT’ to SPN) and the EPSRC. S.P.N. is a Royal Society Wolfson Research Merit Award holder.

The authors thank the ERC (Advanced Researcher award-FUNCAT), 7th Framework Program NMP2-LA-2010-246461 (SYNFLOW), the EPSRC and King Saud University for funding. A general methodology for the α-arylation of ketones using a nickel catalyst has been developed. The new well-defined [Ni(IPr*)(cin)Cl] (1c) pre-catalyst showed great efficiency for this transformation, allowing the coupling of a wide range of ketones, including acetophenone derivatives, with various functionalised aryl chlorides. This cinnamyl-based Ni(NHC) complex has demonstrated a different behaviour to previously reported NHC-Ni catalysts. Preliminary mechanistic studies suggest a Ni0/NiII catalytic cycle to be at play. Postprint

The authors thank the EPSRC and the ERC (FUNCAT) for funding. S.P.N. is a Royal Society Wolfson Merit Award holder. A mechanistic study of the gold-catalysed protodecarboxylation is described. Each reaction step has been investigated experimentally and computationally. More specifically, the activation parameters for the decarboxylation step have been determined through kinetic studies. Further experimental studies on the hydrolysis of the arylgold intermediate have revealed that the protodeauration can become competitive with the decarboxylation process at high conversions. This switch in rate-limiting step has been shown to be pKa-dependent. These studies have been supported by DFT calculations and permit a better understanding of which prevalent features of the reaction mechanism account for the decarboxylation process. Postprint

The authors thank the ERC (Advanced Researcher award-FUNCAT), 7th Framework Program NMP2-LA-2010–246461 (SYNFLOW) and King Saud University for funding. A general catalytic protocol for the a-arylation of aryl ketones has been developed. It involves the use of a preformed, bench-stable Pd–N-heterocyclic carbene precatalyst bearing IHept as an ancillary ligand, and allows the coupling of various functionalized coupling partners at very low catalyst loading. Careful choice of the solvent/base system was crucial to obtain optimum catalyst performance. The pre-catalyst was also successfully tested in the synthesis of an industrially relevant compound. Postprint

A new synthetic protocol that combines the advantages offered by eco-friendly solvent-free reactions and sequential transformations is reported. This strategy offers straightforward access to benzo[c]chromenes and benzo[b]furans from commercially available starting materials. This two-step, one-pot strategy consists of an Au-catalyzed hydrophenoxylation process followed by Pd-catalyzed C-H activation or Mizoroki-Heck reactions. The selectivity of the process towards C-H activation or Mizoroki-Heck reaction can be easily tuned.

A synthetic protocol making use of a well-defined cationic ruthenium complex 2 enabling the racemization of enantiomerically pure secondary alcohols in the presence of a weak base (K2CO3) is described. The compatibility of 2 with Candida Antarctica lipase B (Novozym 435) allows the development of an efficient dynamic kinetic resolution of sec-alcohols in the absence of an additional strong base. This procedure involves the first example of a dynamic kinetic resolution of alcohols in the presence of a cationic ruthenium catalyst. In addition, we describe the conversion of ketones to the enantioenriched acetates in a one-pot reaction, probing the versatility of complex 2.

Two new [Ni(allyl)Cl(NHC)] complexes with the bulky yet flexible N-heterocyclic carbene (NHC) ligands IPr* {N,N'-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazole-2-ylidene} and IPr*OMe {N,N'-bis[2,6-bis(diphenylmethyl)-4-methoxyphenyl]imidazol-2-ylidene} are reported. These complexes were employed in the amination and sulfination of aryl halide species and were shown to perform well in these reactions, which typically required less than half as much catalyst as previous state-of-the-art nickel complexes.

Several hitherto unknown acyclic 2-methyl-but-2-enyl nucleoside phosphonate analogs (ANPs) and their bis-(pivaloyloxymethyl) prodrug forms were prepared by a challenging ultrasonic-assisted olefin cross metathesis and further modifications under microwaves, giving rise to a small library of title compounds. These ANPs were evaluated against a wide spectrum of DNA/RNA viruses. Among them, the most active compound exhibited a micromolar anti-HIV-1 activity with an EC50 of 1.1 µM and an EC90 of 4.2 µM.

Golden delivery: A gold(I)-NHC complex catalyses the protodecarboxylation of various (hetero)aromatic acids. This methodology is simple, highly efficient and combines both the advantages of copper and silver methods with applications to completely deactivated substrates. Moreover, intermediates in this reaction have been isolated and fully characterized and provide fundamental insights into the mechanism of protodecarboxylation with gold.

The title method gives aryl vinyl ethers in high yields, short reaction times, Z-stereoselectivity, and good regioselectivity.

A general synthetic route was used to prepare 15 new N-heterocyclic carbene (NHC) silver(I) complexes bearing anionic carboxylate ligands, [Ag(NHC)(O2CR)], including a homologous series of complexes of sterically flexible ITent ligands, permitting a systematic spectroscopic and theoretical study of the structural and electronic structures of these compounds. The complexes displayed significant ligand accelerated effect in the intramolecular cyclisation of propargylic amides to oxazolidines. The substrate scope is highly complementary to that achieved previously by NHC-Au and pyridyl-silver(I) complexes.

The use of the ITent-based series of Pd-N-heterocyclic carbenes precatalysts (Tent= Tentacular) enables the Buchwald–Hartwig amine arylation reaction in apolar alkane solvents. The use of such solvents is rare because of their poor solvation properties. Nonetheless, they could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. The excellent solubility of the precatalysts permitted the desired products to be obtained in yields ranging from 75 to 96 %, even with deactivated and functionalized coupling partners.

The intermolecular α-allylation of oxazolidinone derived allenamides with diaryl substituted allylic alcohols is optimized.

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.

Indoles from scratch: A gold(I)/N-heterocyclic carbene complex (IPr=1,3-di(isopropylphenyl)imidazol-2-ylidene) was found to be particularly effective as a catalyst, enabling the one-pot synthesis of tricyclic azepinoindoles by an unprecedented cascade reaction. Readily available substrates, high chemoselectivity, good yields, and water as the only stoichiometric by-product are some of the main advantages of this method.

The well-defined [Pd(IPr*)(cinnamyl)Cl] complex is reported as one of the best N-heterocyclic carbene (NHC)-based pre-catalysts for the Buchwald–Hartwig amination reaction. This catalytic system displays high efficiency for the coupling of numerous (hetero)aryl chlorides, with a wide range of amines, at room temperature or at extremely low catalyst loading (as low as 0.025 mol%).

The first nickel catalyzed deprotonative cross coupling of imines with aryl chlorides in the absence of a directing group is reported.