Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

The combination of the ferrocene moiety with gold(I) catalysis remains a relatively unexplored field. In this article, we delve into the synthesis, characterization, and potential catalytic activity of four complexes utilizing both monodentate and bidentate ferrocenyl diphenylphosphane ligands (ppf and dppf), coordinated with two gold(I) metal centers, linked by either chloride or pentafluorophenylthiolate bridging ligands. This leads to the formation of cationic "self-activated" precatalysts capable of initiating the catalytic cycle without the need for external additives. The catalytic activity of these complexes was assessed through a model reaction in gold(I) catalysis, specifically the cyclization of a N-propargylbenzamide to produce an oxazole. In addition, we studied and compared the influence exerted by both the phosphane and the bridging ligand on the performance of these catalysts.

The Potential of Self-Activating Au(I) Complexes in Gold Catalysis.

Gold catalysis has emerged as a groundbreaking field in synthetic chemistry, revolutionizing numerous organic transformations. Despite the significant achieved advancements, the mechanistic understanding behind many gold-catalyzed reactions remains elusive. This Concept article covers the so-called "self-activating" Au(I) complexes, sorting out their pivotal role in gold catalysis. We comment on how Au(I) complexes can undergo self-activation, triggering diverse catalytic transformations without the need for external additives. The most important examples reported so far that underlie the catalytic activity of these species are discussed. This intrinsic reactivity represents a paradigm shift in gold catalysis, offering new avenues for the design of efficient and sustainable catalytic systems. Furthermore, we explore the factors influencing the stability, reactivity, and selectivity of these Au(I) complexes, providing insights into their synthetic utility and potential applications. This area of research not only advances our fundamental understanding of gold catalysis but also paves the way for the development of novel catalytic strategies with broad implications in organic synthesis and the chemical industry.

Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

Invited for the cover of this issue are the groups of Raquel P. Herrera and M. Concepción Gimeno at the Instituto de Síntesis Química y Catálisis Homogénea (University of Zaragoza-CSIC). The image depicts the light of the full moon illuminating a bridge between the gold(I) metal centers. Two dragons, symbolizing the use of bridging ligands, confront each other to determine the ultimate victor. Read the full text of the article at 10.1002/chem.202303585.

Main Avenues in Gold Coordination Chemistry.

In this contribution, we provide an overview of the main avenues that have emerged in gold coordination chemistry during the last years. The unique properties of gold have motivated research in gold chemistry, and especially regarding the properties and applications of gold compounds in catalysis, medicine, and materials chemistry. The advances in the synthesis and knowledge of gold coordination compounds have been possible with the design of novel ligands becoming relevant motifs that have allowed the preparation of elusive complexes in this area of research. Strong donor ligands with easily modulable electronic and steric properties, such as stable singlet carbenes or cyclometalated ligands, have been decisive in the stabilization of gold(0) species, gold fluoride complexes, gold hydrides, unprecedented π complexes, or cluster derivatives. These new ligands have been important not only from the fundamental structure and bonding studies but also for the synthesis of sophisticated catalysts to improve activity and selectivity of organic transformations. Moreover, they have enabled the facile oxidative addition from gold(I) to gold(III) and the design of a plethora of complexes with specific properties.

Gold-Catalyzed 1,3-Thiazine Formation and Uncommon Tautomer Isolation.

This work represents the first example of a gold-catalyzed formation of 1,3-thiazine/1,3-thiazinane by means of a catalytic approach and further uncommon isolation of the two tautomers. The developed protocol gives rise to a broad scope of 1,3-thiazine derivatives with excellent yields in short reaction times. Interestingly, different isomers could be obtained depending on the state of the compound, and in the crystal state the 1,3-thiazinane isomer is obtained, while in solution the 1,3-thiazine is the unique isomer. This work represents an interesting approach for the synthesis of potential biologically relevant molecules and a crucial precedent in tautomerism isolation and characterization.

Stereoselective Three-Step One-Pot Cascade Combining Amino- and Biocatalysis to Access Chiral γ-Nitro Alcohols.

The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due to both compatibility of reaction conditions and complementary reactivity. Herein, we describe the telescopic synthesis of chiral nitro alcohols starting from commercially available benzaldehyde derivatives through the one-pot three-step chemoenzymatic cascade combination of a Wittig reaction, chiral-thiourea-catalysed asymmetric conjugate addition, and ketoreductase-mediated reduction to access the corresponding target compounds in moderate to excellent overall isolated yields (36-80 %) and high diastereomeric and enantiomeric ratios (up to >97 : 3). This represents the first example of the combination of an organocatalysed asymmetric conjugate addition via iminium ion activation and a bioreduction step catalysed by ketoreductases.

Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties.

In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with T1, in particular the complexes [AuT1(PPh3)]OTf, the bis(thiourea) [Au(T1)2]OTf and the gold-thiolate species [Au(SR)T1]. In contrast, with T2 better results are obtained with silver species [AgT1(PPh3)]OTf and the [Ag(T1)2]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents.

Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies.

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted ß-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Simple iodoalkyne-based organocatalysts for the activation of carbonyl compounds.

A novel approach for the formation of bisindolylmethane derivatives (BIMs) is described as a proof of concept to evaluate the catalytic capacity of iodoalkynes. The use of these derivatives is reported as an example of simple halogen bond-based organocatalyst. This kind of activation has not been used before for the synthesis of bisindolylmethane derivatives 3. Interestingly, the preparation of 3-(1H-indol-3-yl)-1-phenylbutan-1-one (8) has been also achieved for the first time with an iodoalkyne derivative. We prove the efficiency of this family of new catalysts by developing a simple and easy operational methodology, opening the door to the development of alternative catalysts in the area of halogen bond-based organocatalysts.

Novel ureido-dihydropyridine scaffolds as theranostic agents.

In this work, the synthesis of interesting urea derivatives 5 based on 1,4-dihydropyridines 3 is described for the first time. Considering that both families exhibit potential as drugs to treat various diseases, their activity as anticancer agents has been evaluated in HeLa (cervix), Jurkat (leukaemia) and A549 (lung) cancer cell lines as well as on healthy mice in vivo. In general, whereas 1,4-dihydropyridines show a moderate cytotoxic activity, their urea analogues cause an extraordinary increase in their antiproliferative activity, specially towards HeLa cells. Because of the chiral nature of these compounds, enantiomerically enriched samples were also tested, showing different cytotoxic activity than the racemic mixture. Although the reason is not clear, it could be caused by a complex amalgam of physical and chemical contributions. The studied compounds also exhibit luminescent properties, which allow performing a biodistribution study in cancer cells. They have emission maxima between 420 and 471 nm, being the urea derivatives in general red shifted. Emission quenching was observed for those compounds containing a nitro group (3e,f and 5e,f). Fluorescence microscopy showed that 1,4-dihydropyridines 3a and 3g localised in the lysosomes, in contrast to the urea derivatives 5h that accumulated in the cell membrane. This different distribution could be key to explain the differences found in the cytotoxic activity and in the mechanism of action. Interestingly, a preliminary in vivo study regarding the acute toxicity of some of these compounds on healthy mice has been conducted, using a concentration up to 7200 times higher than the corresponding IC50 value. No downgrade in the welfare of the tested mice was observed, which could support their use in preclinical tumour models.

Thiolate Bridged Gold(I)-NHC Catalysts: New Approach for Catalyst Design and its Application to Trapping Catalytic Intermediates.

New dinuclear N-heterocyclic gold complexes with bridging thiolate ligands have been designed as catalytic precursors with desired properties such as stability, recyclability and that do not require additives. The dinuclear compound [(AuNHC)2 (µ-SC6 F5 )]OTf could slowly release the active catalytic species [Au(NHC)]+ and the precursor [Au(SC6 F5 )(NHC)] in solution, which means that both species would remain stable throughout the catalytic cycle and the pre-catalyst could easily be recovered. The properties exhibited by the complexes have been taken advantage of to gain new insights on the gold-catalyzed hydroalkoxylation of alkynes, with the aim of clarifying all the steps of the catalytic cycle, together with the characterization of intermediates and final products. Isolation and characterization of the pure final spiroketals and the thermodynamic intermediate have been achieved for the first time. Moreover, the kinetic intermediate has also been detected for the first time.

Gold Catalyzed Multicomponent Reactions beyond A³ Coupling.

The preparation of complex architectures has inspired the search for new methods and new processes in organic synthesis. Multicomponent reactions have become an interesting approach to achieve such molecular diversity and complexity. This review intends to illustrate important gold-catalyzed examples for the past ten years leading to interesting skeletons involved in biologically active compounds.

Synthesis and supramolecular self-assembly of glutamic acid-based squaramides.

We describe the preparation and characterization of two new unsymmetrical squaramide-based organogelators. The synthesis of the compounds was carried out by subsequent amine condensations starting from dimethyl squarate. The design of the gelators involved a squaramide core connected on one side to a long aliphatic chain and on the other side to a glutamic acid residue. The gelator bearing the free carboxylic groups showed a lower gelation capacity than its precursor diester derivative. Some selected gels were further studied by infrared spectroscopy, rheology and electron microscopy. Critical gelation concentrations and gel-to-sol transition temperatures were also determined for each case. In addition, the superior squaramide diester gelator was compared with an analogue triazole-based gelator in terms of critical gelation concentration, gelation kinetics and thermal phase transition.

Optimizing the Accuracy and Computational Cost in Theoretical Squaramide Catalysis: The Henry Reaction.

This study represents the first example where the accuracy of different combinations of density functional theory (DFT) methods and basis sets have been compared in squaramide catalysis. After an optimization process of the precision obtained and the computational time required in the computational calculations, highly precise results were achieved compared to the experimental outcomes while requiring the least amount of time possible. Here, we have explored computationally and experimentally the mechanism of the squaramide-catalyzed Henry reaction. This is a complex reaction of about 100 atoms and a great number of diverse non-covalent interactions. Moreover, this research is one of the scarce examples where the organocatalyst acts in a trifunctional manner and is the first investigation in which a trifunctional squaramide catalyst has been employed. Functional ωB97X-D showed the best results when used with different versions of the 6-311 basis sets, leading to highly accurate calculations of the outcomes of the Henry reaction when using nine aldehydes with different structural characteristics. Furthermore, in these relatively large systems, the use of a split-valence triple-zeta basis set saves a large amount of time compared with using larger basis sets that are sometimes employed in organocatalytic studies, such as the TZV and Def2TZV basis set families.

Organocatalytic Hydrophosphonylation Reaction of Carbonyl Groups.

This revision is covering the limited examples reported for a pivotal strategy in the formation of C-P bonds such as the asymmetric organocatalytic hydrophosphonylation of carbonyl groups (Pudovik reaction). The scope and limitations, and the proposed mechanisms for the scarce different possibilities of asymmetric induction are also shown. The recent evolution and future trends of this undeveloped approach are commented.

Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives.

The first cinchona-alkaloid-organocatalyzed enantioselective synthesis of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona catalyst 3b activates the Michael addition reaction between malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very few examples of the synthesis of chiral 1,4-dihydropyridines by an enantioselective catalytic procedure. The highly substituted final compounds are of interest for their potential biological activity. This efficient protocol opens the door to a new area of research for the asymmetric construction of these skeletons for which enantioselective syntheses are still very limited.

Direct Substitution of Alcohols in Pure Water by Brønsted Acid Catalysis.

With the increasing concern for sustainability, the use of environmentally friendly media to perform chemical processes has attracted the attention of many research groups. Among them, the use of water, as the unique solvent for reactions, is currently an active area of research. One process of particular interest is the direct nucleophilic substitution of an alcohol avoiding its preliminary transformation into a good leaving group, since one of the by-products in this approach would be water. The direct substitution of allylic, benzylic, and tertiary alcohols has been achieved through SN1-type reactions with catalytic amounts of Brønsted or Lewis acids; however, organic solvents are often required. In this review, the pioneering SN1 approaches performed in pure water and in the absence of a metal based Lewis acid are compiled and discussed.

Self-assembled fibrillar networks of a multifaceted chiral squaramide: supramolecular multistimuli-responsive alcogels.

Chiral N,N'-disubstituted squaramide has been found to undergo self-assembly in a variety of alcoholic solvents at low concentrations leading to the formation of novel nanostructured supramolecular alcogels. The gels responded to thermal, mechanical, optical and chemical stimuli. Solubility studies, gelation ability tests and computer modeling of a series of structurally related squaramides proved the existence of a unique combination of non-covalent molecular interactions and favorable hydrophobic/hydrophilic balance in that drive the anisotropic growth of alcogel networks. The results have also revealed a remarkable effect of ultrasound on both the gelation kinetics and the properties of the alcogels.

Fluoride Anion Recognition by a Multifunctional Urea Derivative: An Experimental and Theoretical Study.

In this work we demonstrate the ability of a multifaceted N,N'-disubstituted urea to selectively recognize fluoride anion (F(-)) among other halides. This additional function is now added to its already reported organocatalytic and organogelator properties. The signaling mechanism relies on the formation of a charge-transfer (CT) complex between the urea-based sensor and F¯ in the ground state with a high association constant as demonstrated by absorption and fluorescence spectroscopy. The nature of the hydrogen bonding interaction between the sensor and F¯ was established by ¹H-NMR studies and theoretical calculations. Moreover, the recovery of the sensor was achieved by addition of methanol.

The aminoindanol core as a key scaffold in bifunctional organocatalysts.

The 1,2-aminoindanol scaffold has been found to be very efficient, enhancing the enantioselectivity when present in organocatalysts. This may be explained by its ability to induce a bifunctional activation of the substrates involved in the reaction. Thus, it is easy to find hydrogen-bonding organocatalysts ((thio)ureas, squaramides, quinolinium thioamide, etc.) in the literature containing this favored structural core. They have been successfully employed in reactions such as Friedel-Crafts alkylation, Michael addition, Diels-Alder and aza-Henry reactions. However, the 1,2-aminoindanol core incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts.