A water-soluble polyphosphorhydrazone Janus dendrimer built by "click" chemistry as support for Ru-complexes in catalysis.

The field of supported catalysis has experienced increased attention with respect to the development of novel architectures for immobilizing catalytic species, aiming to maintain or enhance their activity while facilitating the easy recovery and reuse of the active moiety. Dendrimers have been identified as promising candidates capable of imparting such properties to catalysts through selective functionalization. The present study details the synthesis of two polyphosphorhydrazone (PPH) dendrons, each incorporating azide or acetylene groups at the core for subsequent coupling through "click" triazole chemistry. Employing this methodology, a novel PPH Janus dendrimer was successfully synthesized, featuring ten polyethylene glycol (PEG) chains on one side of the structure and ten Ru(p-cymene) derivatives on the other. This design was intended to confer dual properties, influencing solubility modulation, and allowing the presence of active catalytic moieties. The synthesized dendrimer underwent testing in the isomerization of allyl alcohols in organic solvents and biphasic solvent mixtures. The results demonstrated a positive dendritic effect compared with model monometallic and bimetallic species, providing a proof-of-concept for the first PPH Janus dendrimer with tested applications in catalysis.

A tunable family of CAAC-ruthenium olefin metathesis catalysts modularly derived from a large-scale produced ibuprofen intermediate.

A series of tunable CAAC-based ruthenium benzylidene complexes with increased lipophilicity derived from a ketone being a large-scale produced key substrate for a popular nonsteroidal anti-inflammatory drug-ibuprofen was obtained and tested in various olefin metathesis transformations. As a group, these catalysts exhibited higher activity than their known analogues containing a smaller and less lipophilic phenyl substituent on the α-carbon atom, but in individual reactions, the size of the N-aryl moiety was revealed as a decisive factor. For example, in the cross-metathesis of methyl oleate with ethylene (ethenolysis)-a reaction with growing industrial potential-the best results were obtained when the N-aryl contained an isopropyl or tert-butyl substituent in the ortho position. At the same time, in the RCM, CM, and self-CM transformations involving larger olefinic substrates, the catalysts with smaller aryl-bearing CAAC ligands, where methyl and ethyl groups occupy ortho, ortho' positions performed better. This offers a great deal of tunability and allows for selection of the best catalyst for a given reaction while keeping the general structure (and manufacturing method) of the ibuprofen-intermediate derived CAAC ligand the same.

Unexpected Latency of Z-Stereoretentive Ruthenium Olefin Metathesis Catalysts Bearing Unsymmetrical N-heterocyclic Carbene or Cyclic(alkyl)(amino)carbene Ligands.

A set of ruthenium complexes bearing a CAAC or uNHC ligand and a dithiocatechol fragment have been obtained and characterized spectroscopically. The activity and Z-selectivity of the newly obtained catalysts were studied in selected model CM, self-CM, and RCM olefin metathesis reactions. Intriguingly, and in contrast to structurally related NHC-bearing catalysts Ru4a and Ru4b, the CAAC and uNHC analogues showed no or only very little activity in olefin metathesis. Interestingly, despite being not productive in metathesis reactions conducted in solution, Ru8 enabled the synthesis of a model 16-membered macrocyclic lactone of valuable musk smell with excellent chemoselectivity (no C-C double-bond migration was observed) at a concentration 40 times higher than that typically used by organic chemists in similar macrocyclizations (200 mM instead of 5 mM) with excellent Z-selectivity. Unfortunately, also here the conversion was low.

Strategies for the Preparation of Phosphorus Janus Dendrimers and Their Properties.

Dendrimers, being highly branched monodispersed macromolecules, predominantly exhibit identical terminal functionalities within their structural framework. Nonetheless, there are instances where the presence of two distinct surface functionalities becomes advantageous for the fulfilment of specific properties. To achieve this objective, one approach involves implementing Janus dendrimers, consisting of two dendrimeric wedges terminated by dissimilar functionalities. The prevalent method for creating these structures involves the synthesis of dendrons that possess a core functionality that complements that of a second dendron, facilitating their coupling to generate the desired dendrimers. In this comprehensive review, various techniques employed in the fabrication of phosphorus-based Janus dendrimers are elucidated, displaying the different coupling methodologies employed between the two units. The advantages of phosphorus dendrimers over classic dendrimers will be shown, as the presence of at least one phosphorus atom in each generation allows for the easy monitoring of reactions and the confirmation of purity through a simple technique such as 31P NMR, as these structures typically exhibit easily interpretable patterns.

Protocol for olefin metathesis reactions of hydrophobic substrates performed in aqueous emulsion with mechanical stirring or with microwaves support.

In the presented protocol, we describe the olefin metathesis of hydrophobic substrates in water emulsions using ruthenium catalysts in the presence of air. We detail the testing of mechanical foaming for emulsification and the use of microwave heating to optimize metathesis reaction efficiency. By utilizing relatively low catalyst loading and ensuring simple product isolation, the steps outlined in this protocol extend known methods for the aqueous metathesis techniques. For complete details on the use and execution of this protocol, please refer to Tyszka-Gumkowska et al. (2022).

Testing enabling techniques for olefin metathesis reactions of lipophilic substrates in water as a diluent.

Olefin metathesis reactions of diverse polyfunctional substrates were conducted in water emulsions using two hydrophobic ruthenium catalysts in the presence of air. Instead of using surfactants to increase the efficiency of the metathesis reaction in water, ultrasound and microwave techniques were tested on a small-scale reaction, whereas conventional heating and mechanical stirring were effective enough to provide high conversion and selectivity on a larger scale. The developed conditions extend known protocols for the aqueous metathesis methodology, utilizing relatively low catalyst loadings and allowing for simple product isolation and purification. The established synthetic protocol was successfully adopted in the large-scale synthesis of a pharmaceutically related product - sildenafil (Viagra) derivative.

Ruthenium Olefin Metathesis Catalysts Bearing a Macrocyclic N-Heterocyclic Carbene Ligand: Improved Stability and Activity.

Formation of sterically hindered C-C double bonds via catalytic olefin metathesis is considered a very challenging task for Ru catalysts. This limitation led to the development of specialised catalysts bearing sterically reduced N-heterocyclic carbene (NHC) ligands that are very active in such transformations, yet significantly less stable as compared to general purpose catalysts. To decrease the small-size NHC catalysts susceptibility to decomposition, a new NHC ligand was designed, in which two sterically reduced aryl arms were tied together by a C-8 alkyl chain. The installation of this macrocyclic ligand on the ruthenium centre led to the formation of an olefin metathesis catalyst (trans-Ru6). Interestingly, this complex undergoes transformation into an isomer bearing two Cl ligands in the cis-arrangement (cis-Ru6). These two isomeric complexes exhibit similarly high thermodynamic stability, yet different application profiles in catalysis.

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest.

In recent years, the development of continuous-flow reactors has attracted growing attention from the synthetic community. Moreover, findings in the precise control of the reaction parameters and improved mass/heat transfer have made the flow setup an attractive alternative to batch reactors, both in academia and industry, enabling safe and easy scaling-up of synthetic processes. Even though a majority of the pharmaceutical industry currently rely on batch reactors or semibatch reactors, many are integrating flow technology because of easier maintenance and lower risks. Herein, we demonstrate an operationally simple flow setup for homogeneous ring-closing metathesis, which is applicable to the synthesis of active pharmaceutical ingredients precursors or analogues with high efficiency, low residence time, and in a green solvent. Furthermore, through the addition of a soluble metal scavenger in the subsequent step within the flow system, the level of ruthenium contamination in the final product can be greatly reduced (to less than 5 ppm). To ensure that this method is applicable for industrial usage, an upscale process including a 24 h continuous-flow reaction for more than 60 g of a Sildenafil analogue was achieved in a continuous-flow fashion by adjusting the tubing size and flow rate accordingly.

Synthesis and Catalytic Properties of a Very Latent Selenium-Chelated Ruthenium Benzylidene Olefin Metathesis Catalyst.

Herein, we describe a study of the synthesis, characterization, and catalytic properties of a cis-dichlorido seleno-chelated Hoveyda-Grubbs type complex (Ru8). Such a complex has been obtained through a straightforward and high-yielding synthetic protocol in three steps from the commercially available 2-bromobenzaldehyde in good overall yield (54%). The catalytic profile, especially the latency of this complex, has been probed through selected olefin metathesis reactions such as ring-closing metathesis (RCM), self-cross-metathesis (self-CM) and ring-opening metathesis polymerization (ROMP). In addition to its high latency, the selenium Hoveyda-type complex Ru8 exhibits a switchable behavior upon thermal activation. Of interest, while the corresponding sulfur-chelated Hoveyda type catalyst is reported to be only activated by heat, the selenium analogue was found to be active upon both heat and light irradiation.

Ruthenium Olefin Metathesis Catalysts Featuring N-Heterocyclic Carbene Ligands Tagged with Isonicotinic and 4-(Dimethylamino)benzoic Acid Rests: Evaluation of a Modular Synthetic Strategy.

A modular and flexible strategy towards the synthesis of N-heterocyclic carbene (NHC) ligands bearing Brønsted base tags has been proposed and then adopted in the preparation of two tagged NHC ligands bearing rests of isonicotinic and 4-(dimethylamino)benzoic acids. Such tagged NHC ligands represent an attractive starting point for the synthesis of olefin metathesis ruthenium catalysts tagged in non-dissociating ligands. The influence of the Brønsted basic tags on the activity of such obtained olefin metathesis catalysts has been studied.

Ruthenium Complexes Featuring Unsymmetrical N-Heterocyclic Carbene Ligands-Useful Olefin Metathesis Catalysts for Special Tasks.

This review describes a distinct class of ruthenium olefin metathesis catalysts featuring unsymmetrical N-heterocyclic carbene (uNHC) ligands, from its historical beginning to the present state of the art. Thanks to advantageous traits, such as pronounced thermodynamic stability, chemical latency, outstanding selectivity, and compatibility with green solvents, these catalysts led to good results in a number of specialized metathesis transformations. Therefore, while being a niche, the uNHC complexes can potentially be implemented in a number of industrial processes, such as valorization of Fischer-Tropsch olefin fractions, ethenolysis of renewable products, and modern pharmaceutical production.

Nitro and Other Electron Withdrawing Group Activated Ruthenium Catalysts for Olefin Metathesis Reactions.

Advanced applications of the Nobel Prize winning olefin metathesis reaction require user-friendly and highly universal catalysts. From many successful metathesis catalysts, which belong to the two distinct classes of Schrock and Grubbs-type catalysts, the subclass of chelating-benzylidene ruthenium complexes (so-called Hoveyda-Grubbs catalysts) additionally activated by electron-withdrawing groups (EWGs) provides a highly tunable platform. In the Review, the origin of the EWG-activation concept and selected applications of the resulting catalysts in target-oriented synthesis, medicinal chemistry, as well as in the preparation of fine-chemicals and in materials chemistry is discussed. Based on the examples, some suggestions for end-users regarding minimization of catalyst loading, selectivity control, and general optimization of the olefin metathesis reaction are provided.

4-Methyltetrahydropyran as a Convenient Alternative Solvent for Olefin Metathesis Reaction: Model Studies and Medicinal Chemistry Applications.

A number of metathesis reactions were successfully conducted in 4-methyltetrahydropyran, including both standard model dienes, as well as more complex substrates, such as analogues of biologically active compounds and active pharmaceutical ingredients. To place this solvent in a context of pharmaceutical R + D, larger-scale syntheses of SUAM 1221, a prolyl endopeptidase inhibitor with potential application in Alzheimer disease treatment, and a derivative of sildenafil, an analogue of the popular Viagra drug, were executed. In the latter case, despite all the setup being made in air, the metathesis reaction at a 33 g scale proceeded very well with relatively low catalyst loading and without need of aqueous workup or column chromatography.

Large-Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N-Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context.

A large-scale synthesis of known Ru olefin metathesis catalyst VII featuring an unsymmetrical N-heterocyclic carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP) and one thiophenylmethylene N-substituent is reported. The optimised procedure does not require column chromatography in any step and allows for preparation of up to 0.5 kg batches of the catalyst from simple precursors. The application profile of the obtained catalyst was studied in environmentally friendly dimethyl carbonate (DMC). Although VII exhibited low efficiency in cross-metathesis (CM) with electron-deficient partners, good to excellent results were noted for substrates featuring easy to isomerise C-C double bonds. This includes polyfunctional substrates of medicinal chemistry interest, such as analogues of psychoactive 5F-PB-22 and NM-2201 and two PDE5 inhibitors-Sildenafil and Vardenafil. Finally, a larger scale ring-closing metathesis (RCM) of a Vardenafil derivative was conducted in DMC, allowing for straightforward isolation of the expected product (23 g) in high yield and with low Ru contamination level (7.7 ppm).

Sterically Tuned N-Heterocyclic Carbene Ligands for the Efficient Formation of Hindered Products in Ru-Catalyzed Olefin Metathesis.

Formation of tetrasubstituted C-C double bonds via olefin metathesis is considered very challenging for classical Ru-based complexes. In the hope to improve this condition, three ruthenium olefin metathesis catalysts bearing sterically reduced N-heterocyclic carbene (NHC) ligands with xylyl "arms" were synthesized, characterized using both computational and experimental techniques, and tested in a number of challenging reactions. The catalysts are predicted to initiate much faster than the analogue with mesityl N-substituents. We also foreboded the rotation of xylyl side groups at ambient temperature and the existence of all four atropoisomers in the solution, which was in agreement with experimental data. These catalysts exhibited high activity at relatively low temperatures (45-60 °C) and at reduced catalyst loadings in various reactions of sterically hindered alkenes, including complex polyfunctional substrates of pharmaceutical interest, such as yangonin precursors, chrysantemic acid derivatives, analogues of cannabinoid agonists, α-terpineol, and finally a thermally unstable peroxide.

Preparation of Functionalized α,ß-Unsaturated Sulfonamides via Olefin Cross-Metathesis.

The synthesis of functionalized α,ß-unsaturated sulfonamides by means of cross-metathesis of vinyl sulfonamides and olefins has been developed. The reaction proceeds smoothly in the presence of Hoveyda-Grubbs catalyst and its nitro analogue, providing a wide range of substituted products. The usefulness of this methodology has been proven in the preparation of new derivatives of biologically active ingredients, moxifloxacin and naratriptan.

The Influence of Various N-Heterocyclic Carbene Ligands on Activity of Nitro-Activated Olefin Metathesis Catalysts.

A set of nitro-activated ruthenium-based Hoveyda-Grubbs type olefin metathesis catalysts bearing sterically modified N-hetero-cyclic carbene (NHC) ligands have been obtained, characterised and studied in a set of model metathesis reactions. It was found that catalysts bearing standard SIMes and SIPr ligands (4a and 4b) gave the best results in metathesis of substrates with more accessible C-C double bonds. At the same time, catalysts bearing engineered naphthyl-substituted NHC ligands (4d-e) exhibited high activity towards formation of tetrasubstituted C-C double bonds, the reaction which was traditionally Achilles' heel of the nitro-activated Hoveyda-Grubbs catalyst.

2-Methyltetrahydrofuran as a Solvent of Choice for Spontaneous Metathesis/Isomerization Sequence.

A new protocol for ring-closing metathesis/isomerization sequence was developed. The reactions of selected dienes were performed in overheated 2-methyltetrahydrofuran at 120 °C and provided a wide range of cyclic vinyl ethers and amides with good yields and selectivities. Computational analysis suggests that the relative yield of products depends on a thermodynamically driven process on the basis of relative stabilities of isomers.

Ruthenium Complexes Bearing Thiophene-Based Unsymmetrical N-Heterocyclic Carbene Ligands as Selective Catalysts for Olefin Metathesis in Toluene and Environmentally Friendly 2-Methyltetrahydrofuran.

Three mono-N-heterocyclic carbene (NHC) ruthenium 2-isopropoxybenzylidene (10 a-c) and one bis(NHC) indenylidene complex (8) bearing an unsymmetrical N-heterocyclic carbene ligand were synthesized and structurally characterized by single-crystal X-ray diffraction. The catalytic activity of the newly obtained complexes were evaluated in ring-closing metathesis (RCM) and ene-yne (RCEYM) reactions in toluene and environmentally friendly 2-MeTHF under air. The results confirmed that although all tested reactions can be successfully mediated by catalysts 10 a-c, their general reactivity is lower than the benchmark all-purpose Ru catalysts with symmetrical NHC ligands. However, the latter cannot compete with specialized ruthenium complex 10 a in industrially relevant self-CM of terminal olefins in neat conditions.