Markovnikov-Selective Cobalt-Catalyzed Wacker-Type Oxidation of Styrenes into Ketones under Ambient Conditions Enabled by Hydrogen Bonding.

The replacement of palladium catalysts for Wacker-type oxidation of olefins into ketones by first-row transition metals is a relevant approach for searching more sustainable protocols. Besides highly sophisticated iron catalysts, all the other first-row transition metal complexes have only led to poor activities and selectivities. Herein, we show that the cobalt-tetraphenylporphyrin complex is a competent catalyst for the aerobic oxidation of styrenes into ketones with silanes as the hydrogen sources. Remarkably, under room temperature and air atmosphere, the reactions were exceedingly fast (up to 10 minutes) with a low catalyst loading (1 mol %) while keeping an excellent chemo- and Markovnikov-selectivity (up to 99 % of ketone). Unprecedently high TOF (864 h-1 ) and TON (5,800) were reached for the oxidation of aromatic olefins under these benign conditions. Mechanistic studies suggest a reaction mechanism similar to the Mukaiyama-type hydration of olefins with a change in the last fundamental step, which controls the chemoselectivity, thanks to a unique hydrogen bonding network between the ethanol solvent and the cobalt peroxo intermediate.

Boosting the activity of Mizoroki-Heck cross-coupling reactions with a supramolecular palladium catalyst favouring remote Zn⋯pyridine interactions.

Transition metal catalysis benefitting from supramolecular interactions in the secondary coordination sphere in order to pre-organize substrates around the active site and reach a specific selectivity typically occurs under long reaction times and mild reaction temperatures with the aim to maximize such subtle effects. Herein, we demonstrate that the kinetically labile Zn⋯N interaction between a pyridine substrate and a zinc-porphyrin site serving for substrate binding is a unique type of weak interaction that enables identification of supramolecular effects in transition metal catalysis after one hour at a high reaction temperature of 130 °C. Under carefully selected reaction conditions, supramolecularly-regulated palladium-catalyzed Mizoroki-Heck reactions between 3-bromopyridine and terminal olefins (acrylates or styrenes) proceeded in a more efficient manner compared to the non-supramolecular version. The supramolecular catalysis developed here also displayed interesting substrate-selectivity patterns.

Asymmetric Ruthenium Catalysis Enables Fluorophores with Point Chirality Displaying CPL Properties.

A novel enantiopure π-allylruthenium(IV) precatalyst allowed the enantioselective and stereospecific allylations of indoles and gave access to indolin-3-ones, containing vicinal stereogenic centers. Facile separation of diastereoisomers exhibiting opposite circularly polarized luminescence (CPL) activities in diverse solvents, including water, demonstrated the potential of these sustainable transformations and of the newly prepared molecules.

Electronic, steric and catalytic properties of N-heterocyclic carbene rhodium(I) complexes linked to (metallo)porphyrins.

Electronic and steric properties of NHC ligands functionalized with porphyrins were investigated. When porphyrins are used as NHC-wingtips, nickel(II) in the macrocyle significantly improves the catalytic activity of the neighbouring NHC-Rh(I) complex in the conjugate addition of phenylboronic acid to cyclohexen-2-one.

Sustainable Wacker-Type Oxidations.

The Wacker reaction is the oxidation of olefins to ketones and typically requires expensive and scarce palladium catalysts in the presence of an additional copper co-catalyst under harsh conditions (acidic media, high pressure of air/dioxygen, elevated temperatures). Such a transformation is relevant for industry, as shown by the synthesis of acetaldehyde from ethylene as well as for fine-chemicals, because of the versatility of a carbonyl group placed at specific positions. In this regard, many contributions have focused on controlling the chemo- and regioselectivity of the olefin oxidation by means of well-defined palladium catalysts under different sets of reaction conditions. However, the development of Wacker-type processes that avoid the use of palladium catalysts has just emerged in the last few years, thereby paving the way for the generation of more sustainable procedures, including milder reaction conditions and green chemistry technologies. In this Minireview, we discuss the development of new catalytic processes that utilize more benign catalysts and sustainable reaction conditions.

Unravelling Enzymatic Features in a Supramolecular Iridium Catalyst by Computational Calculations.

Non-biological catalysts following the governing principles of enzymes are attractive systems to disclose unprecedented reactivities. Most of those existing catalysts feature an adaptable molecular recognition site for substrate binding that are prone to undergo conformational selection pathways. Herein, we present a non-biological catalyst that is able to bind substrates via the induced fit model according to in-depth computational calculations. The system, which is constituted by an inflexible substrate-recognition site derived from a zinc-porphyrin in the second coordination sphere, features destabilization of ground states as well as stabilization of transition states for the relevant iridium-catalyzed C-H bond borylation of pyridine. In addition, this catalyst appears to be most suited to tightly bind the transition state rather than the substrate. Besides these features, which are reminiscent of the action modes of enzymes, new elementary catalytic steps (i. e. C-B bond formation and catalyst regeneration) have been disclosed owing to the unique distortions encountered in the different intermediates and transition states.

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Invited for the cover of this issue are Matthieu Jouffroy from Discovery Process Research at Janssen Pharmaceutica N.V. and the group of Rafael Gramage-Doria at the University of Rennes. The image depicts an Ir-based catalytic system "fueled" by hydrogen for the direct reductive amination of ketones and secondary amines, allowing complex aliphatic tertiary amines to be prepared and, so, new chemical space to be reached. Read the full text of the article at 10.1002/chem.202201078.

Iridium-Catalyzed Direct Reductive Amination of Ketones and Secondary Amines: Breaking the Aliphatic Wall.

Direct reductive amination (DRA) is a ubiquitous reaction in organic chemistry. This transformation between a carbonyl group and an amine is most often achieved by using a super stoichiometric amount of hazardous hydride reagents, thus being incompatible with many sensitive functional groups. DRA could also be achieved by means of chemo- or biocatalysis, thereby attracting the interest of industry as well as academic laboratories due to the virtually perfect atom economy. Although DRAs are well-established for substrate pairs such as aldehydes with either 1° or 2° amines as well as ketones with 1° amines, the current methodologies are limited in the case of ketones with 2° amines. Herein, we present a general DRA protocol that overcomes this major limitation by means of iridium catalysis. The applicability of the methodology is demonstrated by accessing an unprecedented range of biologically relevant tertiary amines starting from both aliphatic ketones and aliphatic amines. The choice of a disphosphane ligand (Josiphos A or Xantphos) is essential for the success of the transformation.

Ultrashort Hδ+Hδ- intermolecular distance in a supramolecular system in the solid state.

Herein we report experimental evidence for the shortest intermolecular distance reported for two electronically-different hydrogen atoms in the solid state. The Hδ+Hδ- non-covalent interaction was studied using theoretical calculations indicating that electrostatic and dispersion forces are of paramount importance.

Enzyme-like Supramolecular Iridium Catalysis Enabling C-H Bond Borylation of Pyridines with meta-Selectivity.

The use of secondary interactions between substrates and catalysts is a promising strategy to discover selective transition metal catalysts for atom-economy C-H bond functionalization. The most powerful catalysts are found via trial-and-error screening due to the low association constants between the substrate and the catalyst in which small stereo-electronic modifications within them can lead to very different reactivities. To circumvent these limitations and to increase the level of reactivity prediction in these important reactions, we report herein a supramolecular catalyst harnessing Zn⋅⋅⋅N interactions that binds to pyridine-like substrates as tight as it can be found in some enzymes. The distance and spatial geometry between the active site and the substrate binding site is ideal to target unprecedented meta-selective iridium-catalyzed C-H bond borylations with enzymatic Michaelis-Menten kinetics, besides unique substrate selectivity and dormant reactivity patterns.

Beyond hydrogen bonding: recent trends of outer sphere interactions in transition metal catalysis.

Homogeneous catalytic reactions are typically controlled by the stereoelectronic nature of the ligand(s) that bind to the metal(s). The advantages of the so-called first coordination sphere effects have been used for the efficient synthesis of fine chemicals relevant for industrial and academic laboratories since more than half a century. Such level of catalyst control has significantly upgraded in the last few decades by mastering additional interactions beyond the first coordination sphere. These so-called second coordination sphere effects are mainly inspired by the action mode of nature's catalysts, enzymes, and, in general, rely on subtle hydrogen bonding for the exquisite control of activity and selectivity. In order to span the scope of this powerful strategy to challenges that cannot be solved purely by hydrogen bonding, a variety of less common interactions have been successfully introduced in the last few years for a fine chemical synthesis. This review covers the latest and most exciting developments of this newly flourishing area with a particular focus on highlighting how these types of interactions can be rationally implemented to control the reactivity in a remote fashion, which is far away from the active site similar to what enzymes also do.

Steering Site-Selectivity in Transition Metal-Catalyzed C-H Bond Functionalization: the Challenge of Benzanilides.

Selective C-H bond functionalization catalyzed by metal complexes have completely revolutionized the way in which chemical synthesis is conceived nowadays. Typically, the reactivity of a transition metal catalyst is the key to control the site-, regio- and/or stereo-selectivity of a C-H bond functionalization. Of particular interests are molecules that contain multiple C-H bonds prone to undergo C-H bond activations with very similar bond dissociation energies at different positions. This is the case of benzanilides, relevant chemical motifs that are found in many useful fine chemicals, in which two C-H sites are present in chemically different aromatic fragments. In the last years, it has been found that depending on the metal catalyst and the reaction conditions, the amide motif might behave as a directing group towards the metal-catalyzed C-H bond activation in the benzamide site or in the anilide site. The impact and the consequences of such subtle control of site-selectivity are herein reviewed with important applications in carbon-carbon and carbon-heteroatom bond forming processes. The mechanisms unraveling these unique transformations are discussed in order to provide a better understanding for future developments in the field of site-selective C-H bond functionalization with transition metal catalysts.

C-H Bond Alkylation of Cyclic Amides with Maleimides via a Site-Selective-Determining Six-Membered Ruthenacycle.

The first example of a ruthenium-catalyzed C-H bond alkylation via six-membered ruthenacycles is presented. This is disclosed for the C-H bond alkylation of biologically relevant cyclic amides with maleimide derivatives. The cyclic tertiary amide core acted as a directing group (DG) enabling formation of six-membered cycloruthenated species responsible for the control of the regio- and site selectivity of the reaction as well as the excellent functional group tolerance. Unexpectedly, cyclic amides were found to be better DGs than pyridine-containing ones or cyclic imides for this type of C-H bond functionalization.

Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group.

Biologically relevant N-arylisoindolinones efficiently underwent arylation reactions under ruthenium catalysis via C-H bond functionalization. The reactions exclusively led to monoarylated products, and only ortho selectivity was observed in the aromatic ring connected to the nitrogen atom. Interestingly, no C-H bond functionalization was observed in the other benzene ring in the ortho position with respect to the carbonyl group. This ruthenium-catalyzed reaction displayed a high functional group tolerance, and it employed readily available and benchmark stable boronic acid and potassium aryltrifluoroborate derivatives as coupling partners. An appealing late-stage functionalization of indoprofen applying this methodology is showcased.

Ruthenium(ii)-catalysed selective C(sp2)-H bond benzoxylation of biologically appealing N-arylisoindolinones.

Site- and regio-selective aromatic C-H bond benzoxylations were found to take place using biologically appealing N-arylisoindolinones under ruthenium(ii) catalysis in the presence of (hetero)aromatic carboxylic acid derivatives as coupling partners. Besides the presence of two potential C(sp2)-H sites available for functionalization in the substrates, exclusive ortho selectivity was achieved in the phenyl ring attached to the nitrogen atom. Notably, the reactions occurred in a selective manner as only mono-functionalized products were formed and they tolerated a large number of functional chemical groups. The ability of the cyclic tertiary amide within the isoindolinone skeleton to act as a weak directing group in order to accommodate six-membered ring ruthenacycle intermediates appears to be the key to reach such high levels of selectivity. In contrast, the more sterically demanding cyclic imides were unreactive under identical reaction conditions.

Ru-Catalyzed Selective C-H Bond Hydroxylation of Cyclic Imides.

We report on cyclic imides as weak directing groups for selective monohydroxylation reactions using ruthenium catalysis. Whereas acyclic amides are known to promote the hydroxylation of the C(sp2)-H bond enabling five-membered ring ruthenacycle intermediates, the cyclic imides studied herein enabled the hydroxylation of the C(sp2)-H bond via larger six-membered ruthenacycle intermediates. Furthermore, monohydroxylated products were exclusively obtained (even in the presence of overstoichiometric amounts of reagents), which was rationalized by the difficulty to accommodate coplanar intermediates once the first hydroxyl group was introduced into the substrate. The same reactivity was observed in the presence of palladium catalysts.

A Supramolecular Palladium Catalyst Displaying Substrate Selectivity by Remote Control.

Inspired by enzymes such as cytochrome P-450, the study of the reactivity of metalloporphyrins continues to attract major interest in the field of homogeneous catalysis. However, little is known about benefitting from the substrate-recognition properties of porphyrins containing additional, catalytically relevant active sites. Herein, such an approach is introduced by using supramolecular ligands derived from metalloporphyrins customized with rigid, palladium-coordinating nitrile groups. According to different studies (NMR and UV/Vis spectroscopy, XRD, control experiments), the supramolecular ligands are able to accommodate pyridine derivatives as substrates inside the porphyrin pocket while the reactivity occurs at the peripheral side. By simply tuning a remote metal center, different binding events result in different catalyst reactivity, and this enzyme-like feature leads to high degrees of substrate selectivity in representative palladium-catalyzed Suzuki-Miyaura reactions.

Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n = 2, 3, and 4): Scope, Mechanism, and Application in Tandem Hydrogenations.

A general ruthenium(II)-catalyzed methodology enabling the (hetero)arylation of alkenylic C-H bonds utilizing a series of synthetically appealing diazines as directing groups is presented. Despite the presence of additional nitrogen lone pairs remote from the C-H bond activation site, which could eventually poison the catalyst, the reaction times are short (3 h), thus being suitable for selective double C-H bond arylation. Mixtures of E:Z isomeric products were observed in some cases, which were further hydrogenated in a tandem manner in the presence of the remaining ruthenium catalyst from the first step, representing an alternative approach to more difficult C(sp3)-H bond functionalization. According to mechanistic studies, the unexpected E:Z product formation seems to occur by thermal C═C bond isomerization after the reductive elimination step.