Do we really need ligands in Ir-catalyzed C-H borylation?

Direct borylation of C-H bonds is a privileged strategy to access versatile building blocks and valuable derivatives of complex molecules (late-stage functionalization, metabolite synthesis). This perspective aims to provide an overview and classification of the catalytic systems developed in this fast-growing area of research. Unexpected selectivity differences between two established directed-borylation systems have been discovered using high-throughput experimentation highlighting the importance of classical control experiments in catalysis research.

Cyclometallated complexes as catalysts for C-H activation and functionalization.

The development of novel catalysts for C-H activation reactions with increased reactivity and improved selectivities has been attracting significant interest over the last two decades. More recently, promising results have been developed using tridentate pincer ligands, which form a stable C-M bond. Furthermore, based on mechanistic studies, the unique catalytic role of some metallacyclic intermediate species has been revealed. These experimental observations have subsequently translated into the rational design of advanced C-H activation catalysts in both Ru- and Ir-based systems. Recent breakthroughs in the field of C-H activation catalysed by metallacyclic intermediates are thus discussed.

Iridium-Catalyzed Acid-Assisted Hydrogenation of Oximes to Hydroxylamines.

We found that cyclometalated cyclopentadienyl iridium(III) complexes are uniquely efficient catalysts in homogeneous hydrogenation of oximes to hydroxylamine products. A stable iridium C,N-chelation is crucial, with alkoxy-substituted aryl ketimine ligands providing the best catalytic performance. Several Ir-complexes were mapped by X-ray crystal analysis in order to collect steric parameters that might guide a rational design of even more active catalysts. A broad range of oximes and oxime ethers were activated with stoichiometric amounts of methanesulfonic acid and reduced at room temperature, remarkably without cleavage of the fragile N-O bond. The exquisite functional group compatibility of our hydrogenation system was further demonstrated by additive tests. Experimental mechanistic investigations support an ionic hydrogenation platform, and suggest a role for the Brønsted acid beyond a proton source. Our studies provide deep understanding of this novel acidic hydrogenation and may facilitate its improvement and application to other challenging substrates.

Iridium-catalyzed acid-assisted asymmetric hydrogenation of oximes to hydroxylamines.

Asymmetric hydrogenations are among the most practical methods for the synthesis of chiral building blocks at industrial scale. The selective reduction of an oxime to the corresponding chiral hydroxylamine derivative remains a challenging variant because of undesired cleavage of the weak nitrogen-oxygen bond. We report a robust cyclometalated iridium(III) complex bearing a chiral cyclopentadienyl ligand as an efficient catalyst for this reaction operating under highly acidic conditions. Valuable N-alkoxy amines can be accessed at room temperature with nondetected overreduction of the N‒O bond. Catalyst turnover numbers up to 4000 and enantiomeric ratios up to 98:2 are observed. The findings serve as a blueprint for the development of metal-catalyzed enantioselective hydrogenations of challenging substrates.

Spiro N-methoxy piperidine ring containing aryldiones for the control of sucking insects and mites: discovery of spiropidion.

BACKGROUND: Crop protection solutions for the control of key economic sucking pests derive essentially from neuronal and muscular acting chemistries, wherein neonicotinoid uses largely dominated for the last two decades. Anticipating likely resistance development of some of those arthropod species to this particular class, we intensified research activities on a non-neuronal site of action targeting insect growth and development some 10 years ago. RESULTS: Our innovation path featured reactivation of a scarcely used and simple building block from the 1960s, namely N-methoxy-4-piperidone 3. Its judicious incorporation into the 2-aryl-1,3-dione scaffold of IRAC group 23 inhibitors of fatty acid biosynthesis resulted in novel tetramic acid derivatives acting on acetyl-coenzyme A carboxylase (ACCase). The optimization campaign focused on modulation of the aryl substitution pattern and understanding substituent options at the lactam nitrogen position of those spiroheterocyclic pyrrolidine-dione derivatives towards an effective control of sucking insects and mites. This work gratifyingly culminated in the discovery of spiro N-methoxy piperidine containing proinsecticide spiropidion 1. Following in planta release, its insecticidally active dione metabolite 2 is translaminar and two-way systemic (both xylem and phloem mobile) for a full plant protection against arthropod pests. CONCLUSION: Owing to such unique plant systemic properties, growing shoots and roots actually not directly exposed to spiropidion-based chemistry after foliar application nevertheless benefit from its long-lasting efficacy. Spiropidion is for use in field crops, speciality crops and vegetables controlling a broad range of sucking pests. In light of other performance and safety profiles of spiropidion, an IPM fit may be expected. © 2020 Society of Chemical Industry.

Herbicidal aryldiones incorporating a 5-methoxy-[1,2,5]triazepane ring.

Novel 2-aryl-cyclic-1,3-diones containing a 5-methoxy-[1,2,5]triazepane unit were explored towards an effective and wheat safe control of grass weeds. Their preparation builds on the ease of synthetic access to 7-membered heterocyclic [1,2,5]triazepane building blocks. Substitution and pattern hopping in the phenyl moiety revealed structure-activity relationships in good agreement with previously disclosed observations amongst the pinoxaden family of acetyl-CoA carboxylase inhibitors. In light of basic physicochemical, enzyme inhibitory and binding site properties, the N-methoxy functionality effectively acts as a bioisostere of the ether group in the seven-membered hydrazine ring.

First report on bio-catalytic N-formylation of amines using ethyl formate.

A bio-catalyzed N-formylation reaction of different amines has been developed using ethyl formate as a formylating agent. This protocol provides a facile and convenient strategy featuring mild reaction conditions, high efficacy, a broad substrate scope and recyclability of lipase. This method also works on a large scale in high yield.

Efficient synthesis of new fluorinated building blocks by means of hydroformylation.

Hydroformylation of fluorinated alkenes is an efficient method for the preparation of fluorinated functionalized building blocks for the synthesis of biologically active target structures. In this article we summarize known hydroformylation reactions of fluorinated olefins and we add new results from our research groups. Particular attention is paid to the remarkable influence of organofluorine substituents on catalyst activity, regio- and stereoselectivity of the hydroformylation reaction.

Combined transition-metal- and organocatalysis: an atom economic C3 homologation of alkenes to carbonyl and carboxylic compounds.

A combination of regioselective room-temperature/ambient-pressure hydroformylation (transition-metal catalysis) and decarboxylative Knoevenagel reactions (organocatalysis) allowed for the development of an efficient, one-pot C3 homologation of terminal alkenes to (E)-alpha,beta-unsaturated acids and esters, (E)-beta,gamma-unsaturated acids, (E)-alpha-cyano acrylic acids, and alpha,beta-unsaturated nitriles. All reactions proceed under mild conditions, tolerate a variety of functional groups, and furnish unsaturated carbonyl compounds in good yields and with excellent regio- and stereocontrol. Further, an iterative C2 homologation of (E)-alpha,beta-unsaturated carboxylic acids is possible through a combination of decarboxylative hydroformylation employing a supramolecular catalyst followed by decarboxylative Knoevenagel condensation with an organocatalyst.

Transition-state stabilization by a secondary substrate-ligand interaction: a new design principle for highly efficient transition-metal catalysis.

A library of monodentate phosphane ligands, each bearing a guanidine receptor unit for carboxylates, was designed. Screening of the library gave some excellent catalysts for regioselective hydroformylation of beta,gamma-unsaturated carboxylic acids. A terminal alkene, but-3-enoic acid, was hydroformylated with a linear/branched (l/b) regioselectivity up to 41. An internal alkene, pent-3-enoic acid was hydroformylated with regioselectivity up to 18:1. Further substrate selectivity (e.g., acid vs. methyl ester) and reaction site selectivity (monofunctionalization of 2-vinylhept-2-enoic acid) were also achieved. Exploration of the structure-activity relationship and a practical and theoretical mechanistic study gave us an insight into the nature of the supramolecular guanidinium-carboxylate interaction within the catalytic system. This allowed us to identify a selective transition-state stabilization by a secondary substrate-ligand interaction as the basis for catalyst activity and selectivity.

All-carbon quaternary centers via ruthenium-catalyzed hydroxymethylation of 2-substituted butadienes mediated by formaldehyde: beyond hydroformylation.

Ruthenium-catalyzed transfer hydrogenation of 2-substituted dienes 1a-i in the presence of paraformaldehyde results in reductive coupling at the 2-position to furnish the hydroxymethylation products 3a-i, which embody all-carbon quaternary centers. Reductive coupling of diene 1g to paraformaldehyde under standard conditions, but employing deuterio-paraformaldehyde, 2-propanol-d(8), or both, corroborated a catalytic mechanism involving rapid, reversible diene hydrometalation with incomplete regioselectivity in advance of C-C coupling. The present method provides an alternative to the hydroformylation of conjugated dienes, for which efficient, regioselective catalytic systems remain undeveloped.