Dynamic stereomutation of vinylcyclopropanes with metalloradicals.

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release-a transformation that serves widely as a mechanistic probe (radical clock) for the intermediacy of radicals-we herein show that a metal-based radical, that is, a Ni metalloradical, triggers reversible cis/trans isomerization instead of opening.

Post-Transition-State Dynamic Effects in the Transmetalation of Pd(II)-F to Pd(II)-CF.

The observation of post-transition-state dynamic effects in the context of metal-based transformation is rare. To date, there has been no reported case of a dynamic effect for the widely employed class of palladium-mediated coupling reactions. We performed an experimental and computational study of the trifluoromethylation of PdF, which is a key step in the Pd/Pd-catalyzed trifluoromethylation of aryl halides or acid fluorides.

Machine Learning-Guided Development of Trialkylphosphine Ni Dimers and Applications in Site-Selective Catalysis.

Owing to the unknown correlation of a metal's ligand and its resulting preferred speciation in terms of oxidation state, geometry, and nuclearity, a rational design of multinuclear catalysts remains challenging. With the goal to accelerate the identification of suitable ligands that form trialkylphosphine-derived dihalogen-bridged Ni dimers, we herein employed an assumption-based machine learning approach. The workflow offers guidance in ligand space for a desired speciation without (or only minimal) prior experimental data points.

Access to Cyclic -Trifluoromethyl Ureas through Photocatalytic Activation of Carbamoyl Azides.

We report the mild activation of carbamoyl azides to the corresponding nitrenes using a blue light/[Ir]-catalyzed strategy, which enables stereospecific access to -trifluoromethyl imidazolidinones and benzimidazolones. These novel structural motifs proved to be highly robust, allowing their downstream diversification. On the basis of our combined computational and experimental studies, we propose that an electron rebound with the excited metal catalyst is undergone, involving a reduction-triggered nitrogen loss, followed by oxidation to the corresponding carbamoyl nitrene and subsequent C-H insertion.

Accelerated dinuclear palladium catalyst identification through unsupervised machine learning.

Although machine learning bears enormous potential to accelerate developments in homogeneous catalysis, the frequent need for extensive experimental data can be a bottleneck for implementation. Here, we report an unsupervised machine learning workflow that uses only five experimental data points. It makes use of generalized parameter databases that are complemented with problem-specific in silico data acquisition and clustering.

Air-Stable Pd Dimer Enabled Remote Functionalization: Access to Fluorinated 1,1-Diaryl Alkanes with Unprecedented Speed.

While remote functionalization via chain walking has the potential to enable access to molecules via novel disconnections, such processes require relatively long reaction times and can be in need of elevated temperatures. This work features a remote arylation in less than 10 min reaction time at room temperature over a distance of up to 11 carbons. The unprecedented speed is enabled by the air-stable Pd dimer [Pd(μ-I)(PCy Bu)] , which in contrast to its P Bu counterpart does not trigger direct coupling at the initiation site, but regioconvergent and chemoselective remote functionalization to yield valuable fluorinated 1,1-diaryl alkanes.

Base-Free Cross-Couplings of Aryl Diazonium Salts in Methanol: Pd -Alkoxy as Reactivity-Controlling Intermediate.

Pd-catalyzed cross-coupling reactions of aryl diazonium salts are generally assumed to proceed via cationic Pd intermediates which in turn would be highly reactive in the subsequent transmetalation step. Contrary to this belief, we herein report our observation and rationalization of opposing reactivities of ArN in Suzuki (=effective) and Stille (=ineffective) cross-couplings in MeOH. Our systematic experimental and computational studies on the roles of transmetalating agent, solvent, base and the likely involvement of in situ formed diazoether derivatives challenge the currently accepted mechanism.

Catalysis with Palladium(I) Dimers.

Dinuclear Pd complexes have found widespread applications as diverse catalysts for a multitude of transformations. Initially their ability to function as pre-catalysts for low-coordinated Pd species was harnessed in cross-coupling. Such Pd dimers are inherently labile and relatively sensitive to oxygen.

A Next-Generation Air-Stable Palladium(I) Dimer Enables Olefin Migration and Selective C-C Coupling in Air.

We report a new air-stable Pd dimer, [Pd(μ-I)(PCy Bu)] , which triggers E-selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C-C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C-Br, C-OTf/OFs, and C-Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous Pd dimer generations for substrates that bear substituents ortho to C-OTf.

Selective ortho-Functionalization of Adamantylarenes Enabled by Dispersion and an Air-Stable Palladium(I) Dimer.

Contrary to the general belief that Pd-catalyzed cross-coupling at sites of severe steric hindrance are disfavored, we herein show that the oxidative addition to C-Br ortho to an adamantyl group is as favored as the corresponding adamantyl-free system due to attractive dispersion forces. This enabled the development of a fully selective arylation and alkylation of C-Br ortho to an adamantyl group, even if challenged with competing non-hindered C-OTf or C-Cl sites. The method makes use of an air-stable Pd dimer and enables straightforward access to diversely substituted therapeutically important adamantylarenes in 5-30 min.

Arylation of Axially Chiral Phosphorothioate Salts by Dinuclear Pd Catalysis.

S-aryl phosphorothioates are privileged motifs in pharmaceuticals, agrochemicals, and catalysts; yet, the challenge of devising a straightforward synthetic route to enantioenriched S-aryl phosphorothioates has remained unsolved to date. We demonstrate herein the first direct C-SP(=O)(OR')(OR'') coupling of diverse and chiral phosphorothioate salts with aryl iodides, enabled by an air- and moisture-stable Pd dimer. Our mechanistic and computational data suggest distinct dinuclear Pd catalysis to be operative, which allows for operationally simple couplings with broad scope and full retention of stereochemistry.

-Olefins through intramolecular radical relocation.

Full control over the selectivity of carbon-carbon double-bond migrations would enable access to stereochemically defined olefins that are central to the pharmaceutical, food, fragrance, materials, and petrochemical arenas. The vast majority of double-bond migrations investigated over the past 60 years capitalize on precious-metal hydrides that are frequently associated with reversible equilibria, hydrogen scrambling, incomplete stereoselection, and/or high cost. Here, we report a fundamentally different, radical-based approach.

Chemoselective Pd-Catalyzed C-TeCF Coupling of Aryl Iodides.

While the TeCF moiety features promising properties and potential in a range of applications, no direct synthetic method exists for its incorporation into aromatic scaffolds. This report features the first direct catalytic method for the formation of C(sp )-TeCF bonds. The method relies on a Pd/Xantphos catalytic system and allows for the trifluoromethyltellurolation of aryl iodides.

Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective Alkylation of Aryl Bromides over Triflates and Chlorides in Air.

Disclosed herein is the first general chemo- and site-selective alkylation of C-Br bonds in the presence of COTf, C-Cl and other potentially reactive functional groups, using the air-, moisture-, and thermally stable dinuclear Pd catalyst, [Pd(μ-I)PtBu ] . The bromo-selectivity is independent of the substrate and the relative positioning of the competing reaction sites, and as such fully predictable. Primary and secondary alkyl chains were introduced with extremely high speed (<5 min reaction time) at room temperature and under open-flask reaction conditions.

Mechanistic insights on the Pd-catalyzed addition of C-X bonds across alkynes - a combined experimental and computational study.

The Pd-catalyzed intramolecular addition of carbamoyl chlorides and aryl halides across alkynes is investigated by means of DFT calculations and mechanistic test experiments. The data suggest a mechanistic pathway that involves oxidative addition, alkyne insertion, → isomerization and reductive elimination. Our data indicate that oxidative addition is the reactivity limiting step in the addition of aryl chlorides and bromides across alkynes.

Remote C-H alkylation and C-C bond cleavage enabled by an in situ generated palladacycle.

The direct and selective functionalization of C-H bonds of arenes is one of the most challenging yet valuable aims in organic synthesis. Despite notable recent achievements, a pre-installed directing group proved to be essential in most of the methodologies reported so far. In this context, the use of a transient directing group that can be generated in situ has attracted attention and demonstrated the great potential of this strategy.

Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions.

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C-H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu)}.

Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides.

We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl(PhCN) as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl Pd species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable.

Computation and Experiment: A Powerful Combination to Understand and Predict Reactivities.

Computational chemistry has become an established tool for the study of the origins of chemical phenomena and examination of molecular properties. Because of major advances in theory, hardware and software, calculations of molecular processes can nowadays be done with reasonable accuracy on a time-scale that is competitive or even faster than experiments. This overview will highlight broad applications of computational chemistry in the study of organic and organometallic reactivities, including catalytic (NHC-, Cu-, Pd-, Ni-catalyzed) and noncatalytic examples of relevance to organic synthesis.

An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst.

Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)-catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom-economic addition of a carbamoyl chloride across an alkyne.

Highly Efficient C-SeCF3 Coupling of Aryl Iodides Enabled by an Air-Stable Dinuclear Pd(I) Catalyst.

Building on our recent disclosure of catalysis at dinuclear Pd(I) sites, we herein report the application of this concept to the realization of the first catalytic method to convert aryl iodides into the corresponding ArSeCF3 compounds. Highly efficient C-SeCF3 coupling of a range of aryl iodides was achieved, enabled by an air-, moisture-, and thermally stable dinuclear Pd(I) catalyst. The novel SeCF3 -bridged dinuclear Pd(I) complex 3 was isolated, studied for its catalytic competence and shown to be recoverable.