Catalytic Hydrogenation of Polyurethanes to Base Chemicals: From Model Systems to Commercial and End-of-Life Polyurethane Materials.

Polyurethane (PU) is a highly valued polymer prepared from diisocyanates and polyols, and it is used in everyday products, such as shoe soles, mattresses, and insulation materials, but also for the construction of sophisticated parts of medical devices, wind turbine blades, aircrafts, and spacecrafts, to name a few. As PU is most commonly used as a thermoset polymer composed of cross-linked structures, its recycling is complicated and inefficient, leading to increasing PU waste accumulating every year. Catalytic hydrogenation represents an atom-efficient means for the deconstruction of polyurethanes, but so far the identification of an efficient catalyst for the disassembly of real-life and end-of-life PU samples has not been demonstrated.

Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides.

A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems.

COtab: Expedient and Safe Setup for Pd-Catalyzed Carbonylation Chemistry.

Bench-stable tablets (COtabs) have been developed for the rapid and safe production of carbon monoxide. The tablets can be made in less than 5 min without the use of a glovebox and only require a stock solution of an amine base to liberate a specific quantity of CO in a two-chamber system. The COtabs were tested in five different carbonylation reactions and provided similar yields compared to literature procedures.

Recent developments in carbonylation chemistry using [ C]CO, [ C]CO, and [ C]CO.

Carbon monoxide represents the most important C1-building block for the chemical industry, both for the production of bulk and fine chemicals, but also for synthetic fuels. Yet its toxicity and subsequently its cautious handling have limited its applications in medicinal chemistry research and in particular for the synthesis of pharmaceutically relevant molecules. Recent years have nevertheless witnessed a considerable headway on the development of carbon monoxide surrogates and reactor systems, which provide an ideal setting for performing carbonylation chemistry with stoichiometric and substoichiometric carbon monoxide.

generation of stoichiometric HCN and its application in the Pd-catalysed cyanation of aryl bromides: evidence for a transmetallation step between two oxidative addition Pd-complexes.

A protocol for the Pd-catalysed cyanation of aryl bromides using near stoichiometric and gaseous hydrogen cyanide is reported for the first time. A two-chamber reactor was adopted for the safe liberation of generated HCN in a closed environment, which proved highly efficient in the Ni-catalysed hydrocyanation as the test reaction. Subsequently, this setup was exploited for converting a range of aryl and heteroaryl bromides (28 examples) directly into the corresponding benzonitriles in high yields, without the need for cyanide salts.

Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts in Batch and Continuous Flow.

Two protocols for the organocatalyzed decarboxylative trichloromethylation of Morita-Baylis-Hillman (MBH) substrates have been developed. Applying sodium trichloroacetate, as the trichloromethyl anion precursor, in combination with an organocatalyst and acetylated MBH-alcohols, the desired trichloromethylated products were obtained in good yields at room temperature in batch. The method was next extrapolated into a two-step continuous flow protocol, starting directly from the MBH alcohols, in combination with tributylamine acting both as base and catalyst.

Cooperative redox activation for carbon dioxide conversion.

A longstanding challenge in production chemistry is the development of catalytic methods for the transformation of carbon dioxide into useful chemicals. Silane and borane promoted reductions can be fined-tuned to provide a number of C1-building blocks under mild conditions, but these approaches are limited because of the production of stoichiometric waste compounds. Here we report on the conversion of CO with diaryldisilanes, which through cooperative redox activation generate carbon monoxide and a diaryldisiloxane that actively participate in a palladium-catalysed carbonylative Hiyama-Denmark coupling for the synthesis of an array of pharmaceutically relevant diarylketones.

Synthesis and selective H-, C-, and N-labeling of the Tau protein binder THK-523.

A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound.

The Development and Application of Two-Chamber Reactors and Carbon Monoxide Precursors for Safe Carbonylation Reactions.

Low molecular weight gases (e.g., carbon monoxide, hydrogen, and ethylene) represent vital building blocks for the construction of a wide array of organic molecules.

Palladium-Catalyzed Carbonylative α-Arylation of tert-Butyl Cyanoacetate with (Hetero)aryl Bromides.

A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl2 and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of (13)C-labeled carbon monoxide generated from (13)COgen, the corresponding (13)C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific (13)C-isotope labeling.

Palladium-catalyzed carbonylative couplings of vinylogous enolates: application to statin structures.

The first Pd-catalyzed carbonylative couplings of aryl and vinyl halides with vinylogous enolates are reported generating products derived from C-C bond formation exclusively at the γ-position. Good results were obtained with a dienolate derivative of acetoacetate (1,3-dioxin-4-one). These transformations occurred at room temperature and importantly with only stoichiometric carbon monoxide in a two-chamber reactor.

Access to 2-(Het)aryl and 2-Styryl Benzoxazoles via Palladium-Catalyzed Aminocarbonylation of Aryl and Vinyl Bromides.

A sequential one-pot procedure for the synthesis of either 2-(hetero)aryl or 2-styryl benzoxazoles is reported, starting from aryl and vinyl bromides, respectively, involving an initial aminocarbonylation with 2-aminophenols as nucleophiles followed by an acid mediated ring closure to generate the heterocycle. The methodology displays a broad substrate scope in moderate to excellent yields and can be exploited for (13)C-isotope labeling. Finally, this carbonylative protocol was applied to the synthesis of a potential Alzheimer's plaque binder and a selective PPAR antagonist including site-specific labeling with (13)C-carbon monoxide.

Synthesis of acyl carbamates via four component Pd-catalyzed carbonylative coupling of aryl halides, potassium cyanate, and alcohols.

A simple and mild method is demonstrated for assembling acyl carbamates through a base-free four-component Pd-catalyzed carbonylation of aryl halides in the presence of potassium cyanate and alcohols in a two-chamber system. This approach produces a wide range of aryl acyl carbamates in good to excellent yields from the corresponding aryl bromides or iodides with near-stoichiometric carbon monoxide. In addition, the method can be extended to the synthesis of primary amides thereby expanding the usefulness of cyanate as an ammonia equivalent.

General method for the preparation of active esters by palladium-catalyzed alkoxycarbonylation of aryl bromides.

A useful method was developed for the synthesis of active esters by palladium-catalyzed alkoxycarbonylation of (hetero)aromatic bromides. The protocol was general for a range of oxygen nucleophiles including N-hydroxysuccinimide (NHS), pentafluorophenol (PFP), hexafluoroisopropyl alcohol (HFP), 4-nitrophenol, and N-hydroxyphthalimide. A high functional group tolerance was displayed, and several active esters were prepared with good to excellent isolated yields.

Palladium-catalyzed carbonylative coupling of (2-azaaryl)methyl anion equivalents with (hetero)aryl bromides.

Conditions for the palladium-catalyzed coupling of (2-pyridyl)acetones with aryl bromides have been developed. Followed by an acid-promoted deacetylation step, the desired 1-(het)aryl-2-(2-pyridyl)ethanones were obtained in good to excellent yields with high functional group tolerance. Test reactions revealed that both the addition of MgCl2 and a specifically positioned heteroatom in the heteroaromatic ring were crucial for product formation indicating the importance of a chelated intermediate in the reaction mechanism.

Two-chamber hydrogen generation and application: access to pressurized deuterium gas.

Hydrogen and deuterium gas were produced and directly applied in a two-chamber system. These gaseous reagents were generated by the simple reaction of metallic zinc with HCl in water for H2 and DCl in deuterated water for D2. The setup proved efficient in classical Pd-catalyzed reductions of ketones, alkynes, alkenes, etc.

Efficient fluoride-catalyzed conversion of CO2 to CO at room temperature.

A protocol for the efficient and selective reduction of carbon dioxide to carbon monoxide has been developed. Remarkably, this oxygen abstraction step can be performed with only the presence of catalytic cesium fluoride and a stoichiometric amount of a disilane in DMSO at room temperature. Rapid reduction of CO2 to CO could be achieved in only 2 h, which was observed by pressure measurements.

Palladium-catalyzed carbonylative sonogashira coupling of aryl bromides using near stoichiometric carbon monoxide.

A general procedure for the palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides is reported, using near stoichiometric amounts of carbon monoxide. The method allows a broad substrate scope in moderate to excellent yields. The formed alkynone motive serves as a platform for synthesis of various heterocyclic structures, including pyrimidines.

Decarboxylative trichloromethylation of aromatic aldehydes and its applications in continuous flow.

Two new protocols for the efficient synthesis of 2,2,2-trichloromethylcarbinols, starting from aromatic aldehydes, have been developed. A combination of sodium trichloroacetate in the presence of malonic acid proved efficient for the transformation of electron deficient aldehydes using DMSO as solvent. Electron-rich aldehydes did, however, not require the addition of malonic acid, affording the desired 2,2,2-trichloromethylcarbinols without a trace of the competing Cannizzaro reaction.

Pd-catalyzed carbonylative α-arylation of aryl bromides: scope and mechanistic studies.

Reaction conditions for the three-component synthesis of aryl 1,3-diketones are reported applying the palladium-catalyzed carbonylative α-arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)2] (dba=dibenzylideneacetone) as the palladium source and 1,3-bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two-chamber reactor, COware, applying only 1.

Generation of stoichiometric ethylene and isotopic derivatives and application in transition-metal-catalyzed vinylation and enyne metathesis.

Ethylene is one of the most important building blocks in industry for the production of polymers and commodity chemicals. (13)C- and D-isotope-labeled ethylenes are also valuable reagents with applications ranging from polymer-structure determination, reaction-mechanism elucidation to the preparation of more complex isotopically labeled compounds. However, these isotopic derivatives are expensive, and are flammable gases, which are difficult to handle.

An air-tolerant approach to the carbonylative Suzuki-Miyaura coupling: applications in isotope labeling.

Carbonylative Suzuki-Miyaura coupling conditions have been developed that proceed without the exclusion of oxygen and in the presence of nondegassed and nondried solvents. By adapting the method to a two-chamber setup, the direct handling of carbon monoxide, produced from stable CO precursors, is avoided. The protocol afforded the desired benzophenones with excellent functional group tolerance and in good yields.

Reductive carbonylation of aryl halides employing a two-chamber reactor: a protocol for the synthesis of aryl aldehydes including 13C- and D-isotope labeling.

A protocol has been developed for conducting the palladium-catalyzed reductive carbonylation of aryl iodides and bromides using 9-methylfluorene-9-carbonyl chloride (COgen) as a source of externally delivered carbon monoxide in a sealed two-chamber system (COware), and potassium formate as the in situ hydride source. The method is tolerant to a wide number of functional groups positioned on the aromatic ring, and it can be exploited for the isotope labeling of the aldehyde group. Hence, reductive carbonylations run with (13)COgen provide a facile access to (13)C-labeled aromatic aldehydes, whereas with DCO2K, the aldehyde is specifically labeled with deuterium.