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. In this work, we reveal that a commercially available catalyst, Ir- iPrMACHO, under 30 bar H2 and 150-180 °C, is a general catalyst for the effective hydrogenation of the four cornerstones of PU: flexible solid, flexible foamed, rigid solid, and rigid foamed, leading to the isolation of aromatic amines and a polyol fraction. For the first time, a variety of commercial PU materials, including examples of foams, inline skating wheels, shoe soles, and insulation materials, has been deconstructed into the two fractions. Most desirable, our reaction conditions include the use of isopropyl alcohol as a representative of a green solvent. It is speculated that a partial glycolysis at the surface of the PU particles is taking place in this solvent and reaction temperatures in the presence of catalytic amounts of base. As such a more efficient hydrogenation of the solubilized PU fragments in isopropyl alcohol becomes possible. As the isolated anilines are precursors to the original isocyanate building blocks, and methods for their conversion are well-known, the work reported in this paper provides a realistic indication of a potential circular plastic economy solution for PU. Preliminary experiments were also undertaken applying Mn- iPrMACHO for the deconstruction of a commercial flexible PU foam. Although successful, more forcing conditions were required than those when applying Ir- iPrMACHO.

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. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.

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. Finally, a gram-scale reaction was conducted, as well as 13C-isotope labeling of the anticancer drug, olaparib.

Recent developments in carbonylation chemistry using [13 C]CO, [11 C]CO, and [14 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. Such setups are particularly ideal for the introduction of isotope labels such as carbon-11, carbon-13, and carbon-14 into bioactive compounds. This review summarizes this growing field and examines the large number of carbonylation reactions that can be exploited for the introduction of a carbon isotope.

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. The flow process proved superior to the batch approach, reducing the reaction time from 16 hours to only 20 minutes, with increased yields for all investigated entries. Two examples were also taken to scale-up in flow producing more than 10 grams of both trichloromethylated targets. Finally, substitution of the organocatalyst to (DHQ)2 PHAL or (DHQD)2 PHAL induced chiral transfer to the generated stereocenter in the reaction attaining selectivities with nearly 90 % ee.

Synthesis and selective 2 H-, 13 C-, and 15 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 13 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. Iridium-catalyzed hydrogen isotope exchange (HIE) reactions were performed on THK-523 and its 13 C-labeled analog providing access to 4 additional analogues labeled with deuterium as well. Finally, by applying a Buchwald-Hartwig coupling, we were able to prepare a 15 N-THK-523 variant with the isotope label in the quinoline ring system.

Ex situ 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 ex situ 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. Cyanation was achieved employing the Pd(0) precatalyst, P(tBu)3-Pd-G3 and a weak base, potassium acetate, in a dioxane-water solvent mixture. The methodology was also suitable for the synthesis of 13C-labelled benzonitriles with ex situ generated 13C-hydrogen cyanide. Stoichiometric studies with the metal complexes were undertaken to delineate the mechanism for this catalytic transformation. Treatment of Pd(P(tBu)3)2 with H13CN in THF provided two Pd-hydride complexes, (P(tBu)3)2Pd(H)(13CN), and [(P(tBu)3)Pd(H)]2Pd(13CN)4, both of which were isolated and characterised by NMR spectroscopy and X-ray crystal structure analysis. When the same reaction was performed in a THF : water mixture in the presence of KOAc, only (P(tBu)3)2Pd(H)(13CN) was formed. Subjection of this cyano hydride metal complex with the oxidative addition complex (P(tBu)3)Pd(Ph)(Br) in a 1 : 1 ratio in THF led to a transmetallation step with the formation of (P(tBu)3)2Pd(H)(Br) and 13C-benzonitrile from a reductive elimination step. These experiments suggest the possibility of a catalytic cycle involving initially the formation of two Pd(ii)-species from the oxidative addition of L n Pd(0) into HCN and an aryl bromide followed by a transmetallation step to L n Pd(Ar)(CN) and L n Pd(H)(Br), which both reductively eliminate, the latter in the presence of KOAc, to generate the benzonitrile and L n Pd(0).

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 CO2 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. Thus the disilane reagent not only serves as the oxygen abstracting agent from CO2, but the silicon-containing 'waste', produced through oxygen insertion into the Si-Si bond, participates as a reagent for the transmetalation step in the carbonylative coupling. Hence this concept of cooperative redox activation opens up for new avenues in the conversion of CO2.

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. Whereas experimental organic chemists routinely handle solid and liquid reagents, the same is not the case for gaseous reagents. Synthetic transformations employing such reagents are commonly conducted under pressure in autoclaves or under atmospheric pressure with a balloon setup, which necessitates either specialized equipment or potentially hazardous and nonrecommended installations. Other safety concerns associated with gaseous reagents may include their toxicity and flammability and, with certain gases, their inability to be detected by human senses. Despite these significant drawbacks, industrial processes apply gaseous building blocks regularly due to their low cost and ready availability but nevertheless under a strictly controlled manner. Carbon monoxide (CO) fits with all the parameters for being a gas of immense industrial importance but with severe handling restrictions due to its inherent toxicity and flammability. In academia, as well as research and development laboratories, CO is often avoided because of these safety issues, which is a limitation for the development of new carbonylation reactions. With our desire to address the handling of CO in a laboratory setting, we designed and developed a two-chamber reactor (COware) for the controlled delivery and utilization of stoichiometric amounts of CO for Pd-catalyzed carbonylation reactions. In addition to COware, two stable and solid CO-releasing molecules (COgen and SilaCOgen) were developed, both of which release CO upon activation by either Pd catalysis or fluoride addition, respectively. The unique combination of COware with either COgen or SilaCOgen provides a simple reactor setup enabling synthetic chemists to easily perform safe carbonylation chemistry without the need for directly handling the gaseous reagent. With this technology, an array of low-pressure carbonylations were developed applying only near stoichiometric amounts of carbon monoxide. Importantly, carbon isotope variants of the CO precursors, such as (13)COgen, Sila(13)COgen, or even (14)COgen, provide a simple means for performing isotope-labeling syntheses. Finally, the COware applicability has been extended to reactions with other gases, such as hydrogen, CO2, and ethylene including their deuterium and (13)C-isotopically labeled versions where relevant. The COware system has been repeatedly demonstrated to be a valuable reactor for carrying out a wide number of transition metal-catalyzed transformations, and we believe this technology will have a significant place in many organic research laboratories.

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 ß-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. The methodology was applied to the synthesis of two members of the statin family generating the cis-3,5-diol acid motif by a γ-selective carbonylation followed by a cis-stereoselective reduction of the 3,5-dicarbonyl acid intermediates.

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. The protocol was extended to access an important synthetic precursor to the HIV-protease inhibitor, saquinavir, by formation of an NHS ester followed by acyl substitution.

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. The reaction conditions proved suitable for a number of 5- and 6-membered heteroaromatic starting materials affording all products in good yields. The utility of the obtained 1-(het)aryl-2-(2-pyridyl)ethanones was demonstrated by the straightforward synthesis of several multiaromatic derivatives in only few additional steps.

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. in near-quantitative yields. The method was extended to the synthesis and isotope labeling of quinoline and 1,2,3,4-tetrahydroquinoline derivatives. Finally, CX-546 and Olaparib underwent efficient Ir-catalyzed hydrogen isotope exchange reactions.

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. Furthermore, the presented strategy allows effective (13)C labeling.

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. To quantify the amount of CO produced, the reduction was coupled to an aminocarbonylation reaction using the two-chamber system, COware. The reduction was not limited to a specific disilane, since (Ph2MeSi)2 as well as (PhMe2Si)2 and (Me3Si)3SiH exhibited similar reactivity. Moreover, at a slightly elevated temperature, other fluoride salts were able to efficiently catalyze the CO2 to CO reduction. Employing a nonhygroscopic fluoride source, KHF2, omitted the need for an inert atmosphere. Substituting the disilane with silylborane, (pinacolato)BSiMe2Ph, maintained the high activity of the system, whereas the structurally related bis(pinacolato)diboron could not be activated with this fluoride methodology. Furthermore, this chemistry could be adapted to (13)C-isotope labeling of six pharmaceutically relevant compounds starting from Ba(13)CO3 in a newly developed three-chamber system.

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. Finally, the reaction of sodium trichloroacetate in THF with a mixture of aldehyde and malonic acid dissolved in DMSO allowed the protocol to be performed in continuous flow. By performing this decarboxylative reaction in continuous flow, scale-up of the reaction could be achieved with a simple and safe setup. In this flow setup, four electron-deficent aldehydes were successfully transformed into their 2,2,2-trichloromethylcarbinol derivatives on a 100 mmol scale.