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.

A Dual Palladium and Copper Hydride Catalyzed Approach for Alkyl-Aryl Cross-Coupling of Aryl Halides and Olefins.

We report an efficient means of sp2 -sp3 cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron-deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air-stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium-labeling studies indicate that deuterium scrambling does not take place in this sp2 -sp3 cross coupling, implying that ß-hydride elimination is not a significant process in this transformation.

Asymmetric Hydroarylation of Vinylarenes Using a Synergistic Combination of CuH and Pd Catalysis.

Detailed in this Communication is the enantioselective synthesis of 1,1-diarylalkanes, a structure found in a range of pharmaceutical drug agents and natural products, through the employment of copper(I) hydride and palladium catalysis. Judicious choice of ligand for both Cu and Pd enabled this hydroarylation protocol to work for an extensive array of aryl bromides and styrenes, including ß-substituted vinylarenes and six-membered heterocycles, under relatively mild conditions.

Efficient 11C-carbonylation of isolated aryl palladium complexes for PET: application to challenging radiopharmaceutical synthesis.

We describe the successful implementation of palladium-aryl oxidative addition complexes as stoichiometric reagents in carbonylation reactions with (11)CO to produce structurally challenging, pharmaceutically relevant compounds. This method enables the first (11)C-carbonyl labeling of an approved PET tracer, [(11)C]raclopride, for the dopamine D2/D3 receptor by carbonylation with excellent radiochemical purity and yield. Two other molecules, [(11)C]olaparib and [(11)C]JNJ 31020028, were efficiently labeled in this manner. The technique distinguishes itself from existing methods by the markedly improved purity profiles of the tracer molecules produced and provides access to complex structures in synthetically useful yields, hereby offering a viable alternative to other (11)C-labeling strategies.

Rapid and Efficient Conversion of (11) CO2 to (11) CO through Silacarboxylic Acids: Applications in Pd-Mediated Carbonylations.

Herein, we present a new rapid, efficient, and low-cost radiosynthetic protocol for the conversion of (11) CO2 to (11) CO and its subsequent application in Pd-mediated reactions of importance for PET applications. This room-temperature methodology, using readily available chemical reagents, is carried out in simple glass vials, thus eliminating the need for expensive and specialized high-temperature equipment to access (11) CO. With this fast and near-quantitative conversion of (11) CO2 into (11) CO, aryl and heteroaryl iodides were easily converted into a broad selection of biologically active amides in radiochemical yields ranging from 29-84 %.

Organocatalyzed CO2 Trapping Using Alkynyl Indoles.

The first organocatalyzed trapping of CO2 through C-C and C-O bond formation is reported. Alkynyl indoles together with catalytic amounts of an organic base and five equivalents of CO2 resulted in the formation new heterocyclic structures. These tricyclic indole-containing products were successfully prepared under mild reaction conditions from aromatic, heteroaromatic, and aliphatic alkynyl indoles with complete regioselectivity. Further investigations suggest that C-C bond formation is the initial intermolecular step, followed by lactone-forming C-O bond formation.

Palladium-catalyzed carbonylative α-arylation of 2-oxindoles with (hetero)aryl bromides: efficient and complementary approach to 3-acyl-2-oxindoles.

An efficient Pd-catalyzed carbonylative α-arylation of 2-oxindoles with aryl and heteroaryl bromides for the one-step synthesis of 3-acyl-2-oxindoles has been developed. This reaction proceeds efficiently under mild conditions and is complementary to the more common oxindole forming reactions. The transformation only requires a mild base and provides good to excellent yields even with heteroaromatic substrates. Employing a near stoichiometric amount of (13) COgen, the methodology was easily extended to [(13) C] acyl labeling. The general applicability of the reaction conditions was demonstrated in the synthesis of a structure related to the pharmaceutically active 3-acyl-2-oxindoles, tenidap.

Late-stage synthesis of heterobifunctional molecules for PROTAC applications via ruthenium-catalysed C‒H amidation.

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules emerging as a powerful modality in drug discovery, with the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these derivatives are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to access fully elaborated heterobifunctional compounds. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C-H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of both CRBN and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools.

Silacarboxylic acids as efficient carbon monoxide releasing molecules: synthesis and application in palladium-catalyzed carbonylation reactions.

Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh(2)SiCO(2)H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor. Finally, the synthesis of MePh(2)Si(13)CO(2)H and its application in carbonyl labeling of two bioactive compounds was demonstrated.

Cobalt-catalysed C-H methylation for late-stage drug diversification.

The magic methyl effect is well acknowledged in medicinal chemistry, but despite its significance, accessing such analogues via derivatization at a late stage remains a pivotal challenge. In an effort to mitigate this major limitation, we here present a strategy for the cobalt-catalysed late-stage C-H methylation of structurally complex drug molecules. Enabling broad applicability, the transformation relies on a boron-based methyl source and takes advantage of inherently present functional groups to guide the C-H activation. The relative reactivity observed for distinct classes of functionalities were determined and the sensitivity of the transformation towards a panel of common functional motifs was tested under various reaction conditions. Without the need for prefunctionalization or postdeprotection, a diverse array of marketed drug molecules and natural products could be methylated in a predictable manner. Subsequent physicochemical and biological testing confirmed the magnitude with which this seemingly minor structural change can affect important drug properties.

Palladium-Catalyzed Aminocarbonylation in Solid-Phase Peptide Synthesis: A Method for Capping, Cyclization, and Isotope Labeling.

A new synthetic approach for introducing N-capping groups onto peptides attached to a solid support, combining aminocarbonylation under mild conditions using a palladacycle precatalyst and solid-phase peptide synthesis, is reported. The use of a silacarboxylic acid as an in situ CO-releasing molecule allowed the reaction to be performed in a single vial. The method also enables versatile substitution of side chains, side-chain-to-side-chain cyclizations, and selective [13C] acyl labeling of modified peptides.

C-H activation dependent Pd-catalyzed carbonylative coupling of (hetero)aryl bromides and polyfluoroarenes.

The carbonylative coupling of aryl and heteroaryl bromides with polyfluoroarenes via palladium-catalyzed C-H activation is presented. This transformation proceeds efficiently at moderate reaction temperatures and does not require strong base or reactive intermediates. A near stoichiometric amount of CO is sufficient and the methodology can thus be easily expanded to include the preparation of [(13)C]-acyl labeled benzopolyfluorophenones.

Palladium-catalysed carbonylative α-arylation of nitromethane.

A simple and mild Pd-catalysed carbonylative α-arylation of nitromethane has been realised providing access to α-nitro aryl ketones from an array of aryl and heteroaryl iodides. The methodology requires only a mild base and uses the convenient solid CO releasing molecule, COgen in a two-chamber system. Changing to the isotopically labelled (13)COgen, [(13)C]-acyl labelling can be effected through the generation of a near stoichiometric amount of (13)CO. Lastly, the significance of the generated products as synthetic intermediates is demonstrated.

Pd-catalyzed carbonylative access to aroyl phosphonates from (hetero)aryl bromides.

The first transition-metal catalysed carbonylation with a phosphorus nucleophile is presented. This transformation provides efficient and mild access to aroylphosphonates under mild conditions, thus ensuring a broad substrate scope. The utility of aroylphosphonates as useful reagents, capable of participating in a number of transformations, is subsequently demonstrated. Furthermore, access to [(13)C]-carbonyl labelled aroylphosphonates is easily realised for the first time, as only a near stoichiometric amount of CO is required applying this carbonylation.

Mild Pd-catalyzed aminocarbonylation of (hetero)aryl bromides with a palladacycle precatalyst.

A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.

Palladium-catalyzed synthesis of aromatic carboxylic acids with silacarboxylic acids.

Aryl iodides and bromides were easily converted to their corresponding aromatic carboxylic acids via a Pd-catalyzed carbonylation reaction using silacarboxylic acids as an in situ source of carbon monoxide. The reaction conditions were compatible with a wide range of functional groups, and with the aryl iodides, the carbonylation was complete within minutes. The method was adapted to the double and selective isotope labeling of tamibarotene.

Metal-free halonium mediated acetate shifts of ynamides to access α-halo acrylamides/acrylimides.

A metal-free acetate shift of 3-acetoxy ynamides to access α-iodo, bromo, and chloro acrylamides/acrylimides under very mild conditions is demonstrated. The inherent alkyne activation of ynamides is sufficient to ensure the α-halo acrylamides/acrylimides in high yields without the addition of a catalyst. In all cases high Z-stereoselectivity is observed.