Palladium-Catalyzed Carbon Isotope Exchange on Aliphatic and Benzoic Acid Chlorides

Abstract

An operationally simple protocol for a palladium-catalyzed 13CO and 14CO exchange with activated aliphatic and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, and pharmaceuticals have been prepared to showcase the method for late-stage carbon isotope incorporation and its functional group compatibility.

Palladium-Catalyzed Carboformylation Enabled by a Molecular Shuffling Process

“…GC analysis of the crude reaction mixtures showed an increased yield of a side product arising from competing hydroarylation, indicating that CO reinsertion (III to IV) is less favored with electron-poor substrates. Finally, using isotopically labelled reagents, the D and 13 C labels were efficiently incorporated into the desired products (2,20), highlighting the synthetic potential of this method as an addition to medicinal chemistry's toolbox for the preparation of isotopically labelled α,β-unsaturated aldehydes 16,45 . Gratifyingly, the reaction could be performed on a multi-gram scale (25 mmol), delivering the product (1) in excellent yield (83%, 4.8 g) with complete stereoselectivity.…”

The Emergence of Carbon Isotope Exchange

“…In late 2018, Gauthier and co‐workers (Figure a) reported a procedure based on the use of a known dual‐chamber system with a labelled CO precursor to generate the gas in situ and achieve CIE under palladium catalysis. This process, which was applied to activated acid chlorides as the starting materials, provided access to a large scope of both aliphatic and aromatic labelled compounds with good isotope incorporations and yields, even for complex structures such as pharmaceuticals.…”

“…In late 2018, Gauthier and co-workers [6] (Figure 1a) reported ap rocedure based on the use of ak nown dualchamber system [7] with al abelled CO precursor to generate the gas in situ and achieve CIE under palladium catalysis.This process,w hich was applied to activated acid chlorides as the starting materials,p rovided access to al arge scope of both aliphatic and aromatic labelled compounds with good isotope incorporations and yields,even for complex structures such as pharmaceuticals.I na ddition, for carboxylic acids bearing as tereocenter in a-position of the carbonyl group,t he enantiopurity could be retained by fine-tuning of the experimental conditions and the nature of the phosphine ligands. Them ain limitations are the preactivation of the carboxylic acid moiety in its acyl chloride form and the use of [ 14 C]COgen, ar eactant able to produce [ 14 C]CO in special glassware.Indeed, carbon-14 is generated in nuclear reactors as barium carbonate ([ 14 C]BaCO 3 )a nd routinely converted into highly stable carbon dioxide ([ 14 C]CO 2 ).…”

Das aufkommende Konzept des Kohlenstoffisotopenaustauschs

“…Ende 2018 berichteten Gauthier und Mitarbeiter [6] (Abbildung 1a) über ein Verfahren unter Verwendung eines bekannten Zweikammersystems, [7] das einen markierten CO-Vorläufer zur In-situ-Erzeugung des Gases einsetzt und dessen Austausch unter Palladiumkatalyse bewirkt. Dieses Verfahren, das aktivierte Säurechloride als Ausgangsstoffe einsetzt, ermçglichte den Zugang zu einem breiten Spektrum aliphatischer und aromatischer markierter Verbindungen mit guten Isotopeneinbauten und -ausbeuten, selbst bei komplexen Strukturen wie Pharmazeutika.…”

“…Ende 2018 berichteten Gauthier und Mitarbeiter [6] (Abbildung 1a) über ein Verfahren unter Verwendung eines bekannten Zweikammersystems, [7] (5-32 ¾quiv.). Obwohl vor der CIE-Reaktion redoxaktive N-Hydroxyphthalimidester gebildet werden mussten, lieferten milde Bedingungen bei Raumtemperatur eine Bandbreite von markierten komplexen Alkylcarboxylaten mit ausreichendem Isotopeneinbau fürADME-Studien.…”