Karoline T. Neumann

Palladium-catalyzed double carbonylation using near stoichiometric carbon monoxide: expedient access to substituted 13C2-labeled phenethylamines.

A novel and general approach for (13)C(2)- and (2)H-labeled phenethylamine derivatives has been developed, based on a highly convergent single-step assembly of the carbon skeleton. The efficient incorporation of two carbon-13 isotopes into phenethylamines was accomplished using a palladium-catalyzed double carbonylation of aryl iodides with near stoichiometric carbon monoxide.

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.

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 Alzheimers plaque binder and a selective PPAR antagonist including site-specific labeling with (13)C-carbon monoxide.

Carbonylative Coupling of Alkyl Zinc Reagents with Benzyl Bromides Catalyzed by a Nickel/NN2 Pincer Ligand Complex

An efficient catalytic protocol for the three-component assembly of benzyl bromides, carbon monoxide, and alkyl zinc reagents to give benzyl alkyl ketones is described, and represents the first nickel-catalyzed carbonylative coupling of two sp3 -carbon fragments. The method, which relies on the application of nickel complexed with an NN2 -type pincer ligand and a controlled release of CO gas from a solid precursor, works well with a range of benzylic bromides. Mechanistic studies suggest the intermediacy of carbon-centered radicals.

Synthesis and selective 2H-, 13C-, and 15N-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.

Recent developments in carbonylation chemistry using [13C]CO, [11C]CO, and [14C]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.

New Directions in Transition Metal Catalyzed Carbonylation Chemistry

Carbon monoxide (CO) represents an important C1-building block for the construction of some of the most fundamental chemical functionalities carrying a carbon-oxygen double bond. Transition metal catalysis plays a key role in promoting such transformations. We have earlier shown that the combination of palladium catalysis with CO releasing molecules and the two-chamber reactor, COware, provides a convenient and safe means for performing traditional Pd-catalyzed carbonylative couplings, as well as being a platform for the discovery of new carbonylation reactions. Furthermore, the method can be adapted to 13C- and 14C-isotope labeling, as well as providing for a suitable setting for developing efficient carbonylation reactions with 11CO. Herein, we provide a short overview of our latest findings in this area with emphasis on carbonylative couplings with fluorinated building blocks, but also discuss our efforts to develop viable Ni-catalyzed carbonylations with aliphatic substrates, which can be performed efficiently under low CO partial pressures.

Synthesis of Aliphatic Carboxamides Mediated by Nickel NN2‐Pincer Complexes and Adaptation to Carbon‐Isotope Labeling

The development of a nickel-mediated aminocarbonylation utilizing NN2 -pincer Ni-complexes, alkylzinc reagents, stoichiometric carbon monoxide and amines is described for the first time, which can be adapted to late-stage carbon-isotope labeling. This work expands the scope of the highly established palladium-promoted version of the reaction, by allowing carbon-sp3 fragments to take part in the three-component reaction. Finally, the results obtained show a remarkable effect of the pincer ligand for the reductive elimination step with the amine, which is followed by 13 C NMR spectroscopy studies.

Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl Bromides or Fluorosulfates: Palladium‐Catalyzed Carbonylation

A palladium-catalyzed carbonylative approach for the direct conversion of (hetero)aryl bromides into their α,α-bis(trifluoromethyl)carbinols is described, and it employs only stoichiometric amounts of carbon monoxide and trifluoromethyltrimethylsilane. In addition, aryl fluorosulfates proved highly compatible with these reaction conditions. The method is tolerant of a diverse set of functional groups, and it is adaptable to late-stage carbon-isotope labeling.

Correction to Palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides using near stoichiometric carbon monoxide.

S peaks and in some cases minor impurities had been removed from the H and C NMR spectra reported for compounds 3, 5, 7, 9, 10, 12, 15, 18b, 23, 26b, 27, 29, 30b, and 31b. Original FIDs were located for compounds 3, 7, 9, 12, 15, 29, 30b, and 31b, and the spectra were reprocessed and have been replaced in the revised Supporting Information. For compounds 10, 18b, 23, and 26b, the reactions were rerun and the new spectra have been provided in the corrected Supporting Information. For compound 5, the wrong spectra were submitted in the original Supporting Information. The correct spectra are now included in the revised Supporting Information. For compound 27, the original FID was not located, and new spectra were obtained and are provided in the revised Supporting Information. The spectra editing did not affect any of the conclusions of the published paper. The corrected yields based on the revised spectra are as follows: 10 (87% yield), 18b (98% yield), 23 (90% yield), and 26b (95% yield).