ABSTRACT
Herein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative carbonylation approach for isotope labeling with near stoichiometric, ex situ generated 12 C, or 13 C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2 liberated during decarboxylation has also been developed as a proof-of-concept approach that CO2 -derived compounds can be converted to CO-containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low-pressure carbonylation methodologies, along with rational for the development of future methodologies.
ABSTRACT
Herein, we report a strategy for the formation of isotopically labeled carboxylic esters from boronic esters/acids using a readily accessible palladium carboxylate complex as an organometallic source of isotopically labeled functional groups. The reaction allows access to either unlabeled or full 13C- or 14C-isotopically labeled carboxylic esters, and the method is characterized by its operational simplicity, mild conditions, and general substrate scope. Our protocol is further extended to a carbon isotope replacement strategy, involving an initial decarbonylative borylation procedure. Such an approach allows access to isotopically labeled compounds directly from the unlabeled pharmaceutical, which can have implications for drug discovery programs.
ABSTRACT
Herein we disclose the synthesis of sterically encumbered dialkylnickel(II) complexes bearing 2,9-dimethyl-1,10-phenanthroline ligands. A comparison with their unsubstituted analogues by both X-ray crystallography and theoretical calculations revealed significant distortions in their molecular structures. Eyring plots along with stoichiometric and photoexcitation studies revealed that sterically encumbered dialkylnickel(II) complexes enable facile C(sp 3)-C(sp 3) reductive elimination, thus offering an improved understanding of Ni catalysis.
ABSTRACT
Many commercial drugs, as well as upcoming pharmaceutically active compounds in the pipeline, display aliphatic carboxylic acids or derivatives thereof as key structural entities. Synthetic methods for rapidly accessing isotopologues of such compounds are highly relevant for undertaking critical pharmacological studies. In this paper, we disclose a direct synthetic route allowing for full carbon isotope replacement via a nickel-mediated alkoxycarbonylation. Employing a nickelII pincer complex ([(N2N)Ni-Cl]) in combination with carbon-13 labeled CO, alkyl iodide, sodium methoxide, photocatalyst, and blue LED light, it was possible to generate the corresponding isotopically labeled aliphatic carboxylates in good yields. Furthermore, the developed methodology was applied to the carbon isotope substitution of several pharmaceutically active compounds, whereby complete carbon-13 labeling was successfully accomplished. It was initially proposed that the carboxylation step would proceed via the in situ formation of a nickellacarboxylate, generated by CO insertion into the Ni-alkoxide bond. However, preliminary mechanistic investigations suggest an alternative pathway involving attack of an open shell species generated from the alkyl halide to a metal ligated CO to generate an acyl NiIII species. Subsequent reductive elimination involving the alkoxide eventually leads to carboxylate formation. An excess of the alkoxide was essential for obtaining a high yield of the product. In general, the presented methodology provides a simple and convenient setup for the synthesis and carbon isotope labeling of aliphatic carboxylates, while providing new insights about the reactivity of the N2N nickel pincer complex applied.
