A palladium catalyzed, multicomponent synthesis of indolizines is described via the carbon monoxide driven generation of reactive, pyridine-based 1,3-dipoles.
Metal-catalysed hydroformylations efficiently convert feedstock alkenes into aldehydes, though typically relatively simple ones. Now, the palladium-catalysed fragmentation of acid chlorides followed by reassembly with alkynes and silanes has been shown to form valuable, highly substituted α,β-unsaturated aldehydes.
The distribution, metabolism and ultimate fate of molecules within the body is central to the activity of pharmaceuticals. However, the introduction of radioisotopes into the metabolically stable carbon sites on drugs required to probe these features presents a significant hurdle, since it typically requires synthesis with toxic, radioactive gases such as 14CO2 and 14CO. Here, we describe a straightforward alternative approach to directly carbon-label carboxylic acid-containing pharmaceuticals: via a metal catalyzed functional group exchange reaction. This provides a general route to 14C-labeled carboxylic acid-containing drugs without radioactive gases, in one pot, and using an easily available and handled carboxylic acid 14C-source. To enable this process, a new class of functional group metathesis of carbon-carbon covalent bonds in acid chloride functionalities is developed that exploits the ability of earth abundant nickel catalysts to both reversibly activate carbon-chloride bonds and exchange functionalities between organic molecules. The applicability of this system to drug development is illustrated by the direct incorporation of 14C- or 13C-label into an unprecedented array of complex aryl, alkyl, vinyl and heterocyclic carboxylic acid drugs or drug candidates without gases or special apparatus, at simply ambient conditions, and without loss of the radiolabel.
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