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.