TY - JOUR
T1 - Nickel-Mediated Alkoxycarbonylation for Complete Carbon Isotope Replacement
AU - Ton, Stephanie J.
AU - Neumann, Karoline T.
AU - Nørby, Peter
AU - Skrydstrup, Troels
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/10/27
Y1 - 2021/10/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118247674&partnerID=8YFLogxK
U2 - 10.1021/jacs.1c09170
DO - 10.1021/jacs.1c09170
M3 - Journal article
C2 - 34643376
AN - SCOPUS:85118247674
SN - 0002-7863
VL - 143
SP - 17816
EP - 17824
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 42
ER -