Late-Stage Isotopic Carbon Labeling of Pharmaceutically Relevant Cyclic Ureas Directly from CO2

Abstract

A robust, click-chemistry-inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (¹¹ C, ¹³ C, ¹⁴ C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.

Keywords: carbon dioxide; carbon-11; carbon-14; heterocycles; isotopic labeling.

Scheme 1

a) Relevant examples of cyclic ureas; b) synthetic strategies to access radiolabeled ureas. Bn=benzyl.

Scheme 2

Late‐stage labeling of benzoimidazolones with carbon isotopes. The position of the azide on the o‐azidoaniline precursor is highlighted in bold. [a] Yield of the isolated product. [b] Radiochemical conversion. Boc=tert‐butoxycarbonyl.

Scheme 3

Late‐stage labeling of aliphatic ureas with carbon isotopes. The position of the azide on the o‐azidoaniline precursor is highlighted in bold. [a] Yield of the isolated product. [b] Radiochemical conversion.

Scheme 4

Late‐stage carbon isotope labeling of pharmaceutically relevant ureas. RCY: radiochemical yield. The position of the azide on the o‐azidoaniline precursor is highlighted in bold.

Scheme 5

Late‐stage labeling of peptide 5. The position of the azide on the o‐azidoaniline precursor is highlighted in bold. [a] Yield of the isolated product. [b] Radiochemical conversion.