Core-Labeling (Radio) Synthesis of Phenols

Abstract

We report a method that enables the fast incorporation of carbon isotopes into the ipso carbon of phenols. Our approach relies on the synthesis of a 1,5-dibromo-1,4-pentadiene precursor, which upon lithium-halogen exchange followed by treatment with carbonate esters results in a formal [5 + 1] cyclization to form the phenol product. Using this strategy, we have prepared 12 1-¹³C-labeled phenols, show proof-of-concept for the labeling of phenols with carbon-14, and demonstrate phenol synthesis directly from cyclotron-produced [¹¹C]CO₂.

Figure 1

Introduction. (A) Properties and uses for carbon isotopes. (B) Common strategies for peripheral carbon isotope labeling. (C) Prior art in last-step arene labeling. (D) This work, core labeling of phenols.

Figure 2

(A) Representative synthesis of the 1,5-dibromide precursor and (B) optimization of phenol cyclization. Reactions were performed under nitrogen on a 0.04 mmol scale, and yields were determined by ¹H NMR using mesitylene as an internal standard.

Figure 3

Synthesis of [carbonyl-¹³C]dibenzyl carbonate and scope of 1-¹³C phenols. Isolated yields on 0.20 mmol scale.

Figure 4

Demonstration of feasibility for carbon radioisotopes. (A) Synthesis of dibenzyl carbonate from BaCO₃ and Na₂CO₃, common carbon-14 sources. (B) Synthesis of phenols directly from dilute CO₂, a model system for carbon-11. (C) Radiosynthesis of [1-¹¹C]propofol from cyclotron-produced [¹¹C]CO₂.