Core-Labeling Synthesis of Phenols

The synthesis of isotopically labeled compounds with site-specificity is critical to the pharmaceutical and agrochemical fields. For reasons of synthetic accessibility, isotopic labeling methods have traditionally been restricted to the molecular periphery, even among potentially skeletal elements (C, N, O, etc.), limiting the classes and isotopomers of compounds one can prepare in labeled form. Here, we report a method that enables fast incorporation of carbon isotopes into a core atom of an aromatic compound, specifically 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 twelve different 1-13C labeled phenols with a variety of alkyl and aryl substitutions via dibenzyl carbonate as a carbon-13 synthon. Additionally, we show proof of concept for labeling of phenols with other carbon radioisotopes — we demonstrate dibenzyl carbonate synthesis from common carbon-14 sources, as well as phenol synthesis directly from carbon dioxide, providing a potential entry into carbon-11 radiolabeling.