Site specific carbon isotope labeling of small molecules has wide ranging applications across fundamental biology, drug development, and medical imaging. Here, we report a method that enables fast incorporation of carbon isotopes into the aromatic ipso carbon of phenols. Phenols are an interesting scaffold target for core isotopic labeling, as they appear in many endogenous metabolites, such as the amino acid tyrosine or neurotransmitter dopamine, as well as FDA approved drugs, such as the anesthetic Propofol. Our strategy first requires the synthesis of precursors with a common 1,5-dihalo-1,4-pentadiene motif. From these precursors, lithium-halogen exchange followed by treatment with readily available one-carbon sources (e.g. carbon dioxide, carbonates) results in a formal [5+1] addition to form various phenol products. Using this strategy, we have prepared twelve different 1-13C labeled phenols with a variety of alkyl and aryl substitutions. Applications of our methodology to medical imaging will also be discussed.

Core-labeling synthesis of phenols

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