A general route for 13 C-labeled fluorenols and phenanthrenols via palladium-catalyzed cross-coupling and one-carbon homologation Ruilian Wu, a L. A. ‘Pete’ Silks, a * Morgane Olivault-Shiflett, a Robert F. Williams, a Erick G. Ortiz, a Philip Stotter, a David B. Kimball, a and Rodolfo A. Martinez b ** A series of 13 C-labeled polyaromatic hydrocarbons (PAHs), fluorenols and phenanthrenols were synthesized from commercially available 13 C-labeled starting material giving rise to M + 6 isotopomers. This was accomplished using key palladium-catalyzed cross-coupling and one-carbon homologation strategies. The conditions for these reactions were optimized, and the new chemical routes are efficient in the number of chemical steps, can be scaled to afford gram quantities and occur in good yields based on the 13 C label. These labeled compounds as precursors for more complex PAHs and are useful as internal standards in mass spectrometry and NMR spectroscopy studies for monitoring environmental contamination and biological exposure to PAHs and their metabolites. Keywords: polyaromatic hydrocarbons; palladium-catalyzed cross-coupling; one-carbon homologation; mass spectral standards; uniformly 13 C-labeled benzene and Friedel–Crafts reactions Introduction Polyaromatic hydrocarbons (PAHs) make up a class of compounds implicated in carcinogenesis and found to be prevalent in the environment. The most potent carcinogenic members contain four to six benzo rings. These PAHs have structural features such as crowded bay or fjord regions which enhance biological activities (Figure 1). 1 One of the most potent carcinogens known is derivatives of the benzo[a]pyrene family. Strong correlation with carcinogenic activity is found with oxidized versions of benzo[a]pyrene. Metabolism by oxidases is found to give rise to epoxides, which are more reactive than the parent benzo[a]pyrene. Interestingly, the enzymatic reactions proceed with high regioselectivities and stereoselectivities, and these highly reactive intermediates then proceed to attack cellular targets such as DNA. The covalent attachment of PAHs to DNA can lead to significant damage to the cell. Persistent lesions give rise to cellular signals, lead to apoptosis. In addition, during replication, transcription errors can provide a whole host of deleterious cellular events. As cytoxicity is usually accompanied by gross changes in the structure of the DNA helix, which serves to block the reading of the oligomer by RNA and DNA polymerases, mutagenic lesions can give rise to errors in the transcription process. We have recently been interested in the study of the process of the intercalation of PAHs into oligomeric deoxynucleic acids (DNA), and the effect and extent of soft π•••H–X (X=C, N, O) and C–H•••O hydrogen bonding interactions have on the structure of the DNA. In addition, we believe many of these intermediates are useful in monitoring and quantitating the presence of PAHs in biological systems and the environment by mass spectral methods. This report details our synthetic efforts toward a comprehensive approach to stable isotope labeling of PAHs. Because deuterium labeling of PAHs is problematic in terms of stability (dilution of the label), 13 C labeling is required in many cases. Our concept then begins with a reasonable source of 13 C label starting with U- 13 C benzene. While making mass spectral standards and the studies of PAHs and DNA interactions, we needed to synthesize M + 4 labeled fluorenols and phenanthrenols. There are few existing methods 1 for 13 C labeling, however for our site-specific labeling, these are not feasible in terms of both time and cost. Here, we report a new general route to 13 C-labeled fluorenols and phenanthrenols by using a key palladium-catalyzed cross-coupling step followed by a one-carbon homologation (Figure 2). 2 The synthetic route to 9-fluorenol 3 is shown in Scheme 1. 2-Iodobenzoyl chloride smoothly underwent Friedel–Crafts a Bioenergy and Biome Sciences Group, Biophysical Chemistry Team, Los Alamos National Laboratory, Los Alamos, NM 87545, USA b Department of Chemistry, New Mexico Highland University, Las Vegas, NM 87701, USA *Correspondence to: Pete Silks, Bioenergy and Biome Sciences Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA. E-mail: pete-silks@lanl.gov **Correspondence to: Department of Chemistry and Forensic Science. New Mexico Highlands University. Room:HSCI-132. Las Vegas, NM 87701. E-mail: rudy@nmhu.edu Copyright © 2013 John Wiley & Sons, Ltd. J. Label Compd. Radiopharm 2013, 56 581–586 Research Article Received 1 May 2013, Accepted 2 May 2013 Published online 15 July 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jlcr.3066 581