RT Journal Article SR Electronic T1 Robust Sandmeyer-type [11C]Cyanation of (Hetero)ArylDiazonium Salts JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 2559 OP 2559 VO 63 IS supplement 2 A1 Webb, Eric A1 Cha, Jocelyn A1 Cheng, Kevin A1 Wright, Jay A1 Shao, Xia A1 Sanford, Melanie A1 Scott, Peter YR 2022 UL http://jnm.snmjournals.org/content/63/supplement_2/2559.abstract AB 2559 Introduction: Radiocyanation is an attractive strategy for incorporation of carbon-11 into radiotracer targets. However, existing methods for aromatic radiocyanation require harsh conditions, such as the Rosenmund-von Braun cyanation, or necessitate the use of expensive and toxic palladium complexes. (1, 2) As such, our lab is interested in development of milder radiocyanatiuon methods mediated by copper. (3) The objective of this work was to develop a Sandmeyer-type radiocyanation of aromatic diazonium salts using commercial copper sources. (4) The goal was introduction of a rapid and efficient cyanation method that proceeds under mild conditions and is tolerant of air, moisture, and a range of functional groups.Methods: (Hetero)aryl diazonium tetrafluoroborate salts were prepared from the corresponding (hetero)arylamine using tetrafluoroboric acid and either sodium or tert-butyl nitrite as oxidant. (5,6) [11C]CO2 was produced in a GE PETtrace cyclotron via the 14N(p,α)11C nuclear reaction and converted to [11C]HCN in a carbon-11 panel of the PETtrace ProCab by nickel reduction to [11C]CH4 using hydrogen and platinum oxidation with ammonia. The [11C]HCN stream was trapped using a solution of pyridine in acetonitrile. Aliquots of the [11C]HCN were added to a solution of copper complex in acetonitrile, followed by a solution of the (hetero)aryldiazonium tetrafluoroborate salt in acetonitrile. The reaction mixture was stirred for 5 min at room at room temperature under air and then evaluated by radio-TLC and -HPLC.Results: The scope of this reaction was evaluated with a variety of (hetero)aryldiazonium tetrafluoroborate salts. Electron-donating, neutral, and electron-withdrawing groups, as well as ortho-steric congestion were all well tolerated with excellent radiochemical yields (>80%). Significantly, competitive nucleophiles such as free alcohols, benzoic acids, and secondary amines exhibited excellent radiochemical yields (>85%) while aryl halides (-F, -Cl, -Br, and -I) all remained intact for further elaboration. Proximal heteroaromatic and ortho-halide species afforded diminished radiochemical yields, but distal heteroaromatic salts perform comparably to aromatic diazonium tetrafluoroborates. Conclusions: We have translated the Sandmeyer-type cyanation to the radiocyanation of a diverse scope of (hetero)aryldiazonium salts. This operationally simple method proceeds effectively under mild and robust conditions. Efforts are underway to apply this methodology to clinically relevant radiotracers and extend this reactivity platform. Acknowledgements: This work was supported by NIH (R01EB021155).References:(1) Ponchant M, Hinnen F, Demphel S, Crouzel C. [11C]Copper(I) Cyanide: A New Radioactive Precursor for 11C-Cyanation and Functionalization of Haloarenes. Appl. Radiat. Isot. 1997;48(6),755-62. (2) Zhao W, Lee HG, Buchwald SL, Hooker JM. Direct 11CN-Labeling of Unprotected Peptides via Palladium-Mediated Sequential Cross-Coupling Reactions. J. Am. Chem. Soc. 2017; 139(21):7152-55(3) Makaravage KJ, Shao X, Brooks AF, Yang L, Sanford MS, Scott, PJH. Copper(II)-Mediated [11C]Cyanation of Arylboronic Acids and Arylstannanes. Org. Lett. 2018;20(6):1530-33.(4) Beletskaya IP, Sigeev AS, Peregudov AS, Petrovskii PV. Catalytic Sandmeyer Cyanation as a Synthetic Pathway to Aryl Nitriles. J. Organomet. Chem. 2004;689(23):3810–12.(5) Hansen MJ, Lerch MM, Szymanski W, Feringa BL. Direct and Versatile Synthesis of Red-Shifted Azobenzenes. Angew. Chem. Int. Ed. 2016;55(43):13514-18.(6) Zhang K, Xu XH, Qing FL. Copper-Promoted Trifluoromethanesulfonylation and Trifluoromethylation of Arenediazonium Tetrafluoroborates with NaSO2CF3. J. Org. Chem. 2015;80(15);7658–65.