[¹¹C]Methyl-arene formation via palladium-mediated coupling of organozinc reagents with [¹¹C]methyl iodide

Objectives Existing methods of introducing a [¹¹C]methyl group at the aryl carbon position using ¹¹CH₃I are complicated by the need to synthesise and isolate organotin- or organoboron-derived precursors. Organozinc compounds, which can be readily formed from aryl halides via direct reaction with zinc, may provide an appealing alternative. The organozinc species may then be used in the palladium catalysed Negishi coupling reaction with ¹¹CH₃I to form [¹¹C]methylated-arene compounds.

Methods A solution of arylzinc iodide was formed by reaction of Rieke zinc with aryl iodide. This was added to a solution of ¹¹CH₃I and Pd(PPh₃)₂Cl₂ in dimethylacetamide and reacted at room temperature for 5 min. Nitrogen was passed through the solution to purge unreacted gases to a dose calibrator and the radioactivity of the vial was measured. An aliquot of the crude reaction mixture was analysed by HPLC to determine the radiochemical purity of the [¹¹C]methyl-arene product.

Results The arylzinc iodide species were successfully prepared via reaction of Rieke zinc suspension with the corresponding aryl iodide. Without purification, the arylzinc iodide was immediately used in the Negishi coupling reaction to give the corresponding [¹¹C]methylated aromatic compounds in good to excellent RCP and RCY (Table). In the absence of palladium this reaction did not proceed.

Conclusions A new [¹¹C]methylation technique is described using simple apparatus and commercially available reagents. We are currently exploring the use of this reaction to radiolabel the mGluR5 ligand [¹¹C]MPEP, and measure isolated yield and specific activity. An alternative approach in which ¹¹CH₃ZnI is formed from ¹¹CH₃I is also being investigated. Such a nucleophilic ¹¹C-source may participate in reactions with a range of electrophiles, e.g. carbonyl compounds.