Rapid Room-Temperature ¹¹C-Methylation of Arylamines with [¹¹C]Methyl Iodide Promoted by Solid Inorganic Bases in DMF

¹¹[C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t_1/2 = 20.4 min) for molecular imaging with positron emission tomography. However, some substrates for labeling, especially primary arylamines and pyrroles, are sluggishly reactive towards [¹¹C]methyl iodide. We found that insoluble inorganic bases, especially Li₃N or Li₂O, are effective in promoting rapid reactions (≤ 10 min) of such substrates with no-carrier-added [¹¹C]methyl iodide in DMF at room temperature to give ¹¹C-methylated products in useful radiochemical yields. In particular, we discovered that some primary arylamines in Li₃N-DMF were converted into their formanilides, and that these were readily N-methylated with [¹¹C]methyl iodide, preceding easy basic hydrolysis to the desired [¹¹C]N-methyl secondary arylamines. Use of a solid base permitted selective reaction at an arylamino group and in some cases also avoided undesirable side reaction, such as ester group hydrolysis. An ultrasound device proved useful to provide remote and constant agitation of the radioactive heterogeneous reaction mixtures, but imparted no 'ultrasound-specific' chemical effect.