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

Abstract

11[C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon-11 (t1/2 = 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.

The use of tetrabutylammonium fluoride to promote N‐ and O‐11C‐methylation reactions with iodo[11C]methane in dimethyl sulfoxide

“…recently reported the 11 C‐methylation reactions of the nitroanilines 6a–8a at ambient temperature over a 10‐min period using 1 and lithium nitride as a base under ultrasonic conditions. According to the report of Cai et al ., the ortho ‐ and para ‐substituted nitroanilines ( 6a and 8a ) proceeded smoothly through the 11 C‐methylation reaction in 62% and 37% yields, respectively, whereas the meta ‐substituted nitroaniline 7a did not provide any of the desired methylated product . In the current study, the 11 C‐methylation reactions of 6a and 8a proceeded smoothly at ambient temperature using NaH or TBAF (Table , entries 19–22 and 27–30, respectively).…”

“…In contrast, our attempts to achieve the 11 C‐methylation of 7a with NaH or TBAF were unsuccessful and therefore no better than the use of lithium nitride (Table , entries 23–26). The reason for the lower efficiency of 11 C‐labeling of 7b compared with those of 6b and 8b remains unclear, as mentioned by Cai et al …”

“…Anilines, especially those bearing electron‐withdrawing groups, are weak nucleophiles and require the aid of a base to be effectively methylated using 1 . Cai et al . recently reported the 11 C‐methylation reactions of the nitroanilines 6a–8a at ambient temperature over a 10‐min period using 1 and lithium nitride as a base under ultrasonic conditions.…”

Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide

“…For hydroxyminoloysis, the reaction mixture was directed to a crimp‐sealed fluoropolymer vessel, which had been pre‐loaded with a mixture of NH 2 OH · HCl and a selected base in DMSO or DMF. The vessel was sonicated at room temperature for 3 to 5 min.…”

“…The autoclave was sealed and heated at 130 °C for 3 min. The reaction mixture was then flushed out with THF (0.7 ml) into a crimp‐sealed vial (1‐ml, fluoropolymer) that had been charged with NH 2 OH · HCl (32 µmol) and phosphazene base P 1 ‐t‐Bu (38 µmol) in DMSO (33 µl). The mixture was sonicated at RT for 3 min, diluted with water (3 ml), treated with aqueous KOH (1.8 M, 200 µl), and separated by reverse phase HPLC on a Luna C18 column (10 µm, 250 × 10 mm) eluted at 5 ml/min with a mixture of MeCN (B) and 25 mM aqueous ammonium formate (A), with mobile phase composition kept at 25% B for 5 min, increased to 65% B over 6 min, and kept at 65% B until the end of separation.…”