Pd-Mediated ¹¹C-Carbonylation of a Diaryliodonium Tosylate: An Efficient and Mild Route to [¹¹C]Arylcarboxylic Acid

Objectives Most literature methods for preparing [¹¹C]arylcarboxylic acids via carboxylation with [¹¹C]CO₂ or carbonylation with [¹¹C]CO are either moisture/air-sensitive or require harsh conditions. Diaryliodonium salts may be considered more reactive than aryl iodides. We postulated that diaryliodonium salts might serve as useful precursors for preparing [¹¹C]arylcarboxylic acids under mild conditions through Pd-mediated ¹¹C- carbonylation. A challenge in this approach would be to produce mainly the desired [¹¹C]arylcarboxylic acid, because insertion of [¹¹C]CO might occur at either aryl ring. Here we report our initial exploration of the Pd-mediated ¹¹C-carbonylation of (2-methoxyphenyl)(phenyl)iodonium tosylate (1) for [¹¹C]arylcarboxylic acid synthesis.

Methods Several Pd(II) and Pd(0) ligands were screened for reaction efficiency and aryl ring selectivity. In a one-pot procedure, 1 (3 µmol) plus a Pd ligand (0.5 µmol) in DMF-H₂O (4:1 v/v; 100 µL) was sonicated for either 30 or 300 s and loaded into an autoclave. No-carrier-added [¹¹C]CO, produced from cyclotron-produced [¹¹C]CO₂, was heated with the mixture in the autoclave at 100 °C for 2 min under high pressure. The reaction mixture was then collected in a closed glass vial (5-mL). Radioactivity in the vial was measured before and after purging with helium gas for 4 min. An aliquot (50 µL) was then diluted with MeCN-H₂O (1:1 v/v; 500 µL) and analyzed by HPLC. Reactions with Pd(PPh₃)₄ were also conducted as a two-pot process. Thus, 1 (3 µmol) plus Pd(PPh₃)₄ (0.5 µmol) in anhydrous DMF (80 µL) was treated with [¹¹C]CO in an autoclave at 100 °C for 2 min. The reaction mixture was transferred to a glass vial and purged with helium for 4 min. Aq. NaOH-MeCN or aq.NH₄OH-MeCN at RT or water-MeCN at 100 °C was then added preceding HPLC analysis. Reactions mediated by PdCl₂ were also examined at RT.

Results For PdCl₂ and other Pd(II) ligands, [¹¹C]CO trapping efficiency was ~ 50%. Aggregate conversion of [¹¹C]CO to the two expected [¹¹C]arylcarboxylic acids was 72-94%. [¹¹C]Benzoic acid (2) was slighly preferred over [¹¹C]2-methoxybenzoic acid (3) (ratio 1.1-1.7). For Pd(PPh₃)₄, [¹¹C]CO trapping efficiency was 25-35%. However, 2 was the predominant product (ratio 10-20 to 3). For PdCl₂, the reaction at RT gave similar yield and selectivity to that at 100 °C.

Conclusions PdCl₂ rapidly mediates the ¹¹C-carbonylation of 1 in excellent yield, even at RT. Highest aryl ring selectivity was achieved with Pd(PPh₃)₄. Pd-mediated ¹¹C-carbonylation of diaryliodonium salts is a potentially promising process for preparing [¹¹C]arylcarboxylic acids under mild conditions. The selectivity and substrate scope of this process is being further investigated.