The prenyl group is known as an important structural building block in natural and medicinal products. The isotopic substitution of one of the two methyl groups with a [ 11 C]methyl group would provide an access to a large number of interesting 11 C-labelled compounds. Here we report a strategy for the synthesis of 11 C-labelled prenyl group-containing derivatives starting from methyl-substituted alkynes ( 1) via a novel 11 C-C bond forming reaction. A commonly employed strategy to form ฮฑ,ฮฑ'disubstituted alkenes comprises the formation of alkenylzirconocenes by the syn-insertion of a C-C triple bond into the Zr-H bond of Schwartz reagent [Cp 2 Zr(H)Cl] followed by metal-mediated C-C bond formation with electrophiles under retention of the configuration of the C-C douple bond [1,2]. In principle the formation of alkenylzirconocenes by syn-addition of Schwartz reagent onto disubstituted alkynes (1) leads to a mixture of regioisomers 2 and 2โฒ. However, treatment of an excess of Schwartz reagent favors the formation of the sterically less hindered isomer 2. Transmetalation with transition metal complexes M(PPh 3 ) 4 and conversion with [ 11 C]MeI leads to compound 4. Fig. 1. Reaction sequence: Hydrozirconation, transmetalation, methylation with [ 11 C]MeI.
First preliminary investigations were performed using 1-phenyl-1-propyne (1a) as a simple model. After treatment with 1.2 equiv. of Schwartz reagent in THF at room temperature 5 mol% M(PPh 3 ) 4 (M = Ni, Pd, Pt) were added and [ 11 C]MeI was distilled into the solution. The mixture was heated at 60ยฐC for 5 min. Ni or Pt complexes provided only 4% and 11% of 4a, whereas sufficient radiochemical yields of up to 70% could be obtained when Pd(PPh 3 ) 4 was used. These reaction conditions were successfully applied to other methyl-substituted alkynes (1b-1d) to give the desired 11 C-labelled alkenes (4b-4d) in radiochemical yields ranging from 55-80%.
In conclusion we have developed a novel method for 11 C-C bond formation enabling the convenient synthesis of 11 C-labelled prenyl group-containing compounds.