Pd(0)-Mediated rapid coupling between methyl iodide and heteroarylstannanes: an efficient and general method for the incorporation of a positron-emitting (11)C radionuclide into heteroaromatic frameworks.
The Pd(0)-mediated rapid trapping of methyl iodide with an excess amount of a heteroaryl-substituted tributylstannane has been investigated with the aim of incorporating a short-lived (11)C-labelled methyl group into the heteroaromatic carbon frameworks of important organic compounds, such as drugs with various heteroaromatic structures, in order to execute a positron emission tomography (PET) study of vital systems. The reaction was first performed by using our previously developed CH(3)I/stannane/[Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuCl/K(2)CO(3) (1:40:0.5:2:2:2) system in DMF at 60 degrees C for 5 min (conditions A), however, the reaction gave low yields for various heteroaromatic compounds. Increasing the amount of phosphine ligand (conditions B) led to a significant improvement in the yield, but the conditions were still not suitable for a range of basic heteroaromatic structures. Use of the CuBr/CsF system (conditions C) also provided a result similar to that obtained under conditions B with an increased amount of the phosphine. Thus, pyridine and related heteroaromatic compounds remained less reactive substrates. The problem was overcome by replacing the DMF solvent with N-methyl-2-pyrolidinone (NMP). The reaction in NMP at 60-100 degrees C for 5 min using a CH(3)I/stannane/[Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1:40:0.5:16:2:5) combination (conditions D) gave the methylated products in yields of more than 80 % (based on the reaction of CH(3)I) for all of the heteroaromatic compounds listed in this study. Thus, the combined use of NMP and an increased amount of phosphine is important for promoting the reaction efficiently. The use of this general approach to rapid methylation has been well demonstrated by the synthesis of the PET tracers 2- and 3-[(11)C]methylpyridines by using [Pd(2)(dba)(3)]/P(o-CH(3)C(6)H(4))(3)/CuBr/CsF (1:16:2:5) in NMP at 60 degrees C for 5 min, which gives the desired products in HPLC analytical yields of 88 and 91 %, respectively.
Suzuki
Masaaki
M
RIKEN Center for Molecular Imaging Science, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. suzuki.masaaki@riken.jp
Sumi
Kengo
K
Koyama
Hiroko
H
Hosoya
Takamitsu
T
Takashima-Hirano
Misato
M
Doi
Hisashi
H
D002250:Carbon Radioisotopes; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006847:Hydrocarbons, Iodinated / Q000737:chemistry*; D007553:Isotope Labeling; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D009947:Organotin Compounds; D010165:Palladium / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011868:Radioisotopes / Q000737:chemistry*; D014001:Tin / Q000737:chemistry*
D002250:Carbon Radioisotopes; D006571:Heterocyclic Compounds; D006847:Hydrocarbons, Iodinated; D008024:Ligands; D009942:Organometallic Compounds; D009947:Organotin Compounds; D011868:Radioisotopes; C547131:tri-n-butyl(2-thienyl)stannane; D010165:Palladium; D014001:Tin; C014055:methyl iodide