Rapid methylation on carbon frameworks useful for the synthesis of 11CH3-incorporated PET tracers: Pd(0)-mediated rapid coupling of methyl iodide with an alkenyltributylstannane leading to a 1-methylalkene

Abstract

The Pd(0)-mediated rapid coupling of methyl iodide with an excess of alkenyltributylstannane was examined with the aim of incorporating a short-lived ¹¹C-labeled methyl group into a biologically significant organic compound with a 1-methylalkene unit for the synthesis of a PET tracer. Four sets of reaction conditions (A–D) were used, all performed in DMF at 60 °C for 5 min. Condition B, using CH₃I/stannane/Pd₂(dba)₃/P(o-tolyl)₃/CuCl/K₂CO₃ (1 : 40 : 0.5 : 4–6 : 2 : 5), works well in almost all cases. Condition D, using CH₃I/stannane/Pd₂(dba)₃/P(o-tolyl)₃/CuX (X = Br, Cl, or I)/CsF (1 : 40 : 0.5–5 : 2–20 : 2–20 : 5–50), shows the best results with regard to general applicability to tin substrates, affording the corresponding methylated product in >90% yield based on consumption of methyl iodide. P(t-Bu)₂Me was less effective than P(o-tolyl)₃, particularly for α,β-unsaturated carbonyl substrates. No regio- or stereoisomerization occurred under these reaction conditions. The efficiency of the protocol was demonstrated by synthesis of an ¹¹C-methylated compound.