Efficient Reductive N‐¹¹C‐Methylation Using Arylamines or Alkylamines and In Situ–Generated [¹¹C]Formaldehyde From [¹¹C]Methyl Iodide

Abstract

Reductive N‐11C‐methylation using [11C]formaldehyde and amines has been used to prepare N‐11C‐methylated compounds. However, the yields of the N‐11C‐methylated compounds are often insufficient. In this study, we developed an efficient method for base‐free reductive N‐11C‐methylation that is applicable to a wide variety of substrates, including arylamines bearing electron‐withdrawing and electron‐donating substituents. A 2‐picoline borane complex, which is a stable and mild reductant, was used. Dimethyl sulfoxide was used as the primary reaction solvent, and glacial acetic acid or aqueous acetic acid was used as a cosolvent. While reductive N‐11C‐methylation efficiently proceeded under anhydrous conditions in most cases, the addition of water to the reductive N‐11C‐methylation generally increased the yield of the N‐11C‐methylated compounds. Substrates with hydroxy, carboxyl, nitrile, nitro, ester, amide, and phenone moieties and amine salts were applicable to the reaction. This proposed method for reductive N‐11C‐methylation should be applicable to a wide variety of substrates, including thermo‐labile and base‐sensitive compounds because the reaction was performed under relatively mild conditions (70°C) without the need for a base.