Rapid Room-Temperature 11C-Methylation of Arylamines with [11C]Methyl Iodide Promoted by Solid Inorganic-Bases in DMF

• Published in: European Journal of Organic Chemistry Vol. 2012; no. 7; pp. 1303 - 1310
• Main Authors: Cai, Lisheng, Xu, Rong, Guo, Xuelei, Pike, Victor W.
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.03.2012; WILEY‐VCH Verlag; Wiley; Wiley-VCH
• Subjects: Arylamine; Biological and medical sciences; Carbon-11; Chemistry; Chemistry, Organic; Contrast media. Radiopharmaceuticals; Exact sciences and technology; General and physical chemistry; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Isotopic labeling; Medical sciences; Methylation; Noncondensed benzenic compounds; Organic chemistry; Pharmacology. Drug treatments; Physical chemistry of induced reactions (with radiations, particles and ultrasonics); Physical Sciences; Preparations and properties; Radiopharmaceuticals; Science & Technology; Synthesis design; Ultrasonic chemistry; Ultrasound; ACIDS; Carbon-11; FORMYLATION; Synthesis design; C-11; AMINES; RADIOSYNTHESIS; ANILINES; N-ALKYLATION; Methylation; Radiopharmaceuticals; Arylamine; Ultrasound; DERIVATIVES; Isotopic labeling; Insoluble compound; Isotope labelling; Nitrogen heterocycle; Lithium Oxides; Carbon Isotopes; Selectivity; Pyrrole derivatives; Ester; Carbon 11; Radioisotopic product; Chemical synthesis; Anilide; Chemical reagent; Chemical labelling; Hydrolysis; Side reaction; N,N-Dimethylformamide; Medical imagery; Iodomethane; Positron emission tomography; Room temperature; Heterogeneous reaction
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201101499

[11C]Methyl iodide is the most widely used reagent for labeling radiotracers with carbon‐11 (t1/2 = 20.4 min) for molecular imaging with positron emission tomography. However, some substrates for labeling, especially primary arylamines and pyrroles, are sluggishly reactive towards [11C]methyl iodide. We found that insoluble inorganic bases, especially Li3N or Li2O, effectively promote rapid reactions (≤ 10 min) of such substrates with no‐carrier‐added [11C]methyl iodide in N,N‐dimethylformamide (DMF) at room temperature to give 11C‐methylated products in useful radiochemical yields. In particular, we discovered that some primary arylamines in Li3N/DMF were converted into their corresponding formanilides, and that these were readily N‐methylated with [11C]methyl iodide, which preceded easy basic hydrolysis to the desired [11C]N‐methyl secondary arylamines. The use of a solid base permitted selective reaction at an arylamino group and, in some cases, avoided undesirable side reactions, such as ester group hydrolysis. An ultrasound device proved useful to provide remote and constant agitation of the radioactive heterogeneous reaction mixtures but imparted no ultrasound‐specific chemical effect. Solid inorganic‐bases in DMF promote rapid 11C‐N‐methylation of primary arylamines at room temperature when agitated with ultrasound, often through reactive N‐formyl intermediates.