Palladium(0)-Mediated Rapid Methylation and Fluoromethylation on Carbon Frameworks by Reacting Methyl and Fluoromethyl Iodide with Aryl and Alkenyl Boronic Acid Esters: Useful for the Synthesis of [11C]CH3[BOND]C- and [18F]FCH2[BOND]C-Containing PET Tracers (PET=Positron Emission Tomography)

Authors

  • Hisashi Doi Dr.,

    1. RIKEN Center for Molecular Imaging Science (CMIS), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047 (Japan), Fax: (+81) 78-304-7112
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  • Ikuya Ban,

    1. Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194 (Japan)
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  • Akihito Nonoyama,

    1. Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194 (Japan)
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  • Kengo Sumi Dr.,

    1. Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194 (Japan)
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  • Chunxiang Kuang Dr.,

    1. Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194 (Japan)
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  • Takamitsu Hosoya Dr.,

    1. Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-Ku, Yokohama 226-8501 (Japan)
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  • Hideo Tsukada Dr.,

    1. Central Research Laboratory, Hamamatsu Photonics K.K., Hirakuchi 5000, Hamakita-ku, Hamamatsu, Shizuoka 434-8601 (Japan)
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  • Masaaki Suzuki Prof. Dr.

    1. RIKEN Center for Molecular Imaging Science (CMIS), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047 (Japan), Fax: (+81) 78-304-7112
    2. Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, 1–1 Yanagido, Gifu 501-1194 (Japan)
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  • Rapid Methylation on Carbon Frameworks For PET Tracer Synthesis, Part 8; for Parts 1–7, see references [4a–g].

Abstract

A new synthetic methodology for the rapid methylation and fluoromethylation on aryl and alkenyl frameworks by using methyl and fluoromethyl iodide with an organoboronic acid ester has been developed under the simple and mild conditions of [Pd2(dba)3]/P(o-CH3C6H4)3/K2CO3 (dba= dibenzylideneacetone) in DMF at 60 °C for 5 min (see scheme). This boron protocol provides a firm chemical basis for the synthesis of 11C- and 18F-incorporated PET tracers.

original image

The rapid methylation and fluoromethylation on aryl and alkenyl carbon frameworks by reacting methyl and fluoromethyl iodide with aryl and alkenyl boronates have been studied with the focus on the realization of the synthesis of [11C]CH3- and [18F]FCH2-labeled positron emission tomography (PET) tracers. The coupling of methyl iodide and pinacol phenylboronate (40 equiv) is accomplished in >91 % yield within 5 min at 60 °C under the conditions of [Pd2(dba)3]/P(o-CH3C6H4)3/K2CO3 (0.5:2:2; dba=dibenzylideneacetone) in DMF. The reaction shows a high generality and is applicable to various types of aryl and alkenyl boronates, giving the corresponding methylated derivatives in high yields (80–99 %). This reaction is also useful for the rapid incorporation of the fluoromethyl group. Thus, this boron protocol provides a firm chemical basis for the synthesis of 11C- and 18F-incorporated PET tracers and can be used as a complementary method for [11C]methylation together with our previous and ongoing processes using organotributylstannanes.

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