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email.gif - 0.3 Kmessage to the question about article 55 from John Lyga Hideshi Nakamua

Synthesis of 3,5-disubstituted 2-aminopyrazines by palladium-mediated cross-couplings and its use for preparing chemi- and/or bio-luminescent compounds

Hideshi Nakamura, Daisuke Takeuchi, Mihoko Aizawa, Chun Wu and Akio Murai

Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060, Japan


3,6,8-Trisubstituted imidazopyrazine-2-ones are widely distributed in marine organisms and in some cases are used as bioluminescent substances such as a jellyfish Aequorea aequorea and a crustacean Cypridina (Vargula) hirgendorfii. These compounds are also chemiluminescent and utilized to detect chemicals such as Ca2+ or active oxygen species such as superoxide. We have investigated convergent synthesis in order to prepare imidazopyrazinones with different luminescent properties such as colour of luminescence.

Since 5-aryl-3-substituted-2-aminopyrazines have been used to prepare chemi- and/or bio-luminescent imidazopyrazinones, we have developed a new approach to synthesize 3,5-disubstituted 2-aminopyrazines having conjugated chromophores from commercially available 2-aminopyrazine by several steps including palladium-mediated cross-coupling as a key reaction.

Results and discussion

I Synthesis of 3,5-disubstituted 2-aminopyrazines from 2-aminopyrazine.

  1. Alkylation of 2-aminopyrazine with organolithium
  2. Arylation of 3-bromo and 3,5-dibromo-2-aminopyrazine
  3. Alkynylation of 3-bromo and 3,5-dibromo-2-aminopyrazine

II Synthesis of chemi- and/or bioluminescent imidazopyrazinones

  1. Synthesis of Coelenterazine
  2. Synthesis of Cypridina luciferin analogue
  3. Synthesis and chmemiluminescence of imidazopyrazinones


2-Aminopyrazine is shown to be a useful starting material for preparing various types of chemi- and bio-luminescent imidazopyrazinones which allow one to control luminescet properties such as colour and the rate determining steps. The method described above may lead to bioluminescent analogues by a short synthesis, which could be used to investigate the detailed mechanisms of bioluminescence. Bioluminescent compounds together with bioluminescent enzymes will provide a new tool for studies on time-dependent biological phenomena.