Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes

Aiichiro Nagaki, Yutaka Tomida, Hirotsugu Usutani, Heejin Kim, Naofumi Takabayashi, Toshiki Nokami, Hideho Okamoto, Jun Ichi Yoshida

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

A micro flow system consisting of micromixers and microtube reactors provides an effective method for the introduction of two electrophiles onto p-, m-, and o-dibromobenzenes. The Br-Li exchange reaction of p-dibromobenzene with nBuLi can be conducted by using the micro flow system at 20°C, although much lower temperatures (< -48°C) are needed for a batch reaction. The resulting p-bromophenyl-lithium was allowed to react with an electrophile in the micro flow system at 20°C. The p-substituted bromobenzene thus obtained was subjected to a second Br-Li exchange reaction followed by reaction with a second electrophile at 20°C in one flow. A similar transformation can be carried out with m-dibromobenzene by using the micro flow system. However, the Br-Li exchange reaction of o-dibromobenzene followed by reaction with an electrophile should be conducted at -78°C to avoid benzyne formation. The second Br-Li exchange reaction followed by reaction with an electrophile can be carried out at 0°C. By using the present method, a variety of p-, m-, and o-disubstituted benzenes were synthesized in one flow at much higher temperatures than are required for conventional batch reactions.

Original languageEnglish
Pages (from-to)1513-1523
Number of pages11
JournalChemistry - An Asian Journal
Volume2
Issue number12
DOIs
Publication statusPublished - 2007
Externally publishedYes

Keywords

  • Arenes
  • Flow reactions
  • Integrated micro flow synthesis
  • Lithiation
  • Microreactors

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

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    Nagaki, A., Tomida, Y., Usutani, H., Kim, H., Takabayashi, N., Nokami, T., Okamoto, H., & Yoshida, J. I. (2007). Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes. Chemistry - An Asian Journal, 2(12), 1513-1523. https://doi.org/10.1002/asia.200700231