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

• Published in: Chemistry, an Asian journal Vol. 2; no. 12; p. 1513
• Main Authors: Nagaki, Aiichiro, Tomida, Yutaka, Usutani, Hirotsugu, Kim, Heejin, Takabayashi, Naofumi, Nokami, Toshiki, Okamoto, Hideho, Yoshida, Jun-ichi
• Format: Journal Article
• Language: English
• Published: Germany 03.12.2007
• ISSN: 1861-471X
• DOI: 10.1002/asia.200700231

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 degrees C, although much lower temperatures (< -48 degrees C) are needed for a batch reaction. The resulting p-bromophenyllithium was allowed to react with an electrophile in the micro flow system at 20 degrees 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 degrees 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 degrees C to avoid benzyne formation. The second Br-Li exchange reaction followed by reaction with an electrophile can be carried out at 0 degrees 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.