Integrated micro flow synthesis based on sequential Br-Li exchange reactions of p-, m-, and o-dibromobenzenes.
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.
Nagaki
Aiichiro
A
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8510, Japan.
Tomida
Yutaka
Y
Usutani
Hirotsugu
H
Kim
Heejin
H
Takabayashi
Naofumi
N
Nokami
Toshiki
T
Okamoto
Hideho
H
Yoshida
Jun-ichi
J