Generation and reactions of o-bromophenyllithium without benzyne formation using a microreader

Article abstract of DOI:10.1021/ja068330s

Microflow systems were found to serve as powerful tools for mechanistic studies on reactions involving highly unstable intermediates such as o-bromophenyllithium, which is known to decompose to benzyne very quickly even at -78 °C. Precise residence time control and precise temperature control of microsystems are responsible. Based on the information thus obtained, the Br-Li exchange reaction of o-dibromobenzene followed by reactions with electrophiles without benzyne formation was achieved using a microflow system. Sequential use of two bromine atoms in o-dibromobenzene with Br-Li exchange reactions followed by the reactions with electrophiles using the microsystem consisting of four micromixers and four microtube reactors was also accomplished. Copyright

Full text of DOI:10.1021/ja068330s

Published on Web 02/27/2007
Generation and Reactions of o-Bromophenyllithium without Benzyne
Formation Using a Microreactor
Hirotsugu Usutani, Yutaka Tomida, Aiichiro Nagaki, Hideho Okamoto, Toshiki Nokami, and
Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Nishikyo-ku, Kyoto 615-8510, Japan
Received November 20, 2006; E-mail: yoshida@sbchem.kyoto-u.ac.jp
Chemical synthesis in microreactors has received significant
research interests both from academia and industry.1,2 Among
characteristic features of microreactors, residence time control in
the microchannel is especially important.3 The length of time that
the solution remains inside the reactor, that is, residence time, can
be greatly reduced by reducing the microchannel length and
increasing the flow speed. On the basis of residence time control,
a highly unstable intermediate can be transferred to another location
where the follow-up reaction is conducted. Fast heat transfer, which
minimizes local deviation of temperature, is another important
feature of microsystems. In this paper, we wish to demonstrate that
these features are extremely useful in analyzing and controlling
reactions involving highly unstable organometallic intermediates.
We chose to study lithiation of o-dibromobenzene because
o-bromophenyllithium thus generated is well-known to undergo
rapid elimination to form benzyne, which gives various undesired
products, even at -78 °C.4,5 Therefore, in the case of a macroscale
batch reactor, the Br-Li exchange reaction should be carried out
at -100 °C or below, and an electrophile should be added at the
same temperature. We began with optimizing the conditions of the
Figure 1. Microsystem for Br-Li exchange reaction.
Scheme 1
Br-Li exchange reaction6 using the microsystem involving T-
shaped micromixers7 shown in Figure 1. o-Bromophenyllithium was
trapped by the reaction with methanol and the yield of bromoben-
zene was determined.
The reactions were carried with varying the residence time8 and
temperature9 in the microtube reactor R1. As profiled in Figure
2a, the yield was very low at temperatures higher than -60 °C,
presumably because of the decomposition of o-bromo-phenyllithium
intermediate to benzyne. At lower temperatures, the yield increased
with the decrease of the temperature because of slower benzyne
formation. Further decrease of temperature, however, resulted in
the decrease of the yield, because Br-Li exchange reaction did
not complete at lower temperatures. The effect of the residence
time is interesting as shown in Figure 2b. At -70 °C, the yield in-
creased with the residence time and became the maximum at
residence time of 0.8 s. This phenomenon can be explained in terms
of the progress of Br-Li exchange with the residence time. Further
increase of the residence time caused decrease of the yield, presum-
ably because of the benzyne formation. It is important to note that
the present temperature-residence-time profile is quite effective
Figure 2. Effects of temperature and residence time on the yield of
bromobenzene. (a) Counter plot with scatter overlay of the yields (%); (b)
crossection at -70 °C.
to unveil the features of the Br-Li exchange reaction together with
the stability of o-bromophenyllithium, although the efficiency of
the mixing may also affect the residence time. Therefore, microflow
systems serve as a powerful tool for mechanistic studies on reactions
involving highly unstable intermediates.
Using the optimized conditions (-78 °C, 0.8 s), the reactions
with various electrophiles were examined. Methyl triflate, chloro-
dimethylsilane, trimethylsilyl triflate, chlorotributyl-stannane, al-
dehydes, and ketones were effective to give the corresponding
substituted bromobenzene derivatives (Table 1).
With successful generation and reactions of o-bromophenyl-
lithium intermediate in hand, we next examined the sequential use
of two bromine atoms in o-dibromobenzene with Br-Li exchange
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10.1021/ja068330s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Reactions of o-Bromophenyllithium with Electrophiles
successfully achieved with various electrophiles. The method adds
a new dimension in organolithium chemistry.
In conclusion, we have revealed that microflow systems serve
as a powerful tool for mechanistic studies on reactions involving
highly unstable intermediates such as o-bromophenyllithium, which
is known to decompose to benzyne very quickly even at -78 °C.
It is also noteworthy that an efficient way of controlling the
generation and reactions of highly reactive intermediates can be
accomplished by virtue of precise residence time control and
temperature control inherent in microsystems. Various applications
based on the present principle are now in progress in our laboratory.
Acknowledgment. This work was partially supported by the
Grant-in-Aid for Scientific Research and NEDO projects.
a Determined by GC. b Isolated yield.
Supporting Information Available: Experimental procedures,
spectroscopic data of compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Figure 3. Sequential reactions of o-dibromobenzene.
Table 2. Sequential Reactions of o-Dibromobenzene with Two
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a Determined by GC. b Isolated yield
reactions followed by the reaction with electrophiles using the
microsystem consisting of four micromixers and four microtube
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