than mixing, the reaction takes place before the homogeneity
of the solution is achieved. This often happens in macro batch
reactors such as flasks. In such cases, arguments based on
kinetics do not work, and product selectivity is determined
by the manner of mixing (disguised chemical selectivity).6
To obtain a predictable selectivity close to a kinetically based
one, extremely fast mixing is necessary, and micromixing
based on short diffusion paths proved quite effective for this
purpose. Fast heat transfer by virtue of high surface-to-
volume ratios in microspaces makes precise temperature
control possible in highly exothermic reactions. It is also
important to note that short residence time7 in microflow
systems is quite effective in controlling extremely fast
reactions involving highly unstable intermediates such as
organolithium compounds.8,9
With such information in hand, we set out to investigate
halogen-lithium exchange reactions of dibromobiaryls, and
we report herein that selective monolithiation can be achieved
by extremely fast 1:1 micromixing of dibromobiaryls and
n-butyllithium using microflow systems.
It is known that Br-Li exchange reaction of 2,2′-
dibromobiphenyl (1) gives a significant amount of dilithiated
product in a conventional macro batch system (Scheme 1).10
derived from monolithiation) and biphenyl (3, product
derived from dilithiation) were analyzed by GC. As shown
in Table 1, 2 was obtained with high selectivity at -78 °C,
Table 1. Lithiation of 2,2′-Dibromobiphenyl Using a
Conventional Macro Batch System
reaction
time
(min)
1
2
yield
(%)
3
yield
(%)
temperature
conversion
(%)
(°C)
-78
-48
-27
0
60
10
10
10
10
94a
86a
81a
75a
66a
76
69
48
36
14
4
4
18
25
34
24
a 2-Bromo-2′-butylbiphenyl was produced as a byproduct (see the
Supporting Information).
but the yield was not very high. The selectivity decreased
with an increase in temperature, and a significant amount of
3 was obtained at higher temperatures.
Scheme 1. Lithiation of 2,2′-Dibromobiphenyl with n-BuLi
Using a Conventional Macro Batch System
To confirm this, we re-examined the Br-Li exchange
reaction of 1 with 1 equiv of n-BuLi in a flask (20 mL round-
bottom glass flask with a magnetic stirrer). The resulting
organolithium compounds were allowed to react with
methanol, and the yields of 2-bromobiphenyl (2, product
Figure 1. Microflow system for lithiation of 2,2′-dibromobiphenyl.
In the next step, we examined the reaction using a
microflow system composed of two T-shaped micromixers
(M1 and M2) and two microtube reactors (R1 and R2)
shown in Figure 1.
(5) (a) Suga, S.; Nagaki, A.; Yoshida, J. Chem. Commun. 2003, 354.
(b) Nagaki, A.; Togai, M.; Suga, S.; Aoki, N.; Mae, K.; Yoshida, J. J. Am.
Chem. Soc. 2005, 127, 11666. (c) Suga, S.; Nagaki, A.; Tsutsui, Y.; Yoshida,
J. Org. Lett. 2003, 5, 945. (d) Suga, S.; Tsutsui, Y.; Nagaki, A.; Yoshida,
J. Bull. Chem. Soc. Jpn. 2005, 78, 1206. (e) Yoshida, J.; Nagaki, A.; Iwasaki,
T.; Suga, S. Chem. Eng. Technol. 2005, 28, 259.
(6) (a) Rys, P. Acc. Chem. Res. 1976, 9, 345. (b) Rys, P. Angew. Chem.,
Int. Ed. 1977, 12, 807.
(7) (a) Kawaguchi, T.; Miyata, H.; Ataka, K.; Mae, K.; Yoshida, J.
Angew. Chem., Int. Ed. 2005, 44, 2413. (b) Nagaki, A.; Kawamura, K.;
Suga, S.; Ando, T.; Sawamoto, M.; Yoshida, J. J. Am. Chem. Soc. 2004,
126, 14702. (c) Iwasaki, T.; Nagaki, A.; Yoshida, J. Chem. Commun. 2007,
1263.
(8) (a) Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.;
Yoshida, J. J. Am. Chem. Soc. 2007, 129, 3047. (b) Nagaki, A.; Tomida,
Y.; Usutani, H.; Kim, H.; Takabayashi, N.; Nokami, T.; Okamoto, H.;
Yoshida, J. Chem. Asian J. 2007, 2, 1513
.
(9) Halogen-lithium exchange reactions of simple aromatic halides in
microflow systems: (a) Schwalbe, T.; Autze, V.; Hohmann, M.; Stirner,
W. Org. Process Res. DeV. 2004, 8, 440. (b) Zhang, X.; Stefanick, S.;
Villani, F. J. Org. Process Res. DeV. 2004, 8, 455. (c) Ushiogi, Y.; Hase,
Figure 2. Effect of temperature and residence time in lithiation of
T.; Iinuma, Y.; Takata, A.; Yoshida, J. Chem. Commun. 2007, 2947
.
2,2′-dibromobiphenyl using microflow systems. Flow rate of a
solution of 1: 6.00 mL/min. Flow rate of n-BuLi/hexane: 1.20 mL/
min. Flow rate of methanol: 3.00 mL/min.
(10) For the lithiation of 2,2′-dibromobiphenyl: (a) Leroux, F.; Nicod,
N.; Bonnafoux, L.; Quissac, B.; Colobert, F. Lett. Org. Chem. 2006, 3,
165. (b) Morrison, D. J.; Trefz, T. K.; Piers, W. E.; McDonald, R.; Parvez,
M. J. Org. Chem. 2005, 70, 5309.
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Org. Lett., Vol. 10, No. 18, 2008