Switching reaction pathways of benzo[b]thiophen-3-yllithium and benzo[b]furan-3-yllithium based on high-resolution residence-time and temperature control in a flow microreactor

Article abstract of DOI:10.1246/cl.2011.393

Reaction-pathway control of benzo[b]thiophen-3-yllithium and benzo[b]furan-3-yllithium was accomplished in flow microreactor systems. We could switch between the reaction with an electrophile before ring-opening and that after ring-opening at will by choosing an appropriate residence-time and temperature.

Full text of DOI:10.1246/cl.2011.393

doi:10.1246/cl.2011.393
Published on the web March 12, 2011
393
Switching Reaction Pathways of Benzo[b]thiophen-3-yllithium and Benzo[b]furan-3-yllithium
Based on High-resolution Residence-time and Temperature Control in a Flow Microreactor
1
2
2
2
3
3
Tatsuro Asai, Atsushi Takata, Yousuke Ushiogi, Yoshiharu Iinuma, Aiichiro Nagaki, and Jun-ichi Yoshida*
1
The Research Association of Micro Chemical Process Technology (MCPT) in Kyoto, Kyoto University, Kyoto 615-8530
2
Yamada Chemical Co., Ltd., Minami-ku, Kyoto 601-8105
3
Department of Synthetic and Biological Chemistry, Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510
(
Received January 31, 2011; CL-110079; E-mail: yoshida@sbchem.kyoto-u.ac.jp)
ring-opening
reaction
Reaction-pathway control of benzo[b]thiophen-3-yllithium
and benzo[b]furan-3-yllithium was accomplished in flow micro-
reactor systems. We could switch between the reaction with an
electrophile before ring-opening and that after ring-opening at
will by choosing an appropriate residence-time and temperature.
Br
Li
BuLi
Me
Me
X = S, O)
Me
X
X
X
X
(
Li
E: Electrophile
E
E: Electrophile
Me
Me
X
Chemical synthesis in flow microreactor systems has
received significant research interest from both academia and
E
1
,2
Scheme 1. Control of ring-opening reaction of benzo[b]thio-
phen-3-yllithium and benzo[b]furan-3-yllithium.
industry. Recent investigations revealed significant features
of flow microreactor systems including fast mixing stemming
from short diffusion path and fast heat transfer by virtue of
high surface-to-volume ratio. Such features often enhance the
selectivity of chemical reactions. Short residence time in a micro
channel is beneficial for controlling highly reactive intermedi-
ates. By taking advantage of such features of flow microreactor
systems, various chemical reactions for organic synthesis have
3
been developed so far. Flow microreactors are also effective
for integration of reactions to enhance the power of organic
4
synthesis.
Recently, we have reported that the generation of highly
reactive aryllithium compounds based on halogen­lithium
exchange followed by reactions with electrophiles could be
Figure 1. A flow microreactor system for the halogen­lithium
exchange reaction of 3-bromo-2-methylbenzothiophene or 3-
bromo-2-methylbenzofuran with n-BuLi followed by reaction
with iodomethane (X = S) or methanol (X = O). T-shaped
micromixers: M1 and M2, microtube reactors: R1 and R2.
5
conducted in flow microreactor systems. We have also studied
generation and reactions of heteroaryllithiums because they
serve as important reagents for synthesis of pharmaceuticals
6
and functional materials. During the course of our studies on
synthesis of photochromic diarylethenes7 using flow micro-
reactor systems, we observed that heteroaryllithiums generated
by the halogen­lithium exchange reaction of 3-bromo-2-meth-
ylbenzothiophene and 3-bromo-2-methylbenzofuran underwent
starting material is plotted against the temperature (T) and the
R
residence time in R1 (t ) as a contour map with scattered
overlay. In the low temperature (T < 0 °C)­short residence time
R
(t < 0.1 s) region, the starting material remained unchanged to
8
the ring-opening reaction shown in Scheme 1. In connection
some extent because halogen­lithium exchange is rather slow at
low temperatures. In Figure 2b, the yields of the methylated
product, 2,3-dimethylbenzothiophene are plotted against T and
with our interest in extending the synthetic potential of the flow
microreactor method, we studied this in detail, and herein we
report that the reaction pathways can be switched at will based
on residence-time and temperature control in a flow micro-
reactor.
R
t . High yields were obtained with longer residence times at low
R
temperatures (such as t > 1.0 s, T < ¹28 °C). The increase in T
caused the decrease in the yield presumably because the ring-
opening reaction of benzo[b]thiophen-3-yllithium intermediate
took place. In fact, at higher temperatures (T > 0 °C), the
product derived from the ring opening, 1-methylsulfanyl-2-
(prop-1-ynyl)benzene was obtained in good yields (Figure 2c).
Therefore, we can control the reaction pathways by choosing
an appropriate temperature­residence time. For example, 2,3-
dimethylbenzothiophene, the product derived from the benzo-
[b]thiophen-3-yllithium without ring opening was obtained in
A flow microreactor system consisting of two T-shaped
micromixers (M1 and M2) and two microtube reactors (R1 and
R2) shown in Figure 1 was used for halogen­lithium exchange
reaction of 3-bromo-2-methylbenzothiophene followed by the
reaction of an electrophile. To get deeper insight into the
conditions that control the reaction pathways, the reactions were
R
carried out with varying residence time (t ) in R1, and
temperature (T).
R
The results obtained with 3-bromo-2-methylbenzothiophene
and iodomethane are summarized in Figure 2 (See the Support-
86% yield at t = 1.6 s and T = ¹48 °C, while 1-methylsulfan-
yl-2-(prop-1-ynyl)benzene, the product derived from ring open-
9
R
ing Information for details ). In Figure 2a, the conversion of the
ing was obtained in 78% yield at t = 3.1 s and T = 24 °C.
Chem. Lett. 2011, 40, 393­395
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

3
94
(a) 2,3-dimethylbenzothiophene
Br
Me
Yield/%
00
1
80
S
S
6
4
0
0
Me
Me
20
0
(
b) 2-methylbenzofuran
0-2.0 10-1.5 10-1.0 10
-0.5
100
100.5 101.0
1
R
t /s
Figure 4. Plots of the yields of the products obtained without
ring opening of the heteroaryllithium intermediates against the
residence time (t ) at ¹28 °C in the flow microreactor system:
Me
R
(
a) 2,3-dimethylbenzothiophene and (b) 2-methylbenzofuran.
SMe
for 2-methylbenzofuran, the product derived from benzo[b]-
furan-3-yllithium without ring opening (Figure 3b) is slightly
smaller than that for 2,3-dimethylbenzothiophene (Figure 2b),
implying that benzo[b]furan-3-yllithium intermediate is slightly
less stable than benzo[b]thiophen-3-yllithium. At high temper-
ature­long residence times, 2-(prop-1-ynyl)phenol, the product
derived from the ring-opening of benzo[b]furan-3-yllithium was
obtained in good yields (Figure 3c).
Figure 4 clearly demonstrates the difference in the reactivity
between benzo[b]thiophen-3-yllithium and benzo[b]furan-3-yl-
lithium; the former is produced within 0.01 s while the latter is
produced more slowly because the halogen­lithium exchange is
slower, but the latter isomerizes more rapidly through the ring
opening. The reason for the difference in reactivity is not clear at
present.
Figure 2. Temperature­residence time (in R1) map for the
halogen­lithium exchange reaction of 3-bromo-2-methylbenzo-
thiophene with n-BuLi followed by the reaction with iodo-
methane: (a) Contour plot with scatter overlay of the conversion
of 3-bromo-2-methylbenzothiophene, (b) contour plot with
scatter overlay of the yield of 2,3-dimethylbenzothiophene,
and (c) contour plot with scatter overlay of the yield of 1-
methylsulfanyl-2-(prop-1-ynyl)benzene.
(a)
Br
Me
O
In conclusion, we have demonstrated that the precise control
of the residence time and the temperature in a flow microreactor
system enables the switch of the pathway of the reactions
involving heteroaryllithiums. It is also important to note that the
residence time­temperature maps serve as powerful tools for
analyzing behavior of reactive intermediates. Further work is in
progress to explore the full range of reactivity of heteroaryl-
lithium species and to develop synthetic applications of such
useful intermediates.
(
b)
Me
O
(
c)
Me
OH
This work was partially supported by the Grant-in-Aid for
Scientific Research and the NEDO project.
References and Notes
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Figure 3. Temperature­residence time (in R1) map for the
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2
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Chem. Lett. 2011, 40, 393­395
© 2011 The Chemical Society of Japan
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