Efficient Claisen rearrangement of allyl para-substituted phenyl ethers using microreactors

Article abstract of DOI:10.1039/b822513c

A green way to synthesize allyl phenols has been developed. Quantitative yield of 2-allyl-4-methoxyphenol was obtained via a fast Claisen rearrangement in a microreactor system without solvent and work-up.

Full text of DOI:10.1039/b822513c

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www.rsc.org/greenchem | Green Chemistry
Efficient Claisen rearrangement of allyl para-substituted phenyl ethers
using microreactors†
Lingjie Kong, Qi Lin, Xiaoming Lv, Yongtai Yang, Yu Jia* and Yaming Zhou*
Received 19th December 2008, Accepted 30th April 2009
First published as an Advance Article on the web 8th May 2009
DOI: 10.1039/b822513c
A green way to synthesize allyl phenols has been developed.
Quantitative yield of 2-allyl-4-methoxyphenol was obtained
via a fast Claisen rearrangement in a microreactor system
without solvent and work-up.
Organic reactions using microreactors have attracted increasing
1–3
interest in the past few years. The heat transfer efficiency
of a conventional reaction system is usually low and causes
local overheating, which may lead to formation of impurities.
Microreactor systems, in contrast, have excellent heat transfer
characteristic. The surface area-to-volume ratio of a microre-
Scheme 1 The Claisen rearrangement of allyl para-substituted phenyl
ethers in a microreactor system.
2
-3
21,22
actor is up to 10 000–50 000 m m , which is larger than a
temperatures significantly have been reported.
However, the
4,5
conventional reaction vessel by up to two magnitudes. There-
fore, the heat exchange between the reaction mixtures passing
through the micro-channels and the external environment is
very efficient, and the heat transfer value reaches the order of
catalyst used, such as SnCl and BCl , are toxic and moisture
2
3
sensitive. To shorten the reaction time while maintaining high re-
action temperatures is another way to solve the above mentioned
problems that exists in the Claisen rearrangement. Besides the
0 kWm- K . The temperature of the reaction mixture in
2
-1
5
23
1
use of ionic liquid as solvent reported recently, we postulated
a microreactor system is able to achieve an even distribution
that local overheating can be easily avoided. As a result,
that this approach can also be achieved in a greener way by using
a microreactor. Here we report efficient Claisen rearrangement
of allyl para-substituted phenyl ethers in microreactor systems,
by which several allyl phenols have been prepared with high
purities without any solvent and work-up.
6
compared to the traditional reaction systems, products with
less impurities, higher yields and/or higher selectivity can be
7–9
generated in microreactor systems. A microreactor system
is also a naturally closed system. The material exchange of
the reaction mixture with the external environment is avoided
without any additional protection (i.e. inert gas protection).
In recent years, a number of studies on organic reactions
The microchannel we used is one kind of stainless steel pipe
that is commonly used in high-performance liquid chromatog-
raphy (HPLC). It is acid/base resistant and high-temperature
endurable. We fabricated a microreactor system, MR-1, with a
1
0–12
-1
using microreactor systems have been done.
It has covered
pump connected micro syringe (0.005-36 ml h ) and a 120 cm
1
3
14
various reaction types, including nitration, Wittig reaction,
long pipe (170 mm in id) with a maximal heating length of 106 cm.
The necessary cooling and collection devices linked in sequence
following the reaction section. The substrate is injected through
the pipe, heated in the oil bath, subsequently cooled in the second
bath, and finally collected from the other end of the pipe.
We used p-chlorophenyl allyl ether (substrate 1) as our model
substrate for the optimization of Claisen rearrangement in the
microreactor MR-1 (Fig. 1). The effect of temperature and
residence time on the reaction yield was studied. We started
15
16
Newman-Kwart rearrangement, fluorination and coupling
17,18
reactions,
etc. However, the study of Claisen rearrangement
reactions in microreactors at high temperatures has been few
19
reported so far.
The Claisen rearrangement (Scheme 1) is a powerful reaction
for carbon–carbon bond formation. The Claisen rearrangement
of allyl para-substituted phenyl ethers usually requires high
◦
temperatures (e.g. 200 C) and long reaction times under
20
◦
conventional conditions. Long exposure times of the reaction
mixtures to uneven heating at high temperatures is problematic,
and may cause the formation of many impurities. In addition,
at such a high temperature severe carbonization becomes a
problem that results in undesired products and therefore low
yields and tedious work-ups. Some successful applications of
Lewis Acid catalyzed Claisen rearrangements to reduce reaction
with a moderate temperature, 200 C, for the rearrangement,
considering the great heat transfer efficiency of the microreactor.
We explored the effect of different residence time, from 8 min to
24 min with 4 min interval, on the reaction by adjusting the flow
rate of the substrate at this temperature.
Department of Chemistry, Fudan University, Shanghai, 200433, P. R.
China. E-mail: yujia@fudan.edu.cn
†
Electronic supplementary information (ESI) available: Experimental
data. See DOI: 10.1039/b822513c
Fig. 1 The microreaction system 1 (MR-1).
1
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◦
We found that at 200 C, the yield of 2-allyl-4-chlorophenol
time was 24 min, compound 1 was generated in 82% yield, unlike
increased along with the residence time to reach 35% for 24 min.
Longer residence time led to a slow increase in yield (e.g. 37%
for 30 min) (Fig. 2).
the conventional Claisen rearrangement reaction, which gave
only 14% yield (entry 1, Table 1). Both H NMR and HPLC
showed that there are only two components in the crude product
of microreaction: the unreacted starting material and the target
product.
1
We believe this high reaction efficiency primarily benefits from
the excellent heat exchange in the microreactor: the substrate
reaches the energy threshold of the reaction immediately after
it flows into the heated part of the microchannel. In addition,
unlike the conventional reaction, the reaction in a microreactor
is a continuous process in the channel, in which the product
flows out of the reaction system immediately after the reaction
has occurred. Therefore, the reaction time is shortened, so is
the contract time of the reaction mixture with the heat source.
The chance of overheating and decomposition/carbonization
of the substrate and product may be reduced. Moreover, the
closed system design of the microreactor system that isolates the
reaction system from the external air may prevent possible oxi-
dation. Longer residences times were also tested. For example,
a reaction for 36 min was tried. However, there was not much
improvement in yield. This indicates that the reaction completed
within 24 min at this temperature, and further extension of the
residence time does not necessarily increase the yield.
Fig. 2 Effect of residence time on the yield of the reactions of substrate
1
at different temperatures.
◦
When the temperature was raised to 210 C, the yields with
different residence time increased correspondingly. This might
indicate that even in the microreactor system, the temperature
is still a key factor for an efficient rearrangement reaction.
Therefore, we further enhanced the reaction temperature. At
◦
2
20 C, even higher yields were obtained. When the residence
Table 1 Claisen rearrangement of allyl para-substituted phenyl ethers by using microreactors and conventional reactors
a
Yield (%)
◦
d
Entry
1
Substrate
Product
Residence time/min
24
T/ C
Microreaction
Conventional reaction
220
220
82
83
14
78 (3 h)
3
6
2
3
4
5
6
24
200
200
69
73
2
34 (3 h)
3
6
24
225
225
94
97
3
6
39
32
37
43
83 (3 h)
80 (3 h)
71 (3 h)
69 (3 h)
b
20
220
220
Quant.
Quant.
b
2
4
c
24
230
240
77
90
c
c
c
2
4
c
24
235
245
80
93
c
2
4
a
b
c
d
Determined by HPLC. No purification required. Use diphenylether as solvent. For each substrate (5 mmol) or the solution of the solid substrate
5 mmol), the conventional reaction was performed in a reflux device at the same temperature for the same reaction time (corresponding residence
(
time of the microreaction) as in the microreactor, and both the temperature and reaction time are the optimized ones for the microreaction.
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To this point, we have developed a solvent-free method to
efficiently synthesize 2-allyl-4-chlorophenol via Claisen rear-
rangement in a microreactor system in high yield within a short
reaction time. The optimal conditions we have found include
a short but sufficient residence time and a temperature near
the boiling point of the substrate. Based upon these findings,
we continued our study on a number of other para-substituted
substrates (Table 1) using our optimized conditions. Since there
are some differences in the chemical properties among the
substrates, residence times of both 24 min and 36 min were
tested for these reactions.
Fig. 3 Effect of residence time on the yield of the reaction of substrate
◦
4
at 220 C.
The results are summarized in Table 1. The reaction of
substrate 2 gave a relatively moderate yield (entry 2). It is due
to the low reaction temperature, which is limited by the low
boiling point of the substrate (~210 C). However, it is still
greatly superior to the corresponding reaction in a conventional
In order to compare with the microreactions, the conventional
reactions of substrates 1–6 in a hot reflux system were also tested
for both the same time (residence time) and typical long time
(3 h). The yields of conventional reactions for the same time
as microreaction were no more than 43%, which is only 1/3 to
1/2 of those in a microreactor system. Even when the reaction
time was increased to 3 h, the yields were much lower than those
of microreactions. In addition, the microreaction crude product
is pellucid, while the conventional crude product is black and
viscous. Several impurities formed in the conventional reaction
are observable in the HPLC traces (Fig. 4) (see Fig. 5 for an
example of substrate 6).
◦
reactor. The reactions of substrates 3 and 4 gave excellent results
(
entries 3 and 4). The purities of these two products were so
high that neither work-up nor purification was needed. Further
studies on substrate 4, 2-allyl-4-methoxyl-phenol, showed that
less residence time (i.e. 20 min) also gave a nearly quantitative
yield, and an even shorter residence time (12 min) still led to an
excellent yield (98%, Fig. 3).
The above reaction substrates are all liquid at room tem-
perature, and undergo solvent-free reaction very well in the
microreactor system. In order to expand the application of this
new reaction platform, we also used two solid substrates, 5 and
The influence of the substrate flow rate in the microchannel
was also explored in addition to the reaction temperature and
residence time. For each microreactor with a fixed heating length,
the residence time and flow rate of the substrate can not be
changed at the same time (heating length μ residence time ¥
flow rate). Therefore, we set up microreactor MR-2, which was
fabricated by the same way as MR-1 except that its heating
length is twice as that of MR-1. When the residence time is the
same, the flowing velocity of the substrate in MR-2 is twice as
6
. A high boiling point ether Ph O was used as solvent. In order
2
to obtain the maximum efficiency of our microreactor, we used
the least amount of solvent for preparing the most concentrated
solution of the substrate in Ph
2
O. These approaches gave yields
of 90% and 93%, respectively (entries 5 and 6).
2
Fig. 4 Comparative HPLC traces of Claisen rearrangement reaction mixtures of substrate 6 (use Ph O as solvent) in a conventional hot reflux device
(
A) or a microreactor (B). ᭹ indicates unidentified impurities. Reading at 215 nm.
1
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Notes and references
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2
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2
◦
and performed parallel reactions at 220 C with the residence
1
time from 8 to 24 min with 4 min interval.
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croreactors. We have developed a new green synthetic platform
in a microreactor system to synthesize allyl para-substituted
phenyl phenols via Claisen rearrangement in high efficiency.
Compared with the conventional method, much higher yields
and purities have been obtained within much shorter reaction
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This journal is © The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 1108–1111 | 1111