Generation and reactions of heteroaromatic lithium compounds by using in-line mixer in a continuous flow microreactor system at mild conditions

Article abstract of DOI:10.1021/op300205j

A lithium-halogen exchange reaction procedure was applied to introduce electrophilic substituents to the heteroaromatics, which exhibited potential in the syntheses of pharmaceutical intermediates. In this contribution, generation and reactions of heteroa

Full text of DOI:10.1021/op300205j

Communication
pubs.acs.org/OPRD
Generation and Reactions of Heteroaromatic Lithium Compounds by
Using In-Line Mixer in a Continuous Flow Microreactor System at
Mild Conditions
Binjie Liu, Yong Fan, Xiaoming Lv, Xiaofeng Liu, Yongtai Yang, and Yu Jia*
Department of Chemistry, Fudan University, Shanghai 200433, P.R. China
S
* Supporting Information
bromophenyllithium reactions,30 etc. The fast heat transfer by
ABSTRACT: A lithium−halogen exchange reaction
procedure was applied to introduce electrophilic sub-
stituents to the heteroaromatics, which exhibited potential
in the syntheses of pharmaceutical intermediates. In this
contribution, generation and reactions of heteroaromatic
lithium compounds were successfully accomplished at 10
°C in a continuous flow microreactor equipped with an in-
line mixer. Extensive reaction results revealed that such a
synthetic method was widely applicable for different kinds
of heteroaromatics with various substituents. All results
highlighted that the lithium−halogen exchange reaction for
large-scale syntheses might be realized by microreactor
systems.
virtue of high surface-to-volume ratio in microspace makes it
easily to keep the accurate reaction temperature, which is
especially suitable for high exothermic reactions. The residence
time can be varied in the range of milliseconds to seconds by
adjusting the length of a micro channel and flow speed.31 Thus,
it is expected that the highly unstable intermediate of an
organo-reaction can be well transferred to follow-up reaction by
trapping of the reagents.
Lithium−halogen exchange reaction for industrial application
faces two challenges. First, it is how to effectively obtain the
desired products from the reactive intermediates, which often
undergo decomposition or/and isomerization with the
accumulation of reaction time. The second is how to reduce
the energy consumption, which is the key to operate green
production. In the microreactor, reagents are mixed in an
instant and the resident time as well as the reaction temperature
can be preciously controlled.32,33 So organolithium intermedi-
ates could be rapidly generated and transferred by using a
subsequent reaction. The synthesis of phenyllithium and
pyridyllithium by lithium-halogen exchange reactions have
been realized at 0 to 20 °C in microreaction.34−36 However, the
unstable heteroaromatic lithium compounds generated in
microreactor system at higher temperature have not been
reported so far. In this study, we show that heteroaromatic
lithium compounds could be successfully generated even at 10
°C by an in-line mixer and used for reactions with electrophiles
by exploiting the features of microflow systems.
1. INTRODUCTION
Heteroaromatic compounds are widespread in natural products,
which are important pharmaceuticals or pharmaceutical
intermediates because of their high biological activities.
Therefore, the syntheses of heteroaromatic compounds and
their derivatives have received significant research attention.1−4
During the past decades, various methods have been developed
and provide great impetus to the progress of their synthesis.5−10
Lithium−halogen exchange reaction procedure is one of the
most efficient methods to introduce electrophilic substituents
to the heteroaromatics.11−14 For such reaction, conventional
batch reaction procedure often requires cryogenic conditions
(generally −78 °C) under nitrogen atmosphere and the
dropping speed of organo-lithium has to be carefully controlled
to avoid the heat releasing and the side products formation.15,16
However, even in such harsh conditions, side reactions17−19
(such as deprotonation, coupling and decomposition) were still
hardly hampered. Therefore, the synthesis of heteroaromatic
derivatives via lithium−halogen exchange procedure remains
only in laboratory-scale. Thus, it is highly desired to develop a
simple, green and feasible method to large-scale preparation of
heteroaromatic derivatives based on lithium−halogen exchange
reaction for potential industrial application.
2. RESULTS AND DISCUSSION
The Br/Li exchange reaction was usually carried out at −78 °C
in conventional glassware synthesis. The temperatures (−40,
−20, 0, 10, and 20 °C) were chosen to study the difference
between the microreactor and in batch reactor. At first,
lithium−halogen exchange reaction of 2-bromopyridine with n-
BuLi followed by reaction with methanol was carried out by
using conventional glassware, as represented in Scheme 1.
A solution of n-BuLi in hexane (1.6 M) was added dropwise
to a solution of 2-bromopyridine in THF in a 100-mL round-
bottomed flask at −40, −20, 0, 10, and 20 °C. After the mixture
was stirred for 5 min at the same temperature, MeOH was
added. Then the mixture was stirred for another 5 min, and the
solution was analyzed by HPLC to determine the yield of
Microreactor, compared with conventional batch reactor, has
been recognized as an efficient organo-synthetic protocol for
large-scale production20−23 due to their precise control ability,
high surface-to-volume ratio and fast reaction efficiency.24−26
There are many important organic reactions that have been
successfully carried out within the microreactors, such as
nitrations,27 Swern oxidations,28 coupling reactions,29 and o-
Received: July 28, 2012
Published: December 23, 2012
© 2012 American Chemical Society
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collected in a conical flask, and the yield was determined by
HPLC (Figure 1 (2)). In contrast to conventional reactor, the
yield obtained through the microreactor was significantly
improved, even at a higher temperature. When the temperature
rose above 0 °C, the yield sustained only a minor reduction. We
speculated that the reaction yield could be increased through
improving the mixing effect of microtube reactors (R1) at the
same temperature.37,38
Scheme 1. Br/Li exchange reaction of 2-bromopyridine with
n-BuLi followed by reaction with MeOH using a
conventional macro batch system
Then the stainless steel in-line mixer (IM1) was added to the
microtube reactors (R1), as represented in Figure 2b. The in-
line mixer (IM1), which is a splitting-and-recombining type
micromixer, is believed to increase the mixing efficiency. The
yield was also determined by HPLC analysis (Figure 1 (1)) that
showed that the yield was still around 80% at 10 °C, which did
not decline as fast as before. With the manner of mixing by the
in-line mixer (IM1) the Br/Li exchange reaction was mixed
more sufficiently, which may have effectively reduced the
byproducts and decomposition.
The optimized conditions were tested for the Br/Li exchange
reaction in the microfluidic system. The results obtained with
varying the residence times (tR1) and reaction temperature (T)
in R1 are plotted in Figure 3. The reaction could be conducted
Figure 1. (1) Reaction of 2-bromopyridine with n-BuLi followed by
trapping with MeOH using the flow microreactor system with the in-
line mixer. (2) Reaction of 2-bromopyridine with n-BuLi followed by
trapping with MeOH using the flow microreactor system without the
in-line mixer. (3) Reaction of 2-bromopyridine with n-BuLi followed
by trapping with MeOH using a conventional macro batch system.
Figure 3. Effects of temperature and residence time on the yield of
pyridine. Counterplot with scatter overlay of the yields (%).
Figure 2. Flow microreactor system for Br/Li exchange reaction with
2-bromopyridine and n-BuLi followed by the reaction with MeOH. (a)
Without the in-line mixer (IM1) (b) Using the in-line mixer (IM1).
even at 10 °C, and the micro-flow systems showed a significant
advantage. Extremely fast heat transfer of the substrates and
high-resolution control of the residence time seemed to be
responsible for preventing decomposition of the active
intermediates and enabled the reaction to proceed without
cryogenic conditions.
pyridine (Figure 1 (3)). Analysis showed that the yield was
unsatisfactory and decreased with the increase of temperature.
Next, the reaction was carried out by employing a flow
microreactor system consisting of two T-shaped micromixers
(M1 and M2), two microtube reactors (R1 and R2), and three
syringe pumps (P1, P2, P3), as shown in Figure 2a.
The initial effort was focused on the effects of different
temperatures (−40, −20, 0, 10, and 20 °C) in the microreactor;
therefore, the fixed residence time (tR1 = 1 s) was used. In order
to accurately control the ratio of the reagents to achieve the
desirable mixing effect, a solution of 2-bromopyridine in THF
(0.16 M) and a solution of n-BuLi in hexane (0.16 M) were
pumped through the micromixer (M1) by syringe pumps (P1
and P2, respectively). The mixture flowed through the
microtube reactor (R1) and met neat MeOH which was
pumped by the third syringe pump (P3) through the
micromixer (M2). Then all the reactants were mixed and
flowed through the microtube reactors (R2). The product was
Under the optimized reaction conditions (T = 10 °C, tR1 = 1
s), various 2-substituted pyridines followed by reactions with
various electrophiles including Ph2CO, o-chlorobenzaldehyde,
and methyl 2-methoxybenzoate were obtained in acceptable
yields. Then the Br/Li exchange reactions of substrates such as
substituted bromopyridine, bromofuran, bromothiophene,
bromothiazole, and bromoquinoline were successfully carried
out under similar conditions (Table 1). It is noteworthy that
reactions of 5-bromo-2-(trifluoromethyl)pyridine and 3-bro-
moquinoline are better when carried out at 0 °C probably
because the intermediates were unstable. The results illustrate
that the integrated microflow systems serve as a fast and
efficient method for synthesizing various types of substituted
heteroaromatic compounds. Finally, by increasing run time or
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Table 1. Br/Li exchange reaction of heteroaromatic compounds with n-BuLi followed by reaction with electrophiles at 10 °C
using the flow microreactor system
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Table 1. continued
a
b
c
R1 = 2-ClPh, R2 = 2-OMePh. Isolated yield. At 0 °C.
concentrations the scale-up experiments demonstrated the
applicability of the microreactor. The productivity can be
enlarged to gram scale, indicating that scaling up is easy in this
microreactor system.
was used. The whole system was placed in a cooling bath (10
°C). A solution of 2-bromopyridine (0.16 M) in THF (flow
rate: 2.7 mL/min) and a solution of n-BuLi (0.16 M) in n-
hexane (flow rate: 2.7 mL/min) were introduced into M1 by
syringe pumping (P1, P2). The resulting solution passed
through R1 (ϕ = 500 μm, L = 20 cm, tR1 = 1 s) and was mixed
with benzophenone (0.24 M) in THF (flow rate: 2.7 mL/min)
in M2. The resulting solution passed through R2 (ϕ = 500 μm,
L = 150 cm). After a steady state was reached, the product
solution was collected for 2 min while being quenched with
H2O. The organic phase was separated, and the aqueous phase
was extracted with AcOEt. The combined organic phase was
dried, filtered, and concentrated, and the resulting crude
product was purified by flash chromatography on silica gel
(hexane/AcOEt = 10:1) to afford 1a (143 mg, 63% yield).
4.2. Typical Procedure for the Scale-Up Experiments
Using the Microreactor System. The 2-bromopyridine was
used as a model substrate to study the scale-up experiments,
and the electrophilic reagent was the benzophenone.
4.2.1. Longer Run Time for 1a. The experiment was
investigated by using the integrated flow microreactor system as
described above. The system parameters and optimized
conditions were the same, except that the product solutions
were collected for 40 min. No blocking of the microreactor was
found during the experimental process. The same workup and
purification of the crude product were performed to afford 1a
(2.91 g, 64% yield).
3. CONCLUSIONS
In conclusion, the microflow system with an in-line mixer can
effectively synthesize substituted heteroaromatics by Br/Li
exchange followed by reactions with electrophiles by virtue of a
fast mixing. The reactions could be completed at much higher
temperatures than those for a conventional reaction process,
such as 0 and 10 °C, because of rapid mixing and efficient
temperature control. The reaction temperature being close to
ambient temperature may be more conducive to industrial
application because of lower cost and less energy consump-
tion.39,40 At the same time the easy expansion feature of a
microreactor can reduce the production time of the product
from the laboratory to industry. Thus, the results expand the
application range of the Li/Br exchange reaction and provide an
efficient method for the synthesis of substituted heteroar-
omatics.
4. EXPERIMENTAL SECTION
4.1. Typical Procedure for the Preparation of
Substituted Heteroaromatic Compounds Using the
Microreactor System. Reagents and solvents were obtained
from commercial sources. THF and hexane were distilled from
blue solutions with sodium and benzophenone.
4.1.1. Diphenyl(2-pyridyl)methanol (1a). A microreactor
system consisting of two T-shaped micromixers (M1, M2), two
microtube reactors (R1, R2), and an in-line mixer (IM1, 50 μL)
4.2.2. Double Concentrations for 1a. The experiment was
investigated by using the integrated flow microreactor system as
described above. The system parameters and optimized
conditions were the same, except that the concentrations of
all solutions were twice equivalent (0.32 M 2-bromopyridine
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product solutions was 40 min. No blocking of the microreactor
was found during the experimental process. The same workup
and purification of the crude product was performed to afford
1a (5.60 g, 62% yield).
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures; compound characterization
data, including NMR and MS spectra for all described
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
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■
*E-mail: yujia@fudan.edu.cn. Fax: 86-21-6564-3925. Tele-
phone: 86-21-6564-2261.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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This work was financially supported by the National Basic
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