The convenient Michael addition of imidazoles to acrylates catalyzed by Lipozyme TL im from: Thermomyces lanuginosus in a continuous flow microreactor

Article abstract of DOI:10.1039/c8ob02533a

A fast and green protocol for the Michael addition of imidazoles to acrylates catalyzed by Lipozyme TL IM from Thermomyces lanuginosus in a continuous flow microreactor was developed. In contrast with existing methods, this method is simple (35 min), uses mild reaction conditions (45 °C) and is environmentally friendly. This enzymatic Michael addition performed in continuous flow microreactors is an innovation that may open up the use of enzymatic microreactors in imidazole analogue biotransformations.

Full text of DOI:10.1039/c8ob02533a

Organic &
Biomolecular Chemistry
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The convenient Michael addition of imidazoles
to acrylates catalyzed by Lipozyme TL IM from
Thermomyces lanuginosus in a continuous flow
microreactor†
Cite this: DOI: 10.1039/c8ob02533a
Received 12th October 2018,
Accepted 19th December 2018
Li-Hua Du, *a Zhen Dong,a Rui-Jie Long,a Ping-Feng Chen,a Miao Xuea and
DOI: 10.1039/c8ob02533a
rsc.li/obc
Xi-Ping Luo*b
A fast and green protocol for the Michael addition of imidazoles to environmentally hazardous residues or undesirable side-pro-
acrylates catalyzed by Lipozyme TL IM from Thermomyces lanugi- ducts.4 To avoid typical disadvantages resulting from the pres-
nosus in a continuous flow microreactor was developed. In con- ence of such catalysts, a great number of alternatives have
trast with existing methods, this method is simple (35 min), uses been studied in the past few years, such as KF/Al2O3,5
mild reaction conditions (45 °C) and is environmentally friendly. Y(NO3)3·6H2O,6 polyethylene glycol,7 solid-supported cata-
This enzymatic Michael addition performed in continuous flow lysts,8 ionic liquids,9 and others.10 However, most reported
microreactors is an innovation that may open up the use of enzy- protocols suffer from the disadvantages of affording unwanted
matic microreactors in imidazole analogue biotransformations.
byproducts, prolonged reaction times, high temperatures and
are sometimes accompanied by low yields. Hence, there are
continuous efforts toward the development of new and
effective methods for the synthesis of imidazole analogues.
Biocatalysis has gained great importance in organic syn-
thesis as it provides a high selectivity with fewer by-products,
thus making it an environmentally benign alternative to
chemical transformations.11 The alkaline protease (AP) from
Bacillus subtilis was first used to catalyze the Michael reaction
of imidazole,12 giving adducts with reasonable yields within a
few days. The zinc-active-site acylase ‘Amano’ from Aspergillus
oryzae proved to be more active, assuring reaction completion
within several hours.13 However, in both cases, the reaction
time was too long. Recent research has found that biocatalysis
in continuous flow reactors can be more productive, controlled
and environmentally sustainable.14 Flow processing has the
potential to accelerate biotransformations due to enhanced
mass transfer, making large-scale production more economi-
cally feasible in significantly smaller equipment with a sub-
stantial decrease in reaction time, and improvement in space–
time yield.15 The small dimensions of the reactors facilitate
Imidazoles are an important class of heterocycles, showing
interesting biological and chemical properties and being a
part of such crucial biomolecules as the amino acid histidine
and the neurotransmitter histamine. Imidazole analogues are
used as drugs and their therapeutic activities include antifun-
gal, anticancer, and antiviral, to name just a few.1 Imidazole
analogues, such as metronidazole, benznidazole and nimora-
zole, have shown high activities as anti-inflammatory and anti-
bacterial drugs2 on the market (Fig. 1). Imidazoles are incor-
porated into fluorescent skeletons to generate probes and diag-
nostic agents. The introduction of this five-membered hetero-
cycle into target compounds can be of help not only in modu-
lating biological activity, but also in altering water-solubility,
bioavailability and metabolic stability.3
Therefore, incorporation of the imidazole moiety into bio-
logically relevant scaffolds constitutes a valuable synthetic
strategy in medicinal chemistry. Among the known method-
ologies, Michael addition stands out as a very facile and highly
atom-efficient option, as it is one of the fundamental methods
for C–N bond formation. In general, the Michael addition
requires basic conditions or acidic catalysts that may lead to
aCollege of Pharmaceutical Science, ZheJiang University of Technology,
ZhejiangHangzhou, 310014, People’s Republic of China. E-mail: orgdlh@zjut.edu.cn,
orgdlh@gmail.com; Fax: +86 571 88320903
bZhejiang Provincial Key Laboratory of Chemical Utilization of Forestry Biomass,
Zhejiang A&F University, ZhejiangHangzhou, 311300, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02533a
Fig. 1 Some biologically active imidazole compounds.
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control of the reaction parameters, better process control
makes the reaction more efficient and waste generation is
minimized. Overall, these features result in reduced inventory,
waste and energy requirements of the flow biocatalytic
process, as compared to the conventional batch mode.16
Lipases are widely explored for esterification, transesterifica- Fig. 2 Photograph of the continuous flow system.
tion, and aminolysis-type reactions to synthesize various
important molecules related to pharmaceuticals, foods, and
flavorings.17 However, in recent years, the diversity of enzymes
with novel activities for organic synthesis has been greatly
extended and their use has expanded rapidly.18 In the interest
of developing mild methodologies for the synthesis of imid-
azole analogues, we envisaged modifying our procedure to
achieve a continuous flow microreactor protocol for the
Michael addition of imidazoles to acrylates. Specifically, we
first tried to use lipase TL IM from Thermomyces lanuginosus as
Fig. 3 Experimental setup for the Michael addition of imidazole deriva-
tives with acrylates catalyzed by lipase TL IM in a continuous flow
microreactor.
our catalyst (Scheme 1). Lipase TL IM is a microorganism-pro-
duced, food-grade lipase (EC 3.1.1.3) on granular silica gel.
The aim of our research is to investigate a convenient Michael
addition of imidazoles to acrylates catalyzed by Lipozyme TL
IM from Thermomyces lanuginosus in a continuous flow micro-
reactor, and at the same time, study the effect of various reac-
tion parameters on the reaction conversion.
trolled the reaction residence time through adjusting the flow
rate of feed 1 and feed 2. After initial optimization, it was
found that the target imidazole adducts (3a–3d, 3f–3i, 3p–3s)
could be obtained, after reaction for 35 min at the flow rate of
14.6 µL min−1, in excellent yield (70%–90%) after separation
and purification.
First, we performed two groups of blank control trials and
found that this reaction did not occur without the enzyme
involved (entry 1, Table 1). The reaction yield was less than 5%
with the denatured enzyme (entry 2, Table 1). (Lipozyme TL IM
was boiled in boiling urea aqueous solution for 1 hour.) When
the reaction was catalyzed by Lipozyme TL IM, the yield of the
reaction was increased considerably. For enzymatic reactions,
the reaction medium is an important influencing factor which
The experimental setup and a photograph of the continu-
ous flow system for Michael addition of imidazole derivatives
with acrylates catalyzed by lipase TL IM are presented in Fig. 2
and 3. We first designed the micro-flow reactor and then exam-
ined whether the reaction could be performed in continuous
flow microreactors. The micro-flow reactor was composed of a
syringe pump (Harvard Apparatus PHD 2000), reactant injec-
tor, Y-shaped mixer (Φ = 1.6 mm; M), microchannel reactor
and product collector. Syringe pumps were used to deliver
reagents from reactant injectors to the Y-shaped mixer and
then to the microchannel reactor. Reagent feed 1 (10 mL) with
the imidazole derivatives in DMSO solution and reagent feed 2
(10 mL) with acrylates in DMSO solution were fully mixed in
the Y-shaped mixer. Lipozyme TL IM (catalyst reactivity: 250
IUN g−1) was filled into a microchannel reactor made of a PFA
reactor coil (inner diameter ID = 1.8 mm, length = 1 m). The
microchannel reactor with catalyst in it was submerged into a
thermostatic water bath to control the temperature. We con-
Table 1 Solvent and temperature screening for enzymatic Michael
addition in a continuous flow microreactor catalyzed by Lipozyme TL IM
from Thermomyces lanuginosusa
Entry Enzyme
Solvent
DMSO
T (°C) Yieldb (%)
1
2
None
45
45
45
45
45
n.d.
<5
90
Lipozyme TL IM (denatured) DMSO
3
4
5
6
7
8
9
10
11
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
Lipozyme TL IM
DMSO
DMF
THF
82
n.d.
n.d.
n.d.
59
Pyridine 45
Toluene
DMSO
DMSO
DMSO
DMSO
45
35
40
50
55
79
83
80
Scheme 1 The Michael addition of imidazole derivatives with acrylates
catalyzed by lipase TL IM from Thermomyces lanuginosus in a continu-
ous-flow microreactor.
a Experimental conditions: 0.1 M 4-nitroimidazole, 0.4 M methyl acry-
late. b Yield of isolated product. n.d. means no reaction was found.
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Table 2 The effect of substrate ratio (4-nitroimidazole/methyl acrylate)
and reaction time/flow rate on the enzymatic Michael addition reaction
in a continuous flow microreactora
affects the enzyme activity and the process of the reaction.
Therefore, we first optimized our reaction conditions with
respect to the selection of reaction medium. We chose 4-nitro-
imidazole and methyl acrylate as the model reagents and the
reactions were carried out with feed 1 (1 mmol 4-nitroimida-
zole dissolved in 10 mL of solvent) and feed 2 (4 mmol methyl
acrylate dissolved in 10 mL of solvent) under 14.6 µL min−1
flow rates in a microreactor. Several solvents, including
toluene, pyridine, THF, DMF, and DMSO, were tested. We
found experimentally that the reaction only took place in
DMSO and DMF, whereas it was inhibited in the other sol-
vents. Due to its good substrate solubility and optimal reaction
conversion, DMSO was chosen as the best reaction medium
for the following research (Table 1).
Reaction temperature is another important parameter of
enzymatic reactions. After the best reaction medium was
obtained, we next examined the effect of temperature on the
Michael addition of imidazoles to acrylates catalyzed by
Lipozyme TL IM from Thermomyces lanuginosus in a continuous
flow microreactor. The temperature was adjusted from 35 °C to
55 °C and the results are shown in Table 1. It can be seen from
the experimental results that as the reaction temperature gradu-
ally increases, the reaction conversion increases too. When the
reaction was carried out at 35 °C, the reaction yield was only
59%. With the increase of reaction temperature, the reaction
conversion was improved considerably. When the reaction is
controlled at 45 °C, the Michael addition of imidazoles to acry-
lates catalyzed by Lipozyme TL IM from Thermomyces lanugino-
sus in a continuous flow microreactor can achieve the optimal
yield of 90%. Considering the optimal reaction conversion and
the safety and operability of the reaction, we performed the
enzymatic Michael addition of imidazoles to acrylates in a con-
tinuous flow microreactor at 45 °C as the most suitable reaction
temperature for the subsequent study.
Molar ratio of
donor/acceptor
Time
(min)
Flow rate
Yieldb
(%)
Entry
(µL min−1
)
1
2
3
4
5
6
7
8
9
1 : 1
1 : 2
1 : 3
1 : 4
1 : 5
1 : 4
1 : 4
1 : 4
1 : 4
35
35
35
35
35
20
25
30
40
14.6
14.6
14.6
14.6
14.6
25.4
20.4
17.0
12.8
42
57
83
90
88
30
45
80
87
a Experimental conditions: Reactions were carried out in DMSO at
45 °C. b Yield of isolated product.
Fig. 4 summarizes the effect of donor structure on the Michael
addition in the microreactor. As we can see from the results,
4-nitroimidazole was the most reactive substrate and could be
almost completely transformed. The reaction yields were 90%,
82% and 74%, respectively, for 4-nitroimidazole, 2-methyl-4-
nitroimidazole and 6-nitrobenzimidazole. The high conversion
obtained with 4-nitroimidazole can be explained as an effect
of an electron-withdrawing group on the imidazole structure.
Next, we optimized the effect of substrate ratio (donor/
acceptor) and reaction time/flow rate on the enzymatic
Michael addition reaction in a continuous flow microreactor
(Table 2). We chose 4-nitroimidazole and methyl acrylate as
the model reagents and changed the molar ratio (4-nitroimid-
azole/methyl acrylate) from 1 : 1 to 1 : 5. As we can see from
Table 2, with the increased proportion of methyl acrylate, the
reaction conversion increased too, and the best result was
obtained when the molar ratio was 1 : 4. Above that ratio, when
we continued to increase the amount of methyl acrylate, the
conversion of the reagents to the target product decreased.
From monitoring the reaction by TLC and HPLC, we found
that there were some byproducts in this case. Therefore, we
chose 1 : 4 as the optimal substrate ratio in the following
experiments. We also studied the effect of reaction time/flow
rate on synthesis of imidazoles analogues. As we can see from
Table 2, when the reaction time was varied from 20 min to
45 min with the same substrate ratio 1 : 4, we found that the
optimal reaction time was 35 min.
Fig. 4 Effect of imidazole structure on the Michael reaction with
methyl acrylate carried out in microreactors using lipase from
Thermomyces lanuginosus.
In order to study the mechanism of the reaction, we investi-
gated the effects of donor and acceptor structures on the enzy-
Fig. 5 Effect of acceptor structure on the Michael addition perform-
ance with 4-nitroimidazole carried out in microreactors using lipase
matic Michael reaction in a continuous flow microreactor. from Thermomyces lanuginosus.
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The nitro group, as a strong electron-withdrawing group on imidazole ring, while the reaction of 2-methyl-4-nitroimida-
the imidazole ring, greatly enhances the reactivity. In con- zole was less favorable than that of 4-nitroimidazole because
trast, electron-donating groups on the imidazole ring of the presence of an electron-donating methyl group in the
decrease the reactivity. By selecting different substituents on structure.
the imidazoles reacted with methyl acrylate under the same
After establishing the effect of the donor structure on the
reaction conditions, we can see that the reaction of 4-nitromi- reaction, we next studied the effect of the acceptor structure on
dazole was more favorable than that of imidazole due to the the enzymatic Michael addition in a continuous flow micro-
strong electron-withdrawing effect of the nitro group on the reactor. After several experiments, we found that the longer the
ester chain of the acrylates, the lower the yield of the corres-
ponding reaction. Fig. 5 summarizes the effect of different
chain length substituents of acrylate on the Michael addition
in microreactors. As we can see from the results, under the
same reaction conditions, methyl acrylate was the best reac-
tant, while the reaction conversion of ethyl acrylate and butyl
acrylate decreased successively. Because of the steric hindrance
effect, the reactions of tert-butyl acrylate and methyl methacry-
late were heavily disfavored, especially the methyl methacrylate
reaction, whose yield was as low as 5% (Fig. 5).
Table 3 Shaker and continuous flow synthesis of imidazole analogues
catalyzed by Lipozyme TL IMa
Entry
1
Imidazole
Acrylate
Methodb
Time
Yieldc (%)
B
A
35 min
24 h
90(3a)
81(3a)
2
3
4
5
B
A
B
A
B
A
35 min
24 h
35 min
24 h
35 min
24 h
35 min
24 h
83(3b)
75(3b)
75(3c)
71(3c)
64(3d)
60(3d)
Finally, to explore the scope and limitations of this new
highly-efficient Michael addition of imidazole derivatives to
acrylates catalyzed by Lipozyme TL IM from Thermomyces lanu-
ginosus in a continuous flow microreactor, four imidazole
derivatives, 4-nitroimidazole (1a), 2-methyl-4-nitroimidazole
(1b), imidazole (1c), and 6-nitrobenzimidazole (1d), and five
acrylates (2a–e) were subjected to the general reaction con-
ditions, using both a single-mode shaker reactor and a con-
tinuous flow/microreactor process. For the shaker experiments,
the reaction times needed to be about 24 h or more to obtain
ideal conversion (Method A). Using lipase-catalyzed Michael
addition of imidazole derivatives with acrylates under continu-
ous flow conditions, 12 adducts were synthesized in parallel in
a single experiment at the same flow rate (Method B). The
results were better with the flow/microreactor process than
with the single-mode shaker (Table 3, entries 1–20).
Importantly, applying the continuous flow/microreactor
process yielded a conversion to N-substituted imidazole deriva-
tives of 80% or more. This allows us to reduce the reaction
time and simplify the purification of products.
B
A
<5(3e)
<5(3e)
6
B
A
35 min
24 h
82(3f)
75(3f)
7
B
A
B
A
B
A
B
A
35 min
24 h
35 min
24 h
35 min
24 h
35 min
24 h
78(3g)
72(3g)
74(3h)
66(3h)
65(3i)
53(3i)
<5(3j)
<5(3j)
8
9
10
11
12
13
14
15
B
A
35 min
24 h
<5(3k)
<5(3k)
B
A
35 min
24 h
<5(3l)
<5(3l)
B
A
35 min
24 h
<5(3m)
<5(3m)
B
A
35 min
24 h
<5(3n)
<5(3n)
B
A
35 min
24 h
<5(3o)
<5(3o)
16
17
18
19
20
B
A
35 min
24 h
74(3p)
69(3p)
Conclusions
B
A
35 min
24 h
70(3q)
62(3q)
In conclusion, we have developed a fast and green protocol for
the Michael addition of imidazoles to acrylates catalyzed by
Lipozyme TL IM from Thermomyces lanuginosus in a continu-
ous flow microreactor. The reaction conditions, including the
reaction medium, reaction temperature, substrate molar ratio,
reaction time/flow rate and the effect of substrate structure on
the reaction, were examined. Compared with traditional
methods, the salient features of this method include the mild
reaction conditions (45 °C), short reaction times (35 min) and
high yields, which make our methodology a valuable contri-
bution to the field of N-substituted imidazole analogue syn-
thesis. The obtained N-substituted imidazole analogues may
be potentially bioactive and could be used as pharmacological
alternatives. Furthermore, we will continue our research to
B
A
35 min
24 h
65(3r)
58(3r)
B
A
35 min
24 h
58(3s)
50(3s)
B
A
35 min
24 h
<5(3t)
<5(3t)
a For reactions and structure of the products 3a–3t see Scheme 1.
b Method A: Shaker reactor, 5 mL DMSO, 0.2 g Lipozyme TL IM (40 mg
mL−1), 24 h. Method B: continuous flow microreactor, 7.3 µL min−1
feed 1 (0.1 M solution of imidazole derivatives in 10 mL DMSO) and
7.3 µL min−1 feed 2 (0.4 M solution of acrylates in 10 mL DMSO) at
45 °C (residence time 35 min), Lipozyme TL IM (0.87 g, 44 mg ml−1).
c Yield of isolated product.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors would like to thank the Natural Science
Foundation of Zhejiang Province (LY17B020010), the
International Cooperation Project 948 (2014-4-29), the National
Science and Technology Support Project (2015BAD14B0305),
the National Natural Science Foundation of China (21306172),
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