An innovation for development of Erlenmeyer-Pl?chl reaction and synthesis of AT-130 analogous: A new application of continuous-flow method

Article abstract of DOI:10.1039/c6ra00301j

The development of eco-friendly and efficient processes via one-pot multicomponent synthesis is a very attractive topic. In this work, the Erlenmeyer-Pl?chl azlactone synthesis was carried out through unique, safe, fast and practical conditions without any catalyst, applying a simple microreactor and gave the corresponding products exclusively. A continuous, first microflow synthesis of N-benzoylglycine carbamide derivatives as AT-130 analogues catalyzed by Nafion-H@SPIONs was also established successfully.

Full text of DOI:10.1039/c6ra00301j

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An innovation for development of Erlenmeyer–
Plochl reaction and synthesis of AT-130 analogous:
a new application of continuous-flow method†
¨
Cite this: RSC Adv., 2016, 6, 19861
Received 5th January 2016
Accepted 8th February 2016
*
Behnaz Shafiee, Laleh Hadian and Ahmad R. Khosropour
DOI: 10.1039/c6ra00301j
www.rsc.org/advances
The development of eco-friendly and efficient processes via one-pot scaling up, the obtained yields were much higher than when
multicomponent synthesis is a very attractive topic. In this work, the using conventional stirring.8
Erlenmeyer–Plochl azlactone synthesis was carried out through
Recently, catalyst and/or solvent-free reactions, in order to
¨
unique, safe, fast and practical conditions without any catalyst, meet the environmental demands, have become an important
applying a simple microreactor and gave the corresponding products aspect in organic transformations and great efforts have been
exclusively. A continuous, first microflow synthesis of N-benzoylgly- and still are being made to nd and develop new ones.9
cine carbamide derivatives as AT-130 analogues catalyzed by Nafion-
The strategy of one-pot condensation reactions leading to
interesting heterocyclic scaffolds is particularly useful for the
creation of diverse drug-like molecules for biological
screening.10 One of the most attractive condensation reactions
H@SPIONs was also established successfully.
¨
is the Erlenmeyer–Plochl reaction that has been used for the
Introduction
synthesis of 4-arylidene-2-phenyl-5(4H)-oxazolone derivatives11
and has a signicant place in the realm of pharmaceutical and
biological sciences.12 For instance, almazolone as an alkaloid
bearing azlactone core, was isolated from the Senegalese alga
Haraldiophyllum sp. and synthesized experimentally.13 These
systems also play a crucial role for the synthesis of hydrogel
supports for in vivo cell growth.14 Moreover, L-m-tyrosine can be
synthesized on larger-scale via a modication of the Erlen-
meyer’s azalactone synthesis.15 On the other hand, recent
efforts have been directed toward the development of Michael
additions of azlactones for the synthesis of a-amino acid
derivatives.16 Hence, due to their signicance specially from
medicinal and biological points of view, extensive effort has
been focused on the development of easy and efficient synthetic
Enhancing the efficiency of a reaction and at the same time
reducing the number of unnecessary synthetic steps is
a substantial challenge in the development and progress of any
chemical process.1 Moreover, establishing a sustainable one-pot
synthetic strategy is
a fundamental concern in organic
synthesis.2 In green chemistry, an eco-friendly reaction is
dened as “the utilization of a set of principles that reduces or
eliminates the use or generation of hazardous substances in the
design, manufacture, and application of chemical products”
and focuses on minimum hazard as the criteria while designing
new chemical processes.3 This may involve alternative reaction
activation approaches, such as microwave and ultrasonic irra-
diation in mechanochemical mixing4 or microreactor tech-
nology.5 Currently, many recent papers point out a growing
interest in developing microow technology in various organic
transformations.6 This technology, by increasing the perfor-
mance of heat- and mass-transfer characteristics and the ability
to efficiently optimize reaction conditions by controlling resi-
dence time, has developed as a precise attractive process
intensication tool.7 Moreover, the results illustrate that at
a very short residence time in the microreactor, even aer
methods of this heterocyclic nucleus.17 The Erlenmeyer–Plochl
¨
reaction is basically the condensation of an aldehyde with
hippuric acid with acetic anhydride as dehydrating agent and
the presence of a catalyst is essential.18 A variety of modied
methods utilizing different catalysts have been used success-
fully so far for performing this condensation.19 However, most
of them require reuxing for hours in toxic organic solvents, use
of expensive or corrosive catalysts and tedious work-up. As
a consequence, implementation of eco-friendly and straight-
forward chemical methods remains a particularly interesting
task. In order to improvement the synthetic strategy to develop
Department of Chemistry, University of Isfahan, 81746-73441, Isfahan, Iran. E-mail:
khosropour@chem.ui.ac.ir; khosropour@fas.harvard.edu; Fax: +98 3136689732;
Tel: +98 3137932700
¨
the ultimate green Erlenmeyer–Plochl reaction, herein, we
present the rst catalyst-free and solvent-free efficient synthesis
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra00301j
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of azlactones via a lab-scale continuous ow synthesis, as a truly
benign manner of the classic azlactone synthesis (Scheme 1).
In this specic case, it was realized that this technology
opens the opportunity to have a green and rapid azlactone
synthesis.
Result and discussion
The major component of the apparatus included a simple setup
using a syringe pump connected to the microreactor. The
microreactor system used in this study includes an in-house-
made tubing glass reactor which can be implemented in any
chemistry laboratory. The microtube reactor was fabricated in
a glass column (internal diameter, 0.5 mm; internal volume, 0.6
mL; length, 200 cm), which was placed in a water bath. A
temperature controller (TC) was used for balancing and setting
up heating and a back-pressure regulator (BPR) for pressure
control (Scheme 1).
Fig. 1 Effects of temperature and residence time in the microflow
azlactone synthesis.
general, various substitutions on the aromatic ring of aryl
aldehydes, which bear electron-neutral (Table 2, entries 1, 13
and 14), electron-decient (Table 2, entries 2–10 and 15), or
electron-rich substituents (Table 2, entries 11 and 12) afforded
the desired products in high to excellent yields.
Moreover, by using terephthalaldehyde under the same
conditions, the corresponding bis-azlactone A was obtained
exclusively (Scheme 2).
Next, these results encouraged us to expand our investiga-
tion to design a microow system for the synthesis of AT-130
analogues.
Investigation for designing of new and effective anti hepa-
titis B virus (HBV) compounds is a challenge for biologists,
pharmaceuticals and organic chemists.20 Since the discovery of
the naturally occurring 1, clinically used as an anti-HBV agent
AT-130, the N-benzoylglycine carbamide pharmacophore has
attracted considerable attention owing to the biological activity
associated with such compounds (Fig. 2).21
The reaction was initially screened to understand the inu-
ence of key factors in this process. Therefore, as a template
reaction 4-chlorobenzaldehyde (0.2 M), hippuric acid (0.2 M) in
acetic anhydride, were fed to the reactor via a syringe at ambient
pressure and the inuence of the temperature (60, 70, 80, 90
ꢀ
and 100 C) and residence time effects (tR: 30, 40, 50, and 60
min) on the yield of the desired product were investigated.
ꢀ
Initially, the temperature was stepwise increased to 100 C, at
constant residence time (30 min).
Periodic analyses of the mixture illustrated that the corre-
sponding product could be reached in 31% yield at 60 ꢀC (tR: 30
ꢀ
min) while achieving a good yield (72%) at 100 C (tR: 30 min).
Increasing the temperature further did not improve the yield.
Further examination showed a great improvement on yields by
increasing of residence time. As shown in Fig. 1, surprisingly
the yield increased to 85% at 90 ꢀC with tR ¼ 50 min. Lower
yields were obtained at lower temperature or residence time. As
illustrated, further increase of these two crucial factors (temp. >
Up to now, only rare examples have been reported for the
preparation of AT-130 analogues.21,22 However, they have some
drawbacks such as low functional group tolerance, the
requirement of harsh conditions such as needing long reaction
times or using an expensive metallic catalyst. Moreover, in
pharmaceutical products, metal residues are highly chal-
lenging, and thus should be kept to a minimum.
ꢀ
90 C and/or tR > 50 min) has no remarkable inuence on the
yield of the product. Therefore 0.72 ml hꢁ1 was furnished as the
optimum ow rate for this process.
Furthermore, comparison of the batch and continuous ow
systems clearly showed the merit of the new technique in this
transformation (Table 1).
We next investigated the scope and generality of this proce-
dure with regard to both aryl aldehydes and hippuric acids as
substrates under catalyst-free conditions. The representative
results of the investigation are summarized in Table 2. In
Therefore, creating of a new route for the synthesis of these
ne compounds could be an appealing approach.
Inspired by our recent report on the Dakin–West reaction via
a continuous ow system using Naon-H@SPIONs as a new
nano-catalyst,23 and the successful results from the synthesis of
azlactones via a continuous microow system, we envisioned
that the integration of this set into a microreactor device to
afford AT-130 analogues directly, could be valuable.
Table 1 Comparison of batch and continuous flow systems for the
synthesis of the model reactiona
Method
Temp. (ꢀC)
Time (min)
Yield (%)
Flow reactor
Batch reactor
90
90
50
50
87
23
Scheme 1 Microflow set-up for the preparation of Erlenmeyer–Plochl
reaction.
¨
a
Isolated yield.
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Table 2 Catalyst-free Erlenmeyer–Plochl reaction in a microreactor
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¨
Entry Product
Yielda (%) Entry Product
Yielda (%)
1
85
88
9
81
Scheme 3 Microflow set-up for the synthesis of N-benzoylglycine
carbamide.
2
3
4
5
10
81
92
93
89
87
90
84
11
12
13
Fig. 3 Optimization of the reaction conditions for the continuous flow
synthesis of N-benzoylglycine carbamide.
6
82
14
15
85
82
Table 3 Optimization reaction of 4-(4-chlorobenzylidene)-2-phenyl-
1,3-oxazol-5(4H)-one and p-toluidine in the presence of Nafion-
H@SPIONs under the flow reactiona
7
8
83
86
Naon-H loading
(mol%)
Entry
Yieldb (%)
a
Isolated yield.
1
2
3
4
5
6
—
5
0.186
0.215
0.28
0.35
0.35c
50
62
70
75
75
a
Reaction condition: 4-(4-chlorobenzylidene)-2-phenyl-1,3-oxazol-
5(4H)-one (1.0 eq.), and p-toluidine (1.0 eq.) in the presence of 60 mg
Naon-H@SPIONs. b Isolated yield. c In 70 mg Naon-H@SPIONs.
Scheme 2 Synthesis of the bis-azlactone A in the microreactor.
Table 4 Comparison of the batch and continuous flow systems for
synthesis of N-benzoylglycine carbamide
Method
Temp. (ꢀC)
Time (min)
Yielda (%)
Flow reactor
Batch reactor
60
60
75
75
75
24
a
Isolated yield.
Fig. 2 A N-benzoylglycine carbamide derivative with the anti-HBV
activity.
This method is novel, very practical and simple. We started
by employing a similar microreactor system used for the
azlactone synthesis. Hence, a sonicated mixture of an azlactone
(1 eq.), a primary or secondary amine (1.0 eq.) and Naon-
H@SPIONs (60 mg containing of 0.35 mol% Naon-H) in
acetonitrile (10 ml) was injected to the microreactor by
Therefore, according the aforementioned explanations, we
decided to establish a microow method for the synthesis of AT-
130 analogues through condensation reaction of amines with
azlactone derivatives catalyzed by Naon-H@SPIONs
(Scheme 3).
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Table 5 N-Benzoylglycine carbamide synthesis catalyzed by Nafion-H@SPIONs in the microreactor
Entry
Ar
Ar0
Amine
Yielda (%)
Residence time/min
1
2
3
4
5
6
7
p-FC6H4
p-ClC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
o-ClC6H4
CH3CH2NH2
CH3CH2NH2
CH3CH2NH2
C6H5CH2NH2
C6H5CH2NH2
C6H5CH2NH2
C6H5CH2NH2
89
88
75
79
78
67
89
40
50
70
72
60
77
34
p-MeOC6H4
p-ClC6H4
p-NO2C6H4
p-MeOC6H4
p-ClC6H4
8
p-MeOC6H4
C6H5
86
65
9
10
p-ClC6H4
p-NO2C6H4
C6H5
C6H5
p-MeC6H5NH2
p-MeC6H5NH2
75
74
75
67
11
p-NO2C6H4
C6H5
70
78
a
Isolated yield.
yields, however, remarkable yields were obtained when the
same reaction carried out with utilizing of Naon-H loading.
Compared with the results in Table 3 it can be concluded
that the optimum amount of the catalyst is 60 mg containing of
0.35 mol% Naon-H.
In Table 4, comparison between the batch and microow
processes is illustrated. These data show that in the micro-
reaction process the yield is increased remarkably.
Subsequently, we conrmed the scope of this process by
Scheme 4 Synthesis of the bis-N-benzoylglycine carbamide B in the
microreactor.
surveying
a broad range synthesis of N-benzoylglycine
carbamide (Table 5).
As evidenced by the results in Table 5, azlactones with
different substituents smoothly reacted with primary/secondary
amines or anilines, and produced the corresponding products
in generally good to high yields. It was observed that the effi-
ciency of this transformation is signicantly inuenced by the
electronic properties of the substituents on the azlactone ring
and the kind of the amine. This protocol was found to be
tolerant to a variety of functional groups such as F, Cl, MeO or
NO2 on the aromatic ring. To our delight, we also surveyed the
scope of the reaction with respect to the amine components. In
general, it was found that the electronic effect on the N-atom of
the amine is also effective in this transformation.
Fig. 4 Reusability of Nafion-H@SPIONs.
a syringing pump. It should be noted that aer the reaction was
nished, the catalyst could be separated from the mixture by
using a permanent magnet.
Also, as a model reaction, we started our investigation by
using of 4-(4-chlorobenzylidene)-2-phenyl-1,3-oxazol-5(4H)-one
and 4-methylaniline. Initially, a ow rate of 0.48 ml hꢁ1 was
selected with a temperature range between 40 to 70 ꢀC. The
temperature screening illustrated that at 60 ꢀC gave the best
result (75% isolated yield, Fig. 3).
Next, we screened for the effect of the immobilized amount
of Naon-H ꢀon the SPIONs when we run steady-state experi-
ments at 60 C and 75 min of residence time (0.48 ml hꢁ1). It
turned out that the rate and the efficiency of the product,
heavily depends on Naon-H. As shown in Table 3, in the
absence of Naon-H the product was obtained in very low
It is worthwhile to note that when bis-azlactone A was used
as the substrate, the reaction also proceeded smoothly and the
desired bis-N-benzoylglycine carbamide
B was obtained
successfully (Scheme 4).
The reusability of the catalyst was also evaluated with the
template reaction. Aer the reaction was completed, it was
cooled and acetone (10 ml) was added. The catalyst was sepa-
rated with a permanent magnet, washed with ethanol and water
and dried at 120 ꢀC. The results demonstrated recyclability and
its excellent stability under the reaction conditions (Fig. 4).
Indeed, these results in combination with the straightforward
method for separation of the catalyst from the reaction mixture
make it an excellent and practical candidate for further appli-
cations in microow systems.
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In conclusion, we have established a simple, fast, practical syringing pump was equipped with one syringe (1 ml). In the
and efficient system for the continuous ow and catalyst-free syringe, a sonicated mixture of an azlactone (1.0 eq.), a primary
¨
Erlenmeyer–Plochl azlactone synthesis. Moreover, this proce- or secondary amine (1.0 eq.) and Naon-H@SPIONs (60 mg
dure enables us to prepare N-benzoylglycine carbamides via containing of 0.35 mol% Naon-H) in acetonitrile (10 ml) were
combination of a nanocatalyst and the microow system. charged. The mixtures were fed into the system by syringe pump
Conversion rates in the microreactor are faster than those of the (ow rate: 0.48 ml hꢁ1) at 60 C. Aer the residence time was
ꢀ
batch system and the products are obtained in good yields with reached (75 min), the discharge was collected in a glass vessel
high purity. Furthermore, the high recyclability of the catalyst is equipped with an external permanent magnet. The collected
another main advantage of the process. Further scope of this catalyst by the magnet, washed two times with absolute ethanol
method is in progress in our laboratory.
(2 ꢂ 1 ml), air-dried, and used directly for the next run. Aer
separation of the catalyst from the resulting crude product, the
mixture was cooled to the room temperature. Subsequently,
water was added and the related product was ltered off and re-
crystallizated in hot ethanol. Most of the products are known in
the literature and were identied by comparison of their FT-IR
and NMR with literature data. As a sample, the characterization
data for N,N0-(1Z,10Z)-1,10-(1,4-phenylene)bis(3-(benzylamino)-3-
oxoprop-1-ene-2,1-diyl)dibenzamide (B) is:
IR (KBr) nmax: 3315, 3062, 2924, 1651.7, 1521.6, 1474, 1276,
697; 1H-NMR (400 MHz, DMSO-d6) d (ppm): 4.36 (d, 4H, J ¼ 5.75
Hz, CH2 benzylic); 7.17–7.20 (m, 3H, Ar), 7.20–7.31 (m, 9H, Ar),
7.44–7.58 (m, 10H, Ar), 7.96 (d, 4H, J ¼ 7.45 Hz, Ar), 8.70–8.72 (t,
2H, J ¼ 5.65 Hz, carbamoyl), 9.98 (s, 2H, benzamide). 13C-NMR
(100 MHz, DMSO-d6) d (ppm): 42.57, 126.49, 127.06, 127.73,
127.86, 128.06, 128.19, 129.35, 130.58, 131.58, 133.79, 134.47,
139.71, 164.89, 165.99.
Experimental
All chemicals were purchased from Merck and Sigma-Aldrich.
Naon-H@SPIONs was synthesised according to our paper.23
All known organic products were identied by comparison of
their physical and spectral data with those of authentic samples.
Thin layer chromatography (TLC) was performed on UV-active
aluminum-backed plates of silica gel (TLC Silica gel 60 F254).
1H, and 13C NMR spectra were measured on a Bruker DPX 400
MHz spectrometer in CDCl3 with chemical shi (d) given in
ppm. Coupling constants are given in Hz. The FT-IR spectra were
taken on a Nicolet-Impact 400D spectrophotometer in KBr
pellets and reported in cmꢁ1. Melting points were determined
using Stuart Scientic SMP2 apparatus and are uncorrected.
¨
General procedure for the Erlenmeyer–Plochl reaction in
a microreactor system
Acknowledgements
A microreactor system containing microtube reactor immersed
in a water bath, and a syringing pump were used. The syringing
pump was equipped with one syringe (1 ml). In the syringe,
a solution of 4-chlorobenzaldehyde (0.2 M) and hippuric acid (0.2
M) in acetic anhydride were charged. Next, the mixtures were fed
into the system by syringe pump (ow rate: 0.72 ml hꢁ1) at 90 ꢀC.
Aer the residence time was reached (50 min), the discharge was
collected in a glass vessel. Ethanol (5 ml) was added to it and
stirred for 10 min until a yellow solid precipitated. The mixture
was cooled in an ice bath and then an aqueous solution (20%) of
NaHCO3 (10 ml) was added. Aer ltration, the pure products
were recrystallized from ethanol in 80–93% yields. Most of the
products are known in the literature and were identied by
comparison of their FT-IR and NMR with literature data. As
a sample, the characterization data for (Z,Z)-4,40-(1,4-phenyl-
enedimethylidyne)bis(2-phenyl-5(4H)-oxazolone) (A) is:
This work was supported by Center of Excellence of University of
Isfahan (CECUI) and Iran National Science Foundation: INSF
(93009988).
Notes and references
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carbamides catalyzed by Naon-H@SPIONs in a microreactor
system
A
microreactor system containing a microtube reactor
immersed in a water bath, and a syringing pump were used. The
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19866 | RSC Adv., 2016, 6, 19861–19866
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