Batch and continuous flow preparation of hantzsch 1,4-dihydropyridines under microwave heating and simultaneous real- Time monitoring by raman spectroscopy. An exploratory study

Article abstract of DOI:10.3390/molecules19079986

Dialkyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates have been prepared in a batch mode under conventional heating as well as under continuous flow conditions in the Miniflow 200SS, Sairem's microwave- Assisted batch and continuous flow equipment. Real- Time monitoring of the reactions by Raman spectroscopy enabled to compare both heating modes and to determine (optimized) reaction times.

Full text of DOI:10.3390/molecules19079986

Molecules 2014, 19, 9986-9998; doi:10.3390/molecules19079986
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Batch and Continuous Flow Preparation of Hantzsch
1,4-Dihydropyridines under Microwave Heating and
Simultaneous Real-time Monitoring by Raman Spectroscopy.
An Exploratory Study
Sylvain Christiaens 1, Xavier Vantyghem 1, Marilena Radoiu 2 and Jean Jacques Vanden Eynde 1,*
1
Laboratory of Organic Chemistry, University of Mons-UMONS, 23 Place du Parc,
B-7000 Mons, Belgium; E-Mails: spit06@hotmail.com (S.C.); mxiano@hotmail.com (X.V.)
2
SAIREM SAS, 12 porte du Grand Lyon, F-01702 Neyron, France; E-Mail: mradoiu@sairem.com
* Author to whom correspondence should be addressed;
E-Mail: jean-jacques.vandeneynde@ex.umons.ac.be; Tel.: +32-65-373-337.
Received: 23 May 2014; in revised form: 19 June 2014 / Accepted: 26 June 2014 /
Published: 9 July 2014
Abstract: Dialkyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates have been prepared
in a batch mode under conventional heating as well as under continuous flow conditions in
the Miniflow 200SS, Sairem’s microwave-assisted batch and continuous flow equipment.
Real-time monitoring of the reactions by Raman spectroscopy enabled to compare both
heating modes and to determine (optimized) reaction times.
Keywords: 1,4-DHPs; flow chemistry; Hantzsch pyridines; microwave; Raman spectroscopy;
real-time monitoring
1. Introduction
Many organic reactions are now routinely run in domestic or dedicated microwave ovens and the
subject is regularly reviewed [1–6]. High yields, high purity, high selectivity, and shorter reaction
times are often claimed to be associated with microwave-assisted syntheses. However, the experiments
are generally only conducted on a few milligrams of chemicals because of the penetration depth of the
microwaves. The efficiency of the heating is also highly dependent on the nature of the reaction
mixture (solvents and reagents). Due to those restrictions, scaling-up emerges as a challenge that is
difficult to address in the batch mode. Hamelin et al. [7] and Loupy et al. [8] used a one-liter quartz

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reactor in a Prolabo oven [9] to prepare around 200 g of dioxalanes, dithiolanes, or oxathiolanes and
octyl acetate respectively. Leadbeater et al. [10] synthesized one mole (196 g) of 4-acetylbiphenyl by
employing a 3-liter round-bottom flask in a CEM Mars oven.
More interestingly, another way to scale up microwave-assisted reactions is to shift to continuous
flow conditions in open or closed loop modes [11,12]. The idea was initially developed by
Strauss et al. [13] at the end of the 1980s and led to real industrial applications among which the
microwave-assisted synthesis of Laurydone®, a moisturizer found in lipsticks and other make-up
products (see Figure 1).
Figure 1. Sairem microwave-assisted reactor for Laurydone® production (courtesy of
Sairem SAS).

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In such continuous flow systems, the reaction mixture is transferred from a reservoir and transits in
the microwave cavity before ending in a collector. Thus appropriate adjustment of the flow rates is a
requisite to ensure that the reagents are completely consumed before they are pumped out of the
reactor. To facilitate this, kinetic data for the concerned reactions under closely related experimental
conditions must be collected. This is far from a trivial situation especially if sampling during
microwave-assisted reactions requires the irradiation to be stopped and the reactor cooled for
safety reasons. To the best of our knowledge there are two spectroscopic methods that allow
acquisition of analytical data in real-time for syntheses performed in microwave equipment:
• Infrared spectroscopy: in 1999 Te-As-Se based optical glass fibers were developed at the
University of Rennes 1, France by Lucas et al. [14] and used as evanescent wave chemical
sensors by Perio [15] in the Hamelin group. The fibers were directly introduced in the reaction
media and infrared spectra were periodically recorded. In particular the disappearance of the
carbonyl band due to the C=O vibration in 3-pentanone or cyclohexanone was monitored when
those ketones were reacted with trimethyl orthoformate in the presence of Montmorillonite K10
clay or with mercaptoethanol in the presence of para-toluenesulfonic acid. Some patents [16–18]
cover the subject, but for unknown reasons the technology has fallen into oblivion.
• Raman spectroscopy: the method does not require an immersion of the probe into the reactor but
only a contact to the exterior wall. A first report [19] on the subject was published in 1995 and a
full description of the instrumentation and its setup has been disclosed by Pivonka and
Empfield [20] in 2004. These publications have been followed by the work of Leadbeater
et al. [21–27], who used a CEM oven modified to allow introduction of a Raman probe into the
microwave cavity.
In this work we report the results obtained in the preparation of Hantzsch 1,4-dihydropyridines in a
prototype microwave equipment designed and manufactured by Sairem SAS, France. The initial
reactions were performed in batch mode and monitored in real-time by Raman spectroscopy. The data
obtained have been further exploited to extrapolate experimental conditions for continuous flow
processing under microwave irradiation.
2. Results and Discussion
2.1. Choice of Reaction
Dialkyl 1,4-dihydropyridine-3,5-dicarboxylates (1,4-DHPs) are known as Hantzsch 1,4-
dihydropyridines. They are generally obtained by the Hantzsch pyridine synthesis [28] from an
aldehyde, a β-ketoester (2 equivalents), and a source of ammonia (Scheme 1). The reaction has been
reviewed [29] and mention should be made that the Hantzsch pyridine synthesis has already been
scaled up under flow conditions and microwave irradiation [30,31].

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Scheme 1. Preparation of Hantzsch 1,4-dihydropyridines.
Diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (1: R = CH3, R' = C2H5, R'' = H) is one
of the simplest representatives of the family. Due to its structural similarity to coenzyme nicotinamide
adenine dinucleotide (NADH) it is often used [32] as a mimic of the enzyme in biological studies.
Several 1,4-dihydropyridines (1,4-DHPs) are used as calcium channel modulators for the treatment of
hypertension and angina pectoris [33]. Other derivatives have been reported to exhibit antitrypanosomal,
antitubercular, anticancer, antiplasmodial, antileishmanial, antibacterial, and antioxidant activities [33].
2.2. Materials and Methods
2.2.1. The Raman Spectrometer
The Raman spectra were recorded using an Enwave Optronics EZRamanTM-M spectrometer,
(Figure 2). The spectrometer is equipped with a 785 nm frequency stabilized excitation laser source
tunable from 0 to 300–400 mW and a linear CCD array covering a range of wavelength from 250 to
2350 cm−1. The fiber-optic probe is composed of a 100 μm excitation fiber and a 200 µm collection
fiber. The contact measuring stainless lens-tube can be readily replaced by a quartz tube.
Figure 2. The Enwave Optronics EZRaman™-M spectrometer.
2.2.2. The Conventional Heating System
In addition to classical glassware equipment, we also performed reactions by using a Zinsser-Minilab®
system, Figure 3. Holes in the heating block allowed introduction of the lens-tube of the Raman
spectrometer in direct contact with the reactor.

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Figure 3. The Zinsser-Minilab® system.
2.2.3. The Microwave (Dielectric) Heating Method & Equipment
The experiments were performed in a prototype 2.45 GHz microwave equipment, MiniFlow 200SS
(Figure 4) designed and manufactured by Sairem SAS, Neyron, France.
Figure 4. The Sairem prototype microwave equipment. (a) The MiniFlow 200 SS consists
of a microwave solid state (transistor) generator, programmable logic controller, and fiber
optic thermometer; microwave parameters (forward power, reflected power), time, and
temperature are controlled via a touch screen digital display. (b) The U-shaped WR340
waveguide consists of a manual coaxial impedance tuner, a coaxial to WR340 transition, a
monomode (transversal electric) cavity (continuous flow or batch reactors are placed
within the cavity) with a lateral chimney for Raman spectrometer probe, and manual
sliding short circuit for reflected power optimization. (c) Detail of lateral chimney and
Raman spectrometer probe. (d) Custom made continuous flow reactor (internal volume of
40 mL) and detail of the mixing chamber, borosilicate glass. (e) Different custom made
batch reactors, borosilicate glass.

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Figure 4. Cont.
The device is characterized by the following features:
•
•
•
2.45 GHz microwaves are delivered in continuous wave (CW) by a solid state (transistor)
microwave generator; the microwave power can be adjusted from 1 W to 200 W in steps of 1 W;
The microwave power is transmitted from the solid state generator to the U-shaped waveguide
using a coaxial cable 1 m long;
The device enables measurement (via a built-in circulator) and adjustment (using the manual
sliding short circuit and if necessary the manual impedance tuner) of the reflected microwave
power so that maximum energy is available and transferred into the reaction medium with
limited loss;
•
The temperature inside the reactors was measured directly in the mixture with a fiber optic
temperature sensor (Neoptix, Québec City, Québec, Canada) and after the heating ramp period,
the power of the microwave irradiation was automatically adjusted in order to maintain the
chosen final reaction temperature for a given period;
•
•
A lateral chimney allows the introduction of a probe into the cavity of the U-shaped waveguide
and more specifically the introduction of a quartz Raman probe;
The same equipment can be used to perform reactions under both batch and continuous flow.
The performances of the Sairem prototype equipment have been compared with those of the
Biotage Initiator® oven.

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2.3. Preparation of a Reference Sample 1 under Conventional Heating
To obtain a reference sample of diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (1) we
reproduced the protocol reported by Norcross et al. [34]. A mixture of aqueous formaldehyde (37% in
water and 10%–15% of methanol; 1.4 mL; 18.70 mmol), ethyl acetoacetate (5.0 mL; 39.06 mmol),
and concentrated aqueous ammonia (25% in water; 6.2 mL; 82.97 mmol) in ethanol (2.0 mL) was
heated at reflux for 30 min. After cooling the precipitate was filtered, rinsed with well-chilled ethanol
(0–5 °C; 5–10 mL) and recrystallized from ethanol. The procedure enabled isolation of the expected
1,4-DHP but was not appropriate for monitoring by Raman spectroscopy. Indeed after the addition of
the aqueous solution of ammonia, the reaction mixture became biphasic and the 1,4-DHP precipitated
during the heating period. Therefore we preferred to use a methanolic solution of ammonia, to replace
ethanol by methanol, and to increase the volume of solvent. The protocol adopted in this work is thus
described hereafter. A mixture of aqueous formaldehyde (37% in water and 10%–15% of methanol;
0.7 mL; 9.35 mmol), ethyl acetoacetate (2.5 mL; 19.53 mmol), and a methanolic solution of ammonia
(15.5% in methanol; 3.0 mL; 21.02 mmol) in methanol (4.0 mL) was heated at 50 °C for the
appropriate period of time (see text). Under such conditions (solvents and temperature) the reaction
medium was homogeneous and the final DHP did not precipitate.
2.4. Preliminary Study by Raman Spectroscopy
We first recorded the Raman spectra of the solvents, reagents, and the final 1,4-DHP 1. From the
spectra it clearly appeared that the disappearance of the β-ketoester could be visualized by monitoring
the decrease of the carbonyl band at 1735 cm−1. The appearance of the DHP could be monitored by
observing the increase of the corresponding carbonyl band at 1644 cm−1. There is no interference
between those two peaks and other absorption bands.
In order to collect quantitative data, we recorded the intensity of those two peaks as a function of
the concentration in a mixture of water and methanol (corresponding to the experimental conditions of
the preparation of the DHP). Because the intensities of the peaks for a given concentration were not
always perfectly reproducible, we found it more accurate to correlate the concentrations to the ratio of
the intensity of the carbonyl peaks to the intensity of a peak of methanol at 1026 cm−1. This way linear
relationship could be readily established. Spectra were recorded on samples heated at 50 °C (vide supra).
2.5. Reactions in Batch Mode
2.5.1. Reaction in a Mixture of Methanol and Water
The reaction between aqueous formaldehyde, ethyl acetoacetate, and ammonia in methanol was
performed under conventional heating (Zinsser-Minilab® system) or dielectric heating in both sets of
microwave equipment. The disappearance of the β-ketoester was monitored (Figure 5) in real-time by
Raman spectroscopy for the synthesis under conventional heating and in the MiniFlow 200SS. In the
case of the synthesis carried out in the Biotage oven, the reactor was taken out of the irradiation cavity
and the spectrum was immediately recorded.

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Figure 5. Disappearance of ethyl acetoacetate as a function of time for reactions performed
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at 50 °C under conventional heating (blue), and dielectric (microwave) heating: Sairem
Miniflow 200SS (green), Biotage Initiator® (red).
100
% of
AcAcOEt
80
60
40
20
0
10
Time (min)
For reasons of clarity, only data corresponding to the composition of the medium after 0, 5, and
15 min are presented. Figure 5 clearly shows that dielectric (microwave) heating favors the
disappearance of the β-ketoester. This is however related to the period of time required to attain the
reaction temperature fixed at 50 °C. Under conventional heating the final temperature was reached
after a period of about 150 s whereas that period was reduced to 12 s using the Miniflow 200 SS and
24 s using the Biotage Initiator®.
2.5.2. Reaction in a Mixture of Acetonitrile and Water
It is well known that solvents do not absorb electromagnetic waves in the same way. This concept is
expressed by the loss tangent factor (tan δ) [35]. In our hands, with the MiniFlow 200SS, for a forward
power of 100 W, the measured reflected power (after optimization with the manual sliding short circuit
and the manual impedance tuner) was 4 W for methanol and 31 W for acetonitrile (glass reactor with
an outer diameter of 30 mm and filled with 25 mL of solvent). Accordingly, reactions in which the
β-ketoester was dissolved in acetonitrile were slower than those involving the β-ketoester dissolved in
methanol. However, this result cannot be directly linked to a “microwave effect” because we observed
that the same situation occurred for syntheses performed under conventional heating.
2.5.3. Extension to the Preparation of Other 1,4-DHPs
Experimentally we observed that tert-butyl acetoacetate was consumed slower than the ethyl and
methyl analogs (methanol was used as a solvent). This was true under conventional heating and
dielectric heating; steric effects can be reasonably invoked to explain this observation.
2.6. Reaction under Continuous Flow Conditions
When working in batch mode we found that more than 80% of the starting β-ketoester was
consumed within 15 min under microwave irradiation at 50 °C. The volume of the reaction chamber of
the flow cell was 40 mL. Therefore we decided to irradiate the reaction medium for approximately
30 min by adjusting the flow rate to 1.4 mL/min (MINIPULS evolution® peristaltic pump, Gilson,
Middleton, WI, USA). To start the experiment (Figure 6), we filled the connecting tubes, connecting

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vessels, and reaction chamber with methanol. The flow was then started pumping methanol whilst
maintaining a temperature of 50 °C in the chamber. The temperature was obtained within 4 min.
We then started pumping the reaction medium and interestingly, due to the slow flow rate, we were
able to follow visually the evolution of the reaction (Figure 7). As the reaction mixture progressed
through the flow cell, the clear translucent solution of methanol at the bottom of the flow cell was
replaced by a yellow reaction mixture and a reddish colour developed at the top exit of the flow cell.
More importantly, Raman spectra were recorded at the bottom (before microwaves) and at the top of
the cell (after microwaves) but also in the middle (inside the microwave field). Those spectra were
sufficiently resolved to indicate the disappearance of the ketoester after the passage in the microwave
cavity. The pumping was conducted during 3 h period after which methanol was pumped to flush the
reaction medium out of the flow cell. The microwave irradiation was stopped afterwards. At the end
we isolated 50 g of 1,4-DHP which represents a yield of approximately 80%.
Figure 6. Setup of a continuous flow synthesis under microwave irradiation in the
MiniFlow 200SS.

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Figure 7. Connecting vessels before (left) and after (right) the microwave cavity.
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3. Experimental Section
3.1. General
Reactions under conventional heating were conducted in round-bottom flasks or in the Zinsser-
Minilab® system (Zinsser Analytic, Frankfurt, Germany). Reactions under microwave heating were
conducted in the Sairem MiniFlow 200SS oven (Sairem, Neyron, France) or in the Biotage Initiator®
oven (Biotage, Uppsala, Sweden). Reactions under flow conditions were performed using a MINIPULS
evolution® peristaltic pump (Gilson, Middleton, WI, USA).
1H-NMR spectra were obtained using a Bruker AMX instrument (300 MHz) and TMS as internal
reference. IR spectra were recorded on a Perkin-Elmer FTIR 1760K and Raman spectra were recorded
using the Enwave Optronics EZRamanTM-M spectrometer (Enwave Optronics Inc, Irvine, CA, USA).
Solvents and reagents were commercially available from Sigma-Aldrich (Diegem, Belgium) or Acros
Organics (Geel, Belgium) and were used without further purification. All compounds have been
described in the literature [29] and their structure was confirmed by comparison with data recorded on
samples available in our laboratory [36].
3.2. Chemistry
The following general procedure was used to perform reactions in the batch mode: a mixture of
aqueous formaldehyde (37% in water and 10%–15% of methanol; 0.7 mL; 9.35 mmol), a β-ketoester
(19.53 mmol), and a methanolic solution of ammonia (15.5% in methanol; 3.0 mL; 21.02 mmol) in
methanol (4.0 mL) was heated at 50 °C for the appropriate period of time (see text). After cooling the
precipitate was filtered, rinsed with well-chilled ethanol (0–5 °C; 5–10 mL) and recrystallized from
ethanol. Acetonitrile was used as the sovent (instead of methanol) in one experiment (see Section 2.5.2).
Yields: 75%–90%.
For the reaction performed under flow conditions, a cold (5 °C) stock solution of a mixture of
aqueous formaldehyde (37% in water and 10%–15% of methanol; 17.5 mL; 233.75 mmol), ethyl
acetoacetate (62.5 mL; 488.25 mmol), and a methanolic solution of ammonia (15.5% in methanol;

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75.0 mL; 525.5 mmol) in methanol (100.0 mL) was prepared in an Erlenmeyer. The solution was
pumped at a flow rate adjusted to 1.4 mL/min and collected after irradiation in another Erlenmeyer.
After cooling the precipitate was filtered, rinsed with well-chilled ethanol (0–5 °C; 5–10 mL) and
recrystallized from ethanol. Yield: 80%.
4. Conclusions
During this exploratory work we have demonstrated that Raman spectroscopy can readily and
advantageously be used to monitor in real-time organic reactions under conventional and dielectric
heating in a batch mode. Homogeneous clear mixtures are however required to ensure a good quality
of the spectra.
The MiniFlow 200SS microwave equipment enabled reactions to be performed in batch mode as
well as under continuous flow. We observed that experimental conditions established for the batch
mode experiment could be directly extrapolated to continuous flow conditions. In this latter case,
usinga slow flow rate, spectra could be recorded in real-time.
Acknowledgements
JJVE is grateful to the University of Mons-UMONS for a financial support.
Author Contributions
The research program was designed by MR and JJVE; the experiments were performed by SC and
XV who compiled and analyzed the data. MR and JJVE wrote the manuscript. All authors read and
approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).