Microwave-assisted ruthenium catalysed high-pressure synthesis of N-heterocyclic compounds

Article abstract of DOI:10.1007/s00706-019-02440-4

Abstract: The four-component reaction of an α,β-unsaturated aldehyde and a primary amine with carbon monoxide and ethylene in the presence of Ru₃(CO)₁₂ as a precatalyst yielding mixtures of chiral γ-lactams and substituted pyrrole de

Full text of DOI:10.1007/s00706-019-02440-4

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-019-02440-4
ORIGINAL PAPER
Microwave‑assisted ruthenium catalysed high‑pressure synthesis
of N‑heterocyclic compounds
Niklas Feller1 · Wolfgang Imhof1
Received: 13 December 2018 / Accepted: 6 May 2019
© Springer-Verlag GmbH Austria, part of Springer Nature 2019
Abstract
The four-component reaction of an α,β-unsaturated aldehyde and a primary amine with carbon monoxide and ethylene in
the presence of Ru3(CO)12 as a precatalyst yielding mixtures of chiral γ-lactams and substituted pyrrole derivatives has,
for the frst time, been performed under microwave irradiation. It has also been possible to collect samples of the reaction
mixture without releasing the applied pressure of the gas phase, and therefore, monitoring of substrates, intermediates, and
products during the synthetic procedure became accessible. Compared to classical thermally induced reactions, microwave
irradiation leads to a signifcant shortening of reaction times, and requires lower partial pressures of carbon monoxide and
ethylene and a lower precatalyst loading.
Graphical abstract
Ph
O
+
Ph
NH2
H
- H2O
Ph
N
Ph
CO, C2H4
cat. Ru3(CO)12
MW
Ph
Ph
Ph
+
O
+
O
N
N
H
Ph
Ph
Keywords Ruthenium · C–H activation · Lactams · Pyrroles · Microwave irradiation
Introduction
physiological conditions [8]. We were able to show that
γ-lactams (1,3-dihydropyrrolones) are the main products of
the catalytic multi-component reaction of α,β-unsaturated
imines, carbon monoxide, and ethylene (or terminal alkenes
in general) in the presence of Ru3(CO)12 as the precatalyst
[9–16]. Nevertheless, 2,3-disubstituted pyrrole derivatives
have been observed as side-products of the reaction sequence
(Scheme 1) [9–16]. In this context, it is not necessary to
introduce the imine into the reaction, since a four-component
reaction of the corresponding α,β-unsaturated aldehyde and
a primary amine under CO and ethylene pressure in the pres-
ence of the same precatalyst leads to the formation of the
same compounds. In addition, it became obvious that chem-
oselectivity of the reaction highly depends on the choice of
solvent [17]. Therefore, it is possible to exclusively produce
the corresponding γ-lactam if unpolar solvents as hydro-
carbons are used, whereas the reaction in methanol leads to
γ-Lactams or γ-aminobutyric acid derivatives in general
have been investigated due to their potential relevance as
psychotropic drugs as well as for the treatment of diseases
like cancer, osteoporosis, or Alzheimer’s disease or as con-
stituents of non-natural peptide sequences [1–7]. Especially
in the context of the latter research topic, it was pointed
out that the use of γ-aminoacids enhances the stability of
the respective peptides against proteases, thus, enabling
the application of these peptides as active substances under
* Wolfgang Imhof
Imhof@uni-koblenz.de
1
Institute of Integrated Natural Sciences, University Koblenz-
Landau, Universitätsstr. 1, 56070 Koblenz, Germany
Vol.:(0123456789)
1 3

N. Feller, W. Imhof
Scheme 1
reaction mixture. In a given setting of reactive compounds,
solvent, and specifc reaction vessel, the efect of microwave
irradiation is a mixture of diferent infuencing factors quite
commonly (although not necessarily) leading to shorter reac-
tion times, enhanced selectivities, and better turnover num-
bers, and was referred as the “microwave efect” [19–22].
As a further development of typical microwave sys-
tems, devices were introduced in which procedures under
enhanced pressures are possible. Mostly, these are used for
pulping processes in conjunction with analytical issues or
as a possibility to work under conditions that allow for the
heating of the respective reaction mixtures above the boiling
point of the solvent. The latter of course leads to enhanced
pressures in the reaction system. Nevertheless, surprisingly
few reports on the use of these microwave systems for syn-
thetic applications, in which gaseous reactive substrates
under high partial pressures were used, have been published.
The frst-transition metal-catalysed reactions in this respect
being induced by microwave irradiation were hydrogenation
reactions [23–29]. The use of carbon monoxide has been
described in conjunction with hydroformylation, amino-
formylation, alkoxyformylation, hydroxyformylation, and
cycloaddition reactions, and also has recently been reviewed
[30–38].
the formation of the pyrrole in 65% yield [17]. It was also
possible to perform the reaction in ionic liquids as solvents
still leading to mixtures of both products [18].
Results and discussion
One major drawback of the reaction is that reaction times
are quite high, meaning that a complete conversion of the
starting compounds needs app. 14–16 h. Another topic relat-
ing to safety issues are relatively high pressures of toxic
(carbon monoxide) and infammable (carbon monoxide,
ethylene) gaseous compounds. Moreover, required reaction
temperatures are considerably high.
Scheme 1 shows the model reaction that we used for our
investigation. We chose benzyl amine (2) as one of the com-
ponents, because, on one hand, aliphatic primary amines
show an enhanced reactivity due their higher basicity com-
pared to aromatic amines [12, 14] and because CH2 protons
are diastereotopic in case of the formation of the dihydro-
pyrrolone 4, which means that the formation of 4 is eas-
Microwave irradiation represents an alternative method
of energy input into chemical systems compared to classical
thermal reaction regimes. Major advantages of microwave
irradiation are the uniform heating of the complete system
as well as the high heating rates that might be achieved. If
heating is performed by a heat source outside the reaction
vessel (typically an oil bath), a temperature gradient from
the vessel wand to the inside is observed. Avoiding these
“wall efects” by the use of microwave heating is one of the
major advantages of this method. On the other hand, micro-
wave irradiation holds for a rapid and local heating directly
at microwave absorbing molecules being part of the reac-
tion mixture or at specifc additives which are not reactive
components, but, due to their ability of efectively absorbing
microwave irradiation, allow for the heating of the reaction
mixture. These “thermal microwave efects” occur at the
same time in the complete volume of the reaction mixture
and, therefore, provide identical reaction conditions in the
1
ily detected from H NMR spectra even of crude reaction
mixtures. Since we already showed the scope of this one-pot
reaction, we concentrated on the optimization of reaction
conditions using microwave heating instead of classical
external heating devices.
Due to the enhanced chemoselectivity of the catalytic
reaction described herein towards the formation of chiral
γ-lactams in unpolar hydrocarbon solvents, we decided to
use toluene as the solvent in our experiments. On the other
hand, unpolar solvents are not the solvents of choice for
reactions under microwave irradiation, because low rela-
tive permittivities also mean that interaction of the respec-
tive molecules with microwave irradiation is not efective
[39]. We, therefore, utilized additives with diferent par-
ticle sizes and diferent specifc surfaces, respectively, as
additives to ensure efective heating of a toluene-based
reaction mixture by microwave irradiation. The use of
1 3

Microwave-assisted ruthenium catalysed high-pressure synthesis of N-heterocyclic compounds
reaction vessels made of SiC in comparison with glass
vessels was reported before and has also been thoroughly
reviewed [40].
although refection phenomena again became a more pro-
nounced issue leading to the situation that experiments had
to be stopped at a temperature of 100 °C.
Figure 1 shows the results of heating experiments in
glass vessels under diferent conditions and with difer-
ent additives. If 15 g SiC (0.2–1 mm) were suspended in
200 cm3 of toluene and the mixture was irradiated with
microwaves at a constant power of 300 W, the system
reaches a temperature of slightly above 150 °C after circa
10 min [Fig. 1, curves indicated (a)]. After 6 min, the heat-
ing rate diminishes, because SiC particles and the solvent
show only small diferences in their temperature. Never-
theless, the experiment had to be stopped after 25 min
due to the fact that overall refections, i.e., the fraction
of the irradiated microwave power that is not absorbed
by the additive or the solvent, were too high. In all other
experiments, a glass inset into the PTFE reactor was
used which reduced this phenomena. If SiC with a big-
ger specifc surface is used, higher solvent temperatures
might be achieved. Moreover, it is possible to reduce the
amount of SiC. In Fig. 1, curves indicated (b) show the
heating of 200 cm3 toluene by microwave irradiation in
the presence of 5 g SiC (29.1 μm). A higher constant heat-
ing rate (650 W) was applied and a maximum tempera-
ture of 180 °C was defned to maintain the temperature
below the boiling point of toluene at a pressure of 10 bar.
The observed T/t curve clearly demonstrates that 180 °C
might be achieved under these conditions in approxi-
mately 10 min. Further reduction of particle size using SiC
(1.7 μm) did not lead to any improvement of the situation,
If pyrographite with a specifc surface of 1200 m2/g is
used as the additive to toluene heating of the solvent to tem-
peratures up to 200 °C was easily achieved. In Fig. 1, curves
indicated (c) show a corresponding experiment in which, in
contrast to experiments with SiC, no constant power was
used, but the power was adjusted by the system according
to the set parameter that heating should be fnished after
exactly 10 min.
In principle, the use of additives like SiC or pyrographite
is well suited to realize heating of unpolar solvents by micro-
wave irradiation under high-pressure conditions. Neverthe-
less, in the end, we decided to use a stirrer made of Wefon,
which is Tefon with a certain amount of carbon incorpo-
rated, instead of additives for two reasons. First of all, the
use of additives leads to an additional work-up step, because
the additive has to be fltered of after the reaction induced
by microwave irradiation is fnished. Second, we observed
that precipitation of the solid additives takes place even if
the suspension is intensively stirred. We, therefore, envis-
aged the potential problem that the efciency of the heating
process, which is also depending on the even distribution of
additive particles in the reaction mixture, might be depend-
ing on the stirring rate or even on the geometrical design of
the stirrer itself.
In orienting experiments, we, frst of all, applied reac-
tion conditions concerning concentration of substrates and
precatalyst, partial pressures of gaseous substrates, reaction
Fig. 1 Heating of (a) 15 g
SiC (0.2–1 mm) in 200 cm3
toluene at a constant power of
300 W; (b) 5 g SiC (29.1 μm)
in 200 cm3 toluene at a constant
power of 650 W; (c) 5 g pyro-
graphite (1200 m2/g) in 200 cm3
toluene at variable power [red:
temperature of the solution
(°C), black: power (kW)]
1 3

N. Feller, W. Imhof
time, and reaction temperature that were identical to those
used for analogous reactions in stainless steel autoclaves
under external heating [14, 15]. This experiment showed
that the same products 4 and 5 were produced in a compa-
rable ratio under microwave activation. Figure 2 shows a
section of the corresponding 1H NMR spectrum of the crude
reaction mixture from which signals being indicative for the
formation of compounds 4 and 5 are easily detectable.
In additional experiments, we investigated changes in the
above-mentioned parameters. First of all, we had a look on
the question whether anhydrous solvents have to be used
for the catalytic reactions. During the formation of inter-
mediate 3, water is produced as a side-product, anyway (cf.
Scheme 1). Nevertheless, the more water is present in the
reaction mixture, the more the ratio of 4 : 5 is expected to be
shifted towards the formation of 5, because the polarity of
the reaction mixture is increased by the formation of water
[17]. Due to the fact that the amount of water produced by
condensation of substrates 1 and 2 is considerably higher
than the water content of commercially available toluene,
we, indeed, saw no signifcant diference concerning chem-
oselectivity of the reaction if either anhydrous or aqueous
toluene is used. Nevertheless, we observed another possibil-
ity to enhance the selectivity of the reaction to make 4 the
main product of the reaction. In our experiments in con-
nection with the combinatorial synthesis of derivatives of 4
and 5 using a multi-reactor station [14], we used 1 mmol of
the starting compounds in 2 cm3 of toluene, which means
that the concentration of 1 and 2 was 0.5 mol/dm3. In the
microwave high-pressure reactor used for the experiments
described herein, the reaction vessel is much bigger and
we, therefore, had a look whether solutions with a lower
concentration of 1 and 2 would also work. Therefore, we
conducted three experiments with solutions of 0.5, 0.25, and
0.05 mol/dm3 1 and 2, and performed the catalytic reactions
under microwave irradiation using 8 bar ethylene and 12 bar
carbon monoxide, a reaction temperature of 140 °C, and a
reaction time of 8 h and 3 mol % Ru3(CO)12. The result is
depicted in Fig. 3, and shows that the lower the concentra-
tion of 1 and 2 is at the start of the reaction, the higher is the
yield of 4 relative to 5 at the end of the catalytic reaction.
Fig. 3 Dependence of the yield of the γ-lactam 4 on the starting con-
centration of the starting compounds 1 and 2
Fig. 2 Section of the 1H NMR spectrum of a crude reaction mixture obtained from the reaction depicted in Scheme 1 (next to 4 and 5 traces of 3
still are detectable)
1 3

Microwave-assisted ruthenium catalysed high-pressure synthesis of N-heterocyclic compounds
Concerning reaction temperatures, we already knew from
the investigations under a thermal reaction regime that tem-
peratures below 100 °C do not lead to the formation of any
of the expected product molecules. Only non-reacted start-
ing compounds 1 and 2 as well as the intermediate 3 may
be recovered from the solution. We, therefore, tested three
temperatures of 120 °C, 140 °C, and 160 °C, and had a look
on the composition of the reaction mixture every hour. The
other reaction conditions were 0.05 mol/dm3 of 1 and 2,
8 bar ethylene and 12 bar carbon monoxide and 3 mol %
Ru3(CO)12. The results of the experiments at 120 °C and
140 °C are depicted in Fig. 4. The reaction at 160 °C had
to be stopped after 2 h due to problems with cooling of the
high-pressure reactor leading to a situation in which no con-
stant temperature could be maintained. From Fig. 4, it gets
obvious that, at a temperature of 120 °C after 1 h, a small
amount of the starting compounds still is detectable. How-
ever, the reaction mixture mainly consists of the intermedi-
ate imine 3. After 1 h, the amount of 3 slowly decreases and,
to the same extent, concentrations of product molecules rise.
After approximately 7–8 h, the reaction is fnished and the
main product 4 is produced with a GC yield of about 90%.
At 140 °C, the reaction proceeds much faster. Therefore,
after 1 h, the amount of 3 already is quite low and the com-
bined ratio of 4 and 5 already reached almost 60%. After
approximately 5 h, the composition of the reaction mixture
stays constant and the reaction is fnished. Nevertheless, the
amount of the main product 4 now only is circa 80%. In
addition, we observed the formation of another side-product
6 which, according to MS spectra, is a derivative of 3 with
one molecule of ethylene having been inserted in β-position
with respect to the C=N double bond. After the reaction at
160 °C was stopped after 2 h, we observed that 80% of the
starting compounds had been consumed, but the combined
yield of 4 and 5 was about 50% and the before-mentioned
side-product 6 was formed to a higher extend. Therefore,
higher temperatures as expected lead to enhanced reac-
tion rates but, on the other hand, to decreased selectivity.
Under thermal reaction conditions, reaction times of 16 h
were needed for complete consumption of starting material.
Under microwave activation, a complete reaction with high
selectivity is achieved after 8 h at 120 °C and a reaction with
acceptable selectivities is observed after a reaction time of
5 h at 140 °C.
Fig. 4 Composition of the reac-
tion mixture at 120 °C (above)
and 140 °C (below)
1 3

N. Feller, W. Imhof
We also performed experiments concerning precatalyst
loading on the outcome of the reaction by simultaneously
reacting fve samples in a multi-reactor inset. Each test tube
was charged with a solution of 0.6 mmol (0.079 g) cinna-
maldehyde and 0.6 mmol (0.064 g) benzylamine in 12 cm3
toluene. The test tubes were additionally charged with dif-
ferent amounts of Ru3(CO)12 (11.5, 8.6, 5.7, 2.9, and 0 mg),
resulting in precatalyst loadings of 3, 2.25, 1.5, 0.75, and
0 mol % based on the amount of substrates. The frst four
experiments showed almost no infuence on the outcome of
the catalytic reaction. Only a slight decrease in the formation
of the side-product 6 may be observed. If no precatalyst is
introduced to the reaction mixture no formation of any of the
products 4, 5, or 6 is observed.
the frst time, it was possible to have a closer look on the
initial stages of the reaction. We, therefore, chose a reac-
tion temperature of 120 °C to slow down the reaction rate
and collected a sample for GC/MS analysis every quarter
of an hour with the frst sample being taken after 10 min,
which was the moment the reaction mixture reached its fnal
temperature. The results are shown in Fig. 6. It gets obvi-
ous that, already after 10 min, the content of intermediate 3
already is higher than the amount of the starting compounds
1 and 2. Nevertheless, the fraction of 3 reaches a maximum
after about 45 min and then decreases as the content of the
products 4 and 5 increases. Therefore, the assumption that
3 really is an intermediate in the formation of 4 and 5 and
not just another side-product could be experimentally proven
for the frst time. Catalytic C–H activation as the common
initial elementary reaction for all catalytic reaction pathways
only starts after 3 is produced from 1 and 2. The amount of
the side-product 6 being formed by the insertion of ethylene
into the C–H bond in β-position with respect to the C=N
double bond is constant. This means that it has already been
produced to this amount when the reaction temperature of
120 °C has been reached. Therefore, this reaction obviously
is very fast, but the equilibrium at the given reaction tem-
perature of 120 °C only holds for the formation of approxi-
mately 5–7% of 6.
In a last series of experiments concerning reaction condi-
tions, we investigated the dependence of the formation of 4
and 5 on the partial pressures of ethylene and carbon mon-
oxide (Fig. 5). If partial pressures are lowered from 8 bar
ethylene and 12 bar carbon monoxide to 6 bar ethylene and
9 bar carbon monoxide, respectively, a slight increase of
the formation of 4 and a decrease in the formation of the
side-product are observed. If partial pressures are lowered
to 4 bar ethylene and 6 bar carbon monoxide, the alkylated
imine 6 is the main product of the reaction. Further investi-
gations if this might be a suitable way to selectively synthe-
size derivatives of compounds of type 1, which are alkylated
in β-position with respect to the C=N double bond, are on
their way.
Conclusion
In all investigations, we performed so far [9–18] samples
of the reaction mixture which could only be taken by releas-
ing the pressure from the autoclaves which means that the
reaction came to a standstill. Due to the construction of the
high-pressure reactor used in this investigation, it was pos-
sible to take samples without releasing pressure or lower-
ing the temperature of the reaction mixture. Therefore, for
The catalytic formation of heterocyclic compounds 4 and
5 is possible using microwave heating as an alternative to
external heating to activate substrates and catalysts. Since
toluene has to be used as the solvent to enhance the selectiv-
ity of the formation of 4, either stirrers made of Wefon or
the addition of additives like SiC or pyrographite have to be
Fig. 5 Infuence of partial pres-
sures of CO and ethylene on
the composition of the reaction
mixture
1 3

Microwave-assisted ruthenium catalysed high-pressure synthesis of N-heterocyclic compounds
Fig. 6 Course of the reaction at 120 °C (content of 2 is not given for the sake of clarity)
taken into account to ensure efective heating of the reaction
mixture by microwave irradiation. In contrast to analogous
reactions under a thermal reaction, regime reaction times are
lowered, less of the precatalyst is needed and partial pres-
sures of gaseous substrates also may be reduced. In addition,
it was possible, for the frst time, to identify the imine 3 as
an intermediate in the reaction.
General procedure for catalytic reactions
Cinnamaldehyde (10 mmol, 1.322 g) and 10 mmol benzyl
amine (1.072 g) were dissolved in a suspension of 200 cm3
toluene and 0.3 mmol Ru3(CO)12 in the above-mentioned
reaction vessel. The vessel was placed into the PTFE insert
of the microwave high-pressure reactor. After closing the
reactor, it was fushed with argon for 1 min, and then, a
sequence of pressurizing the reactor with 5 bar argon and
then releasing the pressure again was repeated three times to
further remove air. Afterwards, the reactor was pressurised
with the respective amounts of carbon monoxide and ethyl-
ene. Then, the reactor was heated by microwave irradiation
to the required temperature. The heating rate can be con-
trolled by the power in Watt of the microwave irradiation.
Temperature is then maintained for the requested reaction
time. During the reaction time, it is possible to take samples
for GC/MS analysis without releasing the pressure or lower-
ing the temperature of the system. After the reaction time is
completed, microwave irradiation is turned of and the sys-
tem is allowed to cool down to room temperature before the
pressure is released with a rate of 3 bar/min. Evaporating the
solvent results in dark brown crude reaction mixture which
might directly be analysed by GC/MS and NMR techniques
or purifed using column chromatography to obtain pure 4
and 5. For investigation of the infuence of substrate concen-
tration, partial pressures of CO and ethylene or precatalyst
loading the amount of the respective compounds are varied
Experimental
All chemicals and solvents have been checked for purity
before use by GC/MS. Cinnamaldehyde, benzylamine,
and all solvents have been degassed before use. The gase-
ous compounds carbon monoxide (4.7) and ethylene (3.5)
have been used directly from the respective pressurised
gas cylinder without further purifcation. Reactions acti-
vated by microwave irradiation have been performed in a
synthWAVE 1500 microwave high-pressure reactor from
MWS, Leutkirch, Germany, using a tailor-made glass con-
tainer (75×170 mm) as the reaction vessel. For stirring, a
Wefon-made stirrer was used. GC/MS measurements were
performed using a GCQ plus/Polaris MS (Finnigan) device.
Ionisation was done by EI; GC was performed using an
OTIMA 5 MS Accent column (Macherey & Nagel, 0.25 μm,
0.25 mm×30 m). NMR spectra were obtained using a JEOL
ECZS 500 MHz spectrometer. CDCl3 is used as solvent and
internal standard for chemical shifts.
1 3

N. Feller, W. Imhof
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