Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts in the One-Step Isomerisation of Cinchona Alkaloids to Δ3,10-Isobases

Article abstract of DOI:10.1007/s10562-017-2169-3

Abstract: Efficiency of palladium solid supported (Pd/SS) catalysts for one-step isomerisation of the side chain of four natural Cinchona alkaloids have been explored under controlled microwave heating in the green media (50% aqueous ethanol or ethylene g

Full text of DOI:10.1007/s10562-017-2169-3

Catal Lett
DOI 10.1007/s10562-017-2169-3
Effect of Microwave Irradiation on the Catalytic Activity
of Palladium Supported Catalysts in the One-Step Isomerisation
of Cinchona Alkaloids to Δ3,10-Isobases
Teodozja M. Lipińska1 · Dominika Borowska1 · Natalia Swędra1 ·
Katarzyna Trochim1
Received: 7 April 2017 / Accepted: 10 August 2017
© The Author(s) 2017. This article is an open access publication
Abstract Efficiency of palladium solid supported (Pd/SS)
catalysts for one-step isomerisation of the side chain of four
natural Cinchona alkaloids have been explored under con-
trolled microwave heating in the green media (50% aqueous
ethanol or ethylene glycol with HCl). Conversion progress
and products purity was monitored by TLC and by 1H NMR
spectrometry. Final conversion is dependent on the support
(Al2O3, C or BaSO4), reaction time and temperature. Very
good results: high yields and purity of (Z/E) Δ3,10-isomers
were obtained from quinine and quinidine with 10% Pd/
BaSO4 as the catalyst, which is less effective for isomeri-
sation of cinchonine and cinchonidine. Enhancing energy
efficiency can be possible when the responsive support
selective absorbs of microwave energy, which is translated
to the palladium giving acceleration of the formation and
disintegration of the transition state leading to Δ3,10-isomers.
Graphical Abstract
3,10 −Isomers
Natural
(Ε/Ζ )−∆
molecules
H2C
H3C
HO
H
HO
N
N
H
R
N
H
N
Ethylene glycol/H2O + HCl
1.8 % Pd/solid supports
R=OMe: quinidine
R=H: cinchonine
R
oC, 50 min
MW, 85
H3C
CH2
11
H3C
Pd/SS
10
H
Cl
H
R
R
N
H
3
H
N
N
OH
Conversion:
OH
N
R=OMe, up to 98 %
R=H, up to 80 %
R=OMe: quinine
R=H: cinchonidine
Keywords Heterogeneous catalysis · Alkene
isomerisation · Cinchona alkaloids modification ·
Metal–solid support-interaction under microwaves ·
Chemoselectivity · Green methodology
1 Introduction
The vinyl side chain plays an important role in the struc-
ture of natural molecules of Cinchona alkaloids [1, 2]. It
is a stereo-differentiating element [3] imparting a variety
their physicochemical properties and biological activity for
quinidine 1a (antiarrhythmic agent) [4] versus quinine 2a
(antimalarial activity) [5], and for cinchonine 1b versus cin-
chonidine 2b. All the four natural compounds, their deriva-
tives and metal complexes have become more and more
interesting catalysts for asymmetric syntheses [6]. Recently
they play an important role in the preparation of new chiral
nanomaterials [7, 8].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-017-2169-3) contains supplementary
material, which is available to authorized users.
* Teodozja M. Lipińska
tlip@uph.edu.pl
1
Faculty of Sciences, Institute of Chemistry, Siedlce
University of Natural Sciences and Humanities, ul 3 Maja
54, 08-110 Siedlce, Poland
Vol.:(0123456789)
1 3

T. M. Lipińska et al.
The Cinchona Δ3,10-isomers 3a,b and 4a,b (Scheme 1)
were investigated as effective chiral modifiers of solid-sup-
ported metallic catalysts for enantioselective hydrogenation
of activated ketones [9–11]. Δ3,10-Isobases were applied
also as valuable intermediates for modification of the native
structure [12] including the oxidative cleavage of the double
bond [13–16].
chloride trihydrate was used with addition of H2SO4 in etha-
nol for homogeneous quinine isomerisation [12]. Both those
catalysts are expensive and cannot be used for large scale
processes.
Microwave enhancement of many catalytic syntheses has
been described [24–26]. Recently are described transforma-
tions of polar organic molecules in water with enhancing
energy efficiency by microwaves with core/shell catalysts
[27]. The heat generated at the core area of the support by
microwave irradiation can be translated to the shell cata-
lyst directly. Such localized heating allows maximum heat
utilization and enhances the energy efficiency of catalytic
reaction.
The isomerisation of the vinyl bond to the 3,10 position
of Cinchona alkaloid molecules has been investigated for
more than 100 years [17]. At the beginning, H2SO4 has
been used, which resulted in many side processes such as
the cleavage of methyl ethers in molecules 1a and 2a giving
phenols. It was necessary to use of diazomethane for etheri-
fication [18, 19]. Two-step synthesis of the Δ3,10-isobases
3a,b and 4a,b, consisting of hydrogen halide addition and
subsequent elimination by different bases has been elabo-
rated [14–16, 20, 21]. However this way cannot be consid-
ered today as a modern preparative method by reason of
poor atom economy, which is even poorer when additional
stages of protection–deprotection of the hydroxy group must
be performed [13, 14] for prevention of the formation of
isomers possessing an intramolecular ether bond between
C9 and C10.
We have established that the difficult Fischer indole
synthesis can be accelerated by microwaves together with
using green reagents: catalytic amounts of ZnCl2 loaded on
K10 clay [28] or dissolved in triethylene glycol [29]. We
have recently described the results of our research on rela-
tionship structure–reactivity of natural Cinchona alkaloids
O-tosyl derivatives in hydrolysis to 9-epibases. We found
that replacement of conventional heating with microwave
activation leads to different products [30, 31].
Our present synthetic interest concentrates on finding
an effective and cheap method of transformation of four
Cinchona alkaloids 1a,b and 2a,b into the corresponding
Δ3,10-isobases 3a,b and 4a,b. We envisioned that heating
of substrates under microwaves with palladium on solid
supports (Pd/SS) together with HCl can solve this problem.
This paper described our work on influence of controlled
microwave heating on activity of palladium solid supported
(Pd/SS) catalysts in the heterogeneous isomerisation of four
natural Cinchona alkaloids. We studied also possibility of
analysis and isolation of the geometric isomers Z and E in
Δ3,10-isomers, as they will be used as chiral ligands [7, 8],
catalysts and modifiers in asymmetric syntheses [9–12].
In 1968 it was discovered that migration of double bond
in natural quinidine and quinine 1a and 1b occurs during
their commercial hydrogenation with Pd-C catalyst and fur-
thermore that Δ3,10-isomers 3a and 4a are resistant to sub-
sequent hydrogenation [22]. The effective isomerisation of
methoxy alkaloids 1a and 2a to (Z/E)-3a and (Z/E)-4a was
performed using rhodium solid supported catalysts (Rh/SS)
in a medium of 50% EtOH in the presence of HCl under
heating in water bath for a period of 24 h [23]. However,
very low activity of palladium supported catalysts (Pd/SS)
has been noted in this conditions. In 2005 ruthenium (III)
R
N
10
2
11
H
R
N
3
a: R=OMe
b: R=H
H
2 Results and Discussion
OH
H
7
4
N
9
8
N
Literature data8-25
5
1
OH
Four commercial Cinchona alkaloids 1a,b, 2a,b were sub-
jected to catalytic isomerisation of the side chain using
tested palladium catalysts supported on various solids. We
applied microwave activation instead conventional heating in
water bath. Two methods regarding to reaction medium and
temperature were used: method 1—controlled microwave
heating at 70 °C in an aqueous ethanol [31] and method
2—heating at 85 °C in a medium of ethylene glycol (EG).
Our initial small-scale experiments under controlled
microwave heating were performed with 0.5 mmol of the
substrate 1a or 2a at 70 °C in a medium comprised of 50%
EtOH with HCl aq in the presence of catalytic amount
(1.8%) of 10% palladium loaded on various solid supports
(method 1). This procedure was tested to find the optimal
H
6
HX
HX
1a
1b
2a
2b
X
Our
Our
present
work
H
present
work
Pd/SS
MW
green
medium
H2SO4
Rh/SS
RuCl3
H2SO4
Rh/SS
RuCl3
Pd/SS
MW
N
green
medium
H3C
H3C
N
-HX
-HX
R
R
OH
Oxidative cleavage12-15
H
N
O
N
OH
4a
4b
H
3a
3b
N
N
Scheme 1 Modes of transformations of the natural Cinchona alka-
loids 1a,b, 2a,b into the Δ3,10-isobases 3a,b, 4a,b
1 3

Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts…
time for conversion of 1a or 2a to the isomers (Z/E)-3a or
(Z/E)-4a. We monitored the ongoing conversion progress
of substrates by taking micro-samples of the reaction mix-
ture regularly, at 10-min intervals, which after extraction
with diethyl ether in the presence of aqueous ammonia were
analyzed by TLC (silica gel plates, methoxyethanol). The
Rf values of the products 3a and 4a are higher than the Rf
values of the substrates 1a and 2a (see Table 3). The reaction
mixtures were irradiated for 30 min or after 50 min. After
this times crude products were isolated and qualitatively and
quantitatively analysed by 1H NMR spectroscopy (Table 1).
Analysis of 1H NMR spectra give the possibility to esti-
mate the amount of product and unconverted substrate and
also ratio (Z) to (E) isomers in the crude product for each
experimental entry. The region of 6.10–4.00 ppm in the 1H
NMR spectra is useful for relative amount of components
determination as is shown in the Fig. 1. The alkene pro-
tons of =HC–Me from (Z)- and (E)-Δ3,10-isomers give two
separate signals according to the literature data [12, 13, 25].
Determination of unconverted substrates can be possible
from integration of peaks: =CH2 protons (two doublets at
~4.90–5.10 ppm) or –CH= (multiplet at ~6.00 ppm).
Table 1 Results of microwave-
promoted isomerisation of
quinidine 1a and quinine 2a
into 3a and 4a (Scheme 2) with
palladium supported catalysts
in 50% aqueous ethanol in
the presence of HCl at the
controlled temperature 70 °C
(method 1)
Entry
Substrate
Catalyst
Time (min)
Product
Yielda (%)
Conver-
The Z/E ratio in
sionb (%) crude productsb
1
2
3
4
5
6
7
8
1a
1a
2a
2a
1a
1a
2a
2a
1a
1a
2a
2a
Pd/Al2O3
Pd/Al2O3
Pd/Al2O3
Pd/Al2O3
Pd/C
Pd/C
Pd/C
30
50
30
50
30
50
30
50
30
50
30
50
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
95
95
98
98
75
75
65
60
96
96
97
97
80
85
70
72
70
75
60
65
87
94
80
91
7.0
4.7
1.8
1.6
2.7
2.7
1.4
1.4
6.3
5.7
3.0
2.6
Pd/C
9
Pd/BaSO4
Pd/BaSO4
Pd/BaSO4
Pd/BaSO4
10
11
12
aIsolated yields of crude product 3a or 4a from the reaction mixture
bDetermined conversion of 1a or 2a into 3a or 4a and their Z/E ratio from 1H NMR spectra of crude prod-
ucts
Scheme 2 One-pot isomerisa-
tion of the side chain with palla-
dium supported catalysts under
microwave activation
H
R
N
10
2
11
R
H
3
4
H
OH
N
7
9
8
N
5
1
OH
H
6
N
2a: R=OMe
2b: R=H
1a: R=OMe
1b: R=H
Method 1. Pd/SS, EtOH + H2O, HCl, MW 70 oC
Method 2: Pd/SS, EG + H2O, HCl, MW, 85 oC
CH3
H3C
H3C
CH3
N
HO
N
N
R
R
H
HO
N
OH
H
R
H
OH
R
H
+
+
N
N
N
N
(Z)-3a
(Z)-3b
(E)-3a
(E)-3b
R=OMe
R=H
(Z)-4a
(Z)-4b
(E)-4a
(E)-4b
1 3

T. M. Lipińska et al.
1
Fig. 1 Examples of fragments of H NMR spectra (6.20–4.80 ppm)
2a: crude 3a: a1 (see Fig. S1 in Supplementary Materials–SM); a2
(see Fig. S3 in SM); crude 4a: b1 (see Fig. S4 in SM); b2 (see Fig.
S6 in SM)
used for determination of the Z/E ratio in Δ3−10-isomers 3a, 4a and
for analysis of their contamination by unconverted substrates 1a or
The example presented in Fig. 1-a1 shows the analytical
methodology for determination of the amounts of compo-
nents in the crude 3a from entry 1, Table 1 (ESM Fig. S1).
The signal of the alkene proton of the isomer (Z)-3a appears
as a multiplet at 5.30 ppm (integration 0.70) whereas the sig-
nal of the isomer (E)-3a is showed as a quartet at 5.33 ppm
(integration 0.10) but two protons of the =CH2 group from
the unconverted substrate 1a give two doublets in the region
of 5.13–5.03 ppm (integration 0.40). The comparative inte-
gration of the relevant signals give the ratio of (Z)-3a/(E)-3a/
unconverted substrate 1a which is 70:10:20. The conversion
progress of 80% can also be inferred from the comparative
integration of HC9 proton signal summed for the substrate
1a and the products (Z/E)-3a at 5.90 ppm (integration 1.00)
and the signal of –CH= proton of the vinyl group of 1a,
which gives a multiplet (ddd) at 6.06–5.94 ppm (integration
as 0.2).
We wanted to maximise yields of Δ3,10-isomers (Z/E)-
3a and (Z/E)-4a by adopting higher temperature (85 °C)
and changing the reaction medium to 50% aqueous ethyl-
ene glycol (method 2, Table 2). In the case of two catalysts,
Pd/Al2O3 and Pd/SO4 (entries 1–4 and 9–12, Table 2), an
increased conversion of substrates 1a and 2a to the Δ3,10
-
isomers (Z/E)-3a and (Z/E)-4a was observed in comparison
to method 1, (Table 1). However, in the reactions catalysed
by the Pd/C catalyst, the conversion to both Δ3,10-isomers
was lower in method 2 (entries 5–8, Table 2) in comparison
to method 1 (entries 5–8, Table 1).
The differences of results obtained in both methods
(method 1 and method 2) is visible by comparison of the
diagnostic regions of 1H NMR spectra of the crude product
3a and 4a. Figure 1-a2 (see also Fig. S3 in SM) shows the
1H NMR spectrum of the most pure (Z/E)-3a and Fig. 1-b2
(see also Fig. S6 in SM) presents of the best crude product
(Z/E)-4a (entry 12, Table 2).
The conversions of 2a to (Z/E)-4a in our tested reactions
1
were determined from the H NMR spectra of the crude
We noted that the microwave promotion of vinyl bond
isomerisation in both alkaloids, quinidine 1a and quinine
2a, is less selective at temperatures higher than 85 °C. Irra-
diation of the reaction mixture at 100 °C in ethylene glycol
leads to the cleavage of the quinuclidine ring giving qui-
notoxine (quinicine). The process of the high-temperature
cleavage of Cinchona alkaloids in acidic medium is well
known and is described in the literature as Pasteur rearrange-
ment [1, 17].
products as shown in Fig. 1-b1. The conversion in entry
4, Table 1 (see also Fig. S4 in SWM) was determined by
comparison of integrations of two doublets of two protons of
the =CH2 group of 2a and the summed signals of one alkene
proton of (Z/E)-4a isomers. Analysis of the region revealed
that the crude product contains 28% of unconverted substrate
2a together with (Z)-4a+(E)-4a in the ratio 1,6. We can see
from Table 1 that in method 1 the best conversion for quini-
dine 1a into (Z/E)-3a is 94% (entry 10) and for quinine 2a
into (Z/E)-4a is 91% (entry 12) with the Pd/BaSO4 catalyst
when the irradiation time is prolonged to 50 min.
It is interesting to note that only traces of isomerisation
products (Z/E)-3a or (Z/E)-4a were formed in experiments
conducted with palladium solid supported catalysts:
1 3

Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts…
Table 2 Results of microwave-
promoted isomerisation of
quinidine 1a and quinine 2a
into 3a and 4a (Scheme 2) in
50% aqueous ethylene glycol
in the presence of HCl at the
controlled temperature 85 °C
(method 2)
Entry
Substrate
Catalyst
Time (min)
Product
Yielda (%)
Conver-
The Z/E ratio in
sionb (%) crude productsb
1
2
3
4
5
6
7
8
1a
1a
2a
2a
1a
1a
2a
2a
1a
1a
2a
2a
Pd/Al2O3
Pd/Al2O3
Pd/Al2O3
Pd/Al2O3
Pd/C
Pd/C
Pd/C
30
50
30
50
30
50
30
50
30
50
30
50
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
(Z/E)-3a
(Z/E)-3a
(Z/E)-4a
(Z/E)-4a
92
90
93
91
75
74
78
80
95
96
94
95
87
90
75
80
60
70
60
56
95
98
90
96
3.4
5.0
1.5
1.5
2.0
6.0
2.0
2.3
3.8
3.9
1.6
1.7
Pd/C
9
Pd/BaSO4
Pd/BaSO4
Pd/BaSO4
Pd/BaSO4
10
11
12
aIsolated yields of crude product 3a or 4a from the reaction mixture
bDetermined conversion of 1a or 2a into 3a or 4a and their Z/E ratio from 1H NMR spectra of crude prod-
ucts
molecules of cinchonine 1b and cinchonidine 2b by method
Pd/SS
11
11
H3C
11
10
2. We found out that the full conversion to the appropriate
H3C
10
MW
10
Cl
MW
Δ3,10-isomers 3b and 4b cannot be achieved for any com-
bination of catalyst and time. For these alkaloids the best
results were obtained with Pd/Al2O3 catalyst. That fact can
be regarded as the difference in energy of the transition state
in the isomerisation process of each of alkaloids. The crude
product 3b was formed as a mixture of Δ3,10-isomers (Z)-3b
and (E)-3b in a ratio of 2.5 containing 20% of unconverted
1b. The crude product 4b was prepared from 2b as a mix-
ture of the (Z/E) Δ3,10-isomers in a ratio of 2.0 with high
contamination (33%) of unconverted 2b. These data were
found from the 1H NMR spectra, which can be seen on Figs.
S7 and S9 in SM.
H
H
3
3
-HCl, -Pd/SS
3
HCl, Pd/SS
Scheme 3 Plausible mechanism of positional isomerisation of the
vinyl bond in the Cinchona alkaloid molecules
a. with the use of conventional heating instead of micro-
wave irradiation in the same reaction medium, tem-
perature and time prolonged to 24 h as indicated in the
literature [23].
b. when the alkaloids 1a or 2a were irradiated without
hydrochloric acid with all the catalysts investigated at
70–90 °C for 50 min in EtOH/H2O and also in EG/H2O.
Having at hand the optimized protocol, we performed
microwave-promoted syntheses in the scale of 10 mmol [32].
The reaction scale is limited due to the microwave appara-
tus used in the research. The results were compatible with
those obtained in analytical quantities. We checked out that
the purification of the crude products 3a,b and 4a,b can be
achieved by careful recrystallization with aqueous ethanol,
which accomplishes separation of starting materials. How-
ever, the ratio of the geometric isomers in the recrystallized
products is not reproductible and depends on dilution of
ethanol and time of cooling.
The above described results mean that hydrochloric acid
not only facilitate perfect solubility of the basic reactants in
the reaction mixture but also acts together with palladium
leading proton addition to H2C11= and elimination from
HC3 giving positional isomerisation of the double bond
(Scheme 3).
The effect of the best microwave activation of the isom-
erisation process of 1a and 2a catalysed by palladium loaded
on very polar BaSO4 can mean that the support selectively
adsorbs microwave energy, which is translated to the palla-
dium giving acceleration of the formation and disintegration
of the transition state leading to more stable Δ3,10-isomers.
To expand the range of substrates, two effective catalysts,
Pd/Al2O3 and Pd/BaSO4, were evaluated in the microwave-
accelerated one-step isomerisation of the double bond in the
Pure Δ3,10-isobases 3a,b and 4a,b can be isolated by col-
umn chromatography because they have the lowest polarity
(the highest Rf values, see Table 3) in comparison to the Rf
values of the starting alkaloids 1a,b and 2a,b. We isolated
the mixture of geometric isomers: (Z/E)-3a in the ratio of
four from crude 3a in 88.0% yield. The Δ3,10-isocinchonine
has been separated in yield of 55.0% as the (Z/E)-3b in a
ratio 4.5.
1 3

T. M. Lipińska et al.
Table 3 Values of Rf on
silica gel TLC plates of the
substrates 1a,b, 2a,b and main
products 3a,b, 4a,b together
with their yields and the ratio of
components of Z/E geometric
isomers
Substrate/Rfa
Δ3,10-Isomer/Rfa
Yieldb of product and its componentc
Quinidine 1a: 0.44
Cinchonine 1b: 0.41
Quinnie 2a: 0.42
(Z/E)-3a: 0.65
(Z/E)-3b: 0.56
(Z)-4a: 0.63 and (E)-4a: 0.59
(Z)-4b: 0.59 and (E)-4b: 0.55
80%: Z/E=4.0
55%: Z/E=4.5
16.2%: pure (Z)+62.5%: Z/E=1.0
18.5%: pure (Z)+41.7%: Z/E=1.0
Cinchonidine 2b: 0.40
a2-Methoxyethanol was used as a mobile phase
bYields of products isolated by column chromatography
1
cAnalyses of products purity and their components by TLC (during column chromatography) and by H
NMR spectroscopy
The geometric isomers (E)- and (Z)-Δ3,10-isoquinine 4a
as well as (E)- and (Z)-Δ3,10-isocinchonidine 4b are visible
on the TLC plates as separated spots (Rf values are done in
the Table 3). The geometric isomer with the higher Rf value
can be partially isolated in pure form. We obtained from the
crude 4a the sample of the single geometric isomer (Z)-4a
(16.2%) as the first fraction and next, an equimolar mixture
of (Z/E)-4a isomers (62.5% yield). From the crude 4b, at
first the pure isomer (Z)-4b (its 1HNMR spectrum is given
on Fig. S10 in SM) was collected (yield 18.5%), and next a
1:1 mixture of (Z/E)-4b in yield of 41.7%.
We used the small analytical scale to choose the best cata-
lyst and the reaction medium under controlled microwave
irradiation. Next, the method was developed for the scale
of 10 mmoles, which can be expanded to higher preparative
scale. Especially good effects of almost complete conversion
were obtained with Pd/BaSO4 for quinidine 1a and quinine
2a transformations to appropriate Δ3,10-isomers: (Z/E)-3a
and (Z/E)-4a, which were isolated by us in high yields (80%
and 79%). The scope of application of our method was
extended to the transformation of alkaloids without methoxy
groups, 1b and 2b, into (Z/E)-3b and (Z/E)-4b by using Pd/
Al2O3 catalyst. Nevertheless, we developed two easy separa-
tion methods: the crystallisation with aqueous ethanol and
the column chromatography, leading to 55–60% yields of
pure Δ3,10-isobases (Z/E)-3b and (Z/E)-4b. Furthermore, the
pure (Z)-Δ3,10-isomers 4a and 4b were isolated.
Our experiments provide a new look at the reason of the
differences in physicochemical properties of Δ3,10-isobases
Cinchona alkaloids obtained long ago when not existed
possibilities to control molecular composition, which is
depended on methods of isomerisation process and also on
method of products isolation. Their data in the old literature
[18, 19 and ref. givens in 17] have been given probably for
Δ3,10-isomeric alkaloids 3a,b, 4a,b with different ratio of
(E)/(Z) geometric isomers.
Diversity of the structure and stereochemistry of the natu-
ral Cinchona alkaloids results in divergence in conversion
degree to Δ3,10-isomers with the each palladium supported
catalyst. The fact that Pd/BaSO4 is very effective in the cases
of quinine and quinidine, but Pd//Al2O3 is the most effective
for cinchonidine and cinchonine can be regarded as the dif-
ference in energy of the transition state in the isomerisation
processes of both type of alkaloids. So, specific microwave
interaction can be postulated in the formation and disinte-
gration of the catalytic transition state: double bond of sub-
strate–palladium-support in irradiated polar reaction mixture
for each alkaloid. Our results show opportunity to enhance
energy efficiency by the microwave irradiation in heterog-
enous catalytic reactions in polar reaction media.
To the best of our knowledge, the results we obtained
are similar to those presented in the literature for expensive
heterogeneous (rhodium) and homogenous (ruthenium) cata-
lysts used in this one-step reaction. Δ3,10-Isomers of natural
Cinchona alkaloids will be applied in material and medici-
nal chemistry as reactants for preparation of organometallic
catalysts and organocatalysts for asymmetric synthesis.
3 Conclusion
We elaborated the microwave-accelerated one-step catalytic
isomerisation of the vinyl double bond, the side chain of
Cinchona alkaloids, using inexpensive palladium solid sup-
ported catalyst, which was ineffective for this process under
conventional heating. Mixture of ethylene glycol with hydro-
chloric acid was found as green reaction media. The reaction
proved to be tolerant towards other functional groups present
in natural molecules of Cinchona alkaloids. The conversion
is depended on the kind of support, and on time and tem-
perature of reaction.
4 Experimental Section
4.1 General Information
Commercial Cinchona alkaloids from Fluka were used. Cat-
alysts and other reagents and solvents were purchased from
commercial suppliers (Sigma-Aldrich) and used without fur-
ther purification. Microwave heating at the controlled tem-
perature was performed with SYNTHEWAVE 402 reactor
1 3

Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts…
(Prolabo, open system, external IR detector for temperature
monitoring, connected with the software of computer for
online temperature regulation). The course of reactions was
monitored by thin-layer chromatography (aliquots were
taken and extracted by ethyl ether in the presence of ammo-
nia), which was carried out on 0.25 mm Merck silica gel
(60 F254) plates on aluminum. Pure products were isolated
by column chromatography with the Merck silica gel 60
(230–400 mesh). The column output was monitored with
TLC. Melting points (uncorrected) were determined on the
Bëthius apparatus. The optical rotations were measured on a
Perkin Elmer 241 polarimeter. High resolution mass spectra
were measured on AMD 604 Inectra GmbH spectrometer
(EI) or on GC/MSQP 5050 Shimadzu spectrometer (ESI).
IR spectra (KBr pellets) were recorded on FT-IR MAGNA
769 (Nicolet). The 1H and 13C NMR spectra were recorded
with VARIAN 400MR spectrometer (1H; 400 MHz, 13C:
100 MHz). Chemical shifts are given relative to TMS (δ=0)
in ppm and refer to residual solvent CDCl3 as internal stand-
4.3 Preparative Scale Isomerisation and Purification
of Crude Products
To a quartz cylindrical vial (volume 50 mL) was added
10 mmol of Cinchona alkaloid (3.24 g 1a or 2a vs2.94 g of
1b or 2b), 15.0 mL of 50% ethylene glycol, 3.0 mL 36 mmol,
350% mol of concentrated HCl and 200 mg, of 10% Pd/
BaSO4 (20 mg, 0.18 mmol Pd, 1.8% mol). The reaction mix-
ture was irradiated in the Synthewave 402 microwave reactor
(open system) at the programmed temperature or 85 °C for
a period 50 min. The reaction mixture was filtered by Celite
and added to the excess of cold aqueous ammonia. The white
solid was filtered off, washed with water and dried. Separa-
tion by column chromatography of (Z/E)-Δ3,10-isomers from
crude products was performed using 200 g of silica gel and a
mixture of ethyl acetate:methanol in the ratio 20:1 as eluent.
4.3.1 The Mixture of Geometric Isomers
(Z/E)‑(S)‑[(2R,4S)‑5‑Ethylidenequinuclidin‑2‑yl]
(6‑methoxyquinolin‑4‑yl)methanol, (Z/E)‑3a
in the Ratio 4
1
ard. Examples of analytical H NMR spectra are given in
Supplementary Material (SM).
4.2 General Procedure for Small Scale Catalytic
Isomerisation of Cinchona Alkaloids by Method 1
and by Method 2 (Results in the Tables 1, 2)
The crude Δ3,10-isoquinidine 3a (3.20 g, 96.0%) was
obtained according to entry 10. Table 2 and its purity was
1
determined by H NMR spectroscopy (SM, Fig. S3): the
conversion 98%, the ratio (Z/E)=(78:20). The crude product
was purified by column chromatography and the product
as the mixture Δ3,10-isomer (Z/E)-3a in the ratio 4:1 was
obtained as possessing the most higher Rf value (Table 3).
Yield 2.84 g, 88.0%, mp 191.0–192.5 °C, [α] D22 +181.0º
(c1 in EtOH); {lit, [13]: mp 178–180 °C, [α] D15 +193.2 (c
1, EtOH) called as an apoquinidine methyl ether}. 1H NMR
(400 MHz, CDCl3, δ, ppm): 8.68 (d, J=4.4 Hz, 1H, 2′-H),
7.90 (d, J=8.8 Hz, 1H, 8′-H), 7.54 (d, J=4.4 Hz, 1H, 3′-H),
7.23 (dd, J = 8.9, 2.4 Hz, 1H, 7′-H), 7.13 (d, J = 2.4 Hz,
1H, 5′-H), 5.97 (br s, 1H, 9-H), 5.33–5.27 (m, 0.8H, 10-H
of (Z)-3a), 5.27–5.18 (m, 0.2H 10-H of (E)-3a), 4.43 (d,
J=15.6 Hz, 1H, 2-H), 3.88 (s, 3H, MeO), 3.50 (d, J=15.6,
1H, 2-H), 3.28 (m, 1H, 8-H), 3.06 (m, 1H, 6-H) 2,87 (m, 1H,
6-H), 2.44 (br s, 1H, 4-H), 2.06 (m, 1H, 5-H), 1.68 (m, 2H,
5-H, 7-H), 1.62 (d, J = 6.4 Hz, 0.6H (E)–CH3CH=), 1.54
(d, J=6.4 Hz, 2.4H (Z)–CH3CH=), 1.40 (m, 1H, 7-H);13C
NMR (100 MHz, CDCl3, δ, ppm): 157.4 (C6′), 148.2 (C4′),
147.3 (C2′), 144.0 (C9′), 141.8 (C3), 131.3 (C8′), 126.5
(C10′), 121.5 (C3′), 118.6 (C7′), 113.1 (C10), 101.3 (C5′),
71.4 (C9), 59.6 (C8), 55.6 (MeO), 51.2 (C2), 50.0 (C6), 33.5
(C4), 22.5 (C5), 22.3 (C7), 12.3 (C11); IR (KBr), cm−1:
3419. 3160, 2936, 1509, 1432, 1366, 1240, 1120, 1096,
1077, 1054, 1027; MS (EI), m/e (%): 324 (M+, 100%), 309
(16), 189 (45), 136 (95), 108 (20); HRMS (EI): founded
324.18372, for M+, calculated for C20H24N2O2: 324.18378.
To a quartz cylindrical vial (volume 10 mL) was loaded
with 0.5 mmol of Cinchona alkaloid (162 mg 1a or 2a ver-
sus 147 mg of 1b or 2b), 0.75 mL of 50% ethanol (method
1) or 0.75 mL of 50% ethylene glycol (method 2), 0.15 ml
(1.8 mmol, 350% mol) of concentrated HCl and 10 mg
(1 mg=0.009 mmol Pd, 1.8% mol) of 10% palladium cata-
lyst (Pd/Al2O3 or Pd/C or Pd/BaSO4). The reaction mixture
was irradiated in the Synthewave 402, Prolabo microwave
reactor (open system) at the programmed temperature 70 °C
(method 1) or 85 °C (method 2). The conversion of substrate
was monitored by taking of micro-samples of the reaction
mixtures regularly, in the interval of each 10 min, which
after extraction with diethyl ether in the presence of aqueous
ammonia were analyzed by TLC (silica gel plates, 2-meth-
oxyethanol, Rf values are shown in the Table 3).The irradia-
tion was stopped after 30 min or after 50 min. The reaction
mixture was filtered by Celite and added to the cold aqueous
ammonia (5 mL). The white solid was filtered off, washed
with water and dried. The obtained crude product was ana-
1
lyzed by H NMR to determine of the conversion degree
and the ratio of geometric isomers. The results of analysis
are given in Table 1 (method 1) and in Table 2 (method 2).
The examples of spectra of crude products are given in Sup-
porting Material.
1 3

T. M. Lipińska et al.
4.3.2 Pure (Z)‑4a and the Mixture 1:1 (Z/E)‑4a
the ratio 4.5:1: 1H NMR (see, Fig. S8 in SM): (400 MHz,
CDCl3, δ, ppm): 8.75 (d, J = 4.8 Hz, 1H, 2′-H), 8.05 (d,
J = 8.3 Hz, 1H, 8′-H), 7.84 (d, J= 8.6 Hz, 1H, 5′-H), 7.58
(t, J = 8.3 Hz, 1H, 7′-H), 7.56 (d, J = 4.8 Hz, 1H, 3′-H),
7.20 (t, J=8.3 Hz, 1H, 6′-H), 5.71 and 5.68 (d, J=3.6 Hz
and d, J = 4.0 Hz, Σ 1H, 9-H in Z/E-3b), 5.34 (br s, 1H,
OH), 5.23–5.15 (m, 0,82 H, 10-H in (Z)-3b), 5.15–5.08 (m,
0.18 H, 10-H in (E)-3b), 4.14 (d, J = 16,4 Hz, 1H, 2-H),
3.21 (d, J = 16,4 Hz, 1H, 2-H), 3.14–296 (m, 1H, 8-H),
2.88–2.78 (m, 2H, 6-H), 2.72–2.62 (m, 1H, 6-H), 2.32 (br s,
1H, 4-H), 2.00–1.92 (m, 1H, 5-H), 1.61–1.45 (m, Σ 5H=m,
2H, from 5-H and 7-H+2×d, 3H 10-H3 at 1.58 and 1.48,
J = 6.4 Hz, for H3C–CH= in (Z/E)-3b), 1.41–133 (m, 1H,
7-H);13C NMR (100 MHz, CDCl3, δ, ppm): 150.4, 149.7,
148.3, 141.9, 130.5, 129.3, 126.8, 125.8, 123.2, 118.6,
113.4, 72.0, 60.2, 51.4, 51.1, 33.7, 27.7, 27,5, 12.6; IR (KBr,
cm−1); 3416 (br), 3068, 2917, 2975, 2716 (br), 1620, 1590,
1569, 1509, 1459, 1383, 1333, 1299, 1235, 1209, 1168,
1119, 1099, 1054, 1028, 993, 951, 885, 864, 832, 798, 759,
689; HR MS (ESI) [M+H]+: founded: 295.1811, calculated
for C19H23N2O: 295.1810.
The crude Δ3,10-isoquinine 4a (3.08 g, 95.0%) was obtained
according to the entry 12, Table 2 and its purity was deter-
1
mined by H NMR spectrum (Fig. S6: conversion 96%,
Z/E=6.1/3.5). The crude product was purified by column
chromatography. At the beginning the pure Δ3,10-isomer (Z)-
22
4a was obtained{0.52 g, 16.2%, mp 180–181 °C, [α]
D
−158.6° (c1 in EtOH)} and next the mixture 1:1 of (Z/E)-
4a Δ3,10-isomers was collected: yield 0.51 g, 62.5%, mp
22
184–185 °C, [α]
−172.4° (c1 in EtOH). Lit [18, 19]:
D
β-isoquinine or apoquinine methyl ether, mp 183–185 °C,
[α] D15 −201.9° (c1 in EtOH) and α-isoquinine or isoapo-
quinine methyl ether: mp 192–194 [α] D22 −253.4° (c 0.811,
EtOH). Spectral data for the Δ3,10-isoquinine as Z:E mix-
ture in ratio 1:1 (Z/E)-4a, (Z/E)-R-[(2S,4S,)-5-ethylidene-
1
quinuclidin-2-yl](6methoxyquinolin-4-yl)methanol: H
NMR (400 MHz, CDCl3, δ, ppm): 8.71 (d, J=4.4 Hz, 1H,
2′-H), 7.92 (d, J = 9.2 Hz, 1H, 8′-H), 7.60 (d, J = 4.4 Hz,
1H, 3′-H), 7.24 (d, J=2.4 Hz, 1H, 5′-H), 7.14 (dd, J=9.2,
2.4 Hz, 1H, 7′-H), 5.89 (br s, 1H, 9-H), 5.27–5.20 (m, 0,5 H,
10-H from (Z)-4a), 5.20–5.13 (m, 0.5 H, 10-H from (E)-4a),
3,84 and 3.82 (2×s 3H, MeO from (Z/E)-4a), 3.60–3.45 (m,
2H, 2-H), 3.24–3.16 (m, 1H, 8-H), 2.94–2.80 (m, 2H, 6-H),
2.42–2.38 (m, 1H, 4-H), 2.08–2.00 (m, 1H, 5-H), 1.92–1.84
(m, 1H, 7-H), 1.70–1.60 (m, 1H, 5-H), 1.52 (d, J=7.6 Hz,
1,5 H, 11-H from (Z)-4a), 1.45 (d, J=5.8 Hz, 1.5 H, 11-H
from (E)-4a), 1.42–138 (m, 1H, 7-H);13C NMR (100 MHz,
CDCl3, δ, ppm): 157.4 (C6′), 147.9 (C4′), 147.2 (C2′),
143.2 (C9′), 139.1 (C3), 131.1 (C8′), 126.4 (C10′), 121.3
(C3′), 118.5 (C7′), 113.1 (C10), 101.3 (C5′), 70.9 (C9), 60.8
(C8), 56.5 (C2), 55.7 (MeO), 44.0 (C6), 33.1 (C4), 27.4
(C5, C7), 12.3 (C11); IR (KBr), cm−1: 3200 br, 2990, 1622,
1591, 1566, 1511, 1459, 1384, 1340, 1262, 1190, 1171,
1124, 1090, 1079, 1035. MS (EI), m/e (%): 324 (M+, 85%),
309 (18), 189 (75), 136 (100), 108 (25); HRMS (EI): M+
founded 324.18381, calculated for C20H24N2O2 324.18378.
4.3.4 Pure (Z)‑4b and Mixture 1:1 (Z/E)‑4b
The crude Δ3,10-isocinchonidine 4b was obtained by method
2 from 10 mmol (2.94 g) 2b with 200 mg Pd/Al2O3 in yield
1
92%. Its analysis by H NMR (spectrum, Fig. S9 in SM)
was showed 65% containing of (Z/E)-4b in the ratio 42:23
and 35% of unconverted substrate 2b. The crude product
(2.68 g) was purified by column chromatography. At the
beginning the pure Δ3,10-isomer (Z)-4b 0.56 g, (18.5%)
was separated (1H NMR spectrum—Fig. S10 in SM), m.p.
22
230.0–232.0 °C, [α]
−95.5° (c1 in EtOH), and next
was collected 1.24 g, (D41.7%) of the mixture 1:1 (Z/E)-4b
Δ3,10-isomers [α] D22 −172.4° (c1 in EtOH). Spectral data
for pure (R)-[(2S,4S,Z)-5-ethylidenequinuclidin-2-yl]
1
(quinolin-4-yl)methanol, (Z)-4b: H NMR (400 MHz,
CDCl3, δ, ppm): 8.87 (d, J = 4.6 Hz, 1H, 2′-H), 8.09 (dd,
J=7.8, 1.2 Hz, 1H, 6′-H), 7.99 (dd, J=8.2, 1.2 Hz, 8′-H),
7.66 (ddd J=8.2, 7.0, 1.2 Hz, 1H, 7′-H), 7.59 (d, J=4.6 Hz,
1H, 3′-H), 7.43 (ddd, J = 7.8. 7.0, 1.2 Hz, 1H, 6′-H), 5.80
(d, J = 3.2 Hz, 1H, 9-H), 5.18 (qt, J = 6.8, 2.4 Hz, 1H,
10-H), 3.67–3.58 (m, 1H, 8-H), 3.50 (d, J = 16.4 Hz, 1H,
2-H), 3.37 (d, J = 16.4 Hz, 1H, 2-H), 3.14 (ddd, J = 14.4,
12.2. 4.8 Hz, 1H, 6-β‑H), 2,74 (ddd, J=12.2, 8.7, 4.8 Hz,
6-α-H), 2.35 (d, J=2.4 Hz, 1H, 4-H), 1.97 (ddd, J=12.7,
8.7, 1.5 Hz, 5-α-H), 1.79 (tt, J= 11,3,4.3 Hz, 1H, 7-β‑H),
1.64–1.54 (m, 1H, 5-β-H), 1.48–1.38 (m, 1H, 7-α-H), 1.42
(d, 3H, J=6.8 Hz, 11-H);13C NMR, (100 MHz, CDCl3, δ,
ppm): 150.8, 150.5, 150.0, 149.1, 148.5, 130.7, 129.4, 127.0,
123.3, 118.5, 115.3, 72.1, 61.5, 57.0, 44.4, 33.6, 26.1, 25.8,
13.1; IR (KBr, cm−1); 3428 (br), 3018, 2929, 2859, 2715
(br), 1622, 1590, 1569, 1508, 1446, 1381, 1345, 1302, 1236,
4.3.3 The Mixture of Geometric Isomers (Z/E)‑3b
in the Ratio 4.5
The crude Δ3,10-isocinchonine 3b was obtained by method
2 from 10 mmol (2.94 g) 1b with 200 mg Pd/Al2O3 in yield
95%. Its analysis by 1H NMR (Fig. S7 in SM) was showed
70% containing of (Z/E)-3b in the ratio 2.5 and 20% of
unconverted substrate 1b. The crude product (2.80 g) was
purified by column chromatography 1.60 g (55.0%) of the
pure Δ3,10-isomer (Z/E)-3b in the ratio 4.5:1 was collected
(1H NMR spectrum see Fig. S8 in SM), mp 210.0–212.0 °C,
[α] D22 +157.8 º (c1 in EtOH). Literature data for apocincho-
nine [22, 23]:: mp 214–216 °C, [α] D22 +158.8º (c0.510 in
EtOH).Spectral data for (Z/E)-(S)-[(2R,4S)-5-ethylidene-
quinuclidin-2-yl](quinolin-4-yl)methanol, (Z/E)-3b in
1 3

Effect of Microwave Irradiation on the Catalytic Activity of Palladium Supported Catalysts…
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1 3