Application of the ring-closing metathesis to the formation of 2-aryl-1H-pyrrole-3-carboxylates as building blocks for biologically active compounds

Article abstract of DOI:10.1016/j.tet.2016.09.059

Ring-closing metathesis (RCM) is a powerful tool for the preparation of cyclic organic compounds. Yet, one of the major limitations of this method is the difficulty to prepare large quantities of target molecules. Herein we describe a comprehensive study

Full text of DOI:10.1016/j.tet.2016.09.059

Accepted Manuscript
Application of the ring-closing metathesis to the formation of 2-aryl-1H-pyrrole-3-
carboxylates as building blocks for biologically active compounds
Katarzyna Grychowska, Bartłomiej Kubica, Marcin Drop, Evelina Colacino, Xavier
Bantreil, Maciej Pawłowski, Jean Martinez, Gilles Subra, Pawel Zajdel, Frédéric
Lamaty
PII:
S0040-4020(16)30989-9
10.1016/j.tet.2016.09.059
TET 28130
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 July 2016
Revised Date: 19 September 2016
Accepted Date: 26 September 2016
Please cite this article as: Grychowska K, Kubica B, Drop M, Colacino E, Bantreil X, Pawłowski M,
Martinez J, Subra G, Zajdel P, Lamaty F, Application of the ring-closing metathesis to the formation of 2-
aryl-1H-pyrrole-3-carboxylates as building blocks for biologically active compounds, Tetrahedron (2016),
doi: 10.1016/j.tet.2016.09.059.
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ACCEPTED MANUSCRIPT
Application of the ring-closing metathesis to the
formation of 2-aryl-1H-pyrrole-3-carboxylates as
building blocks for biologically active compounds
Katarzyna Grychowska1, Bartłomiej Kubica1, Marcin Drop,1 Evelina Colacino2, Xavier
Bantreil2, Maciej Pawłowski1, Jean Martinez2,3, Gilles Subra3, Pawel Zajdel1 and
Frédéric Lamaty*2
1
Department of Medicinal Chemistry, Jagiellonian University Medical College, 9
Medyczna Street, 30-688 Krakow, Poland
2 Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, CNRS, Université de
Montpellier, ENSCM, Université de Montpellier Campus Triolet Place Eugène
Bataillon 34095 Montpellier cedex 5, France. E-mail: frederic.lamaty@umontpellier.fr
3 Institut des Biomolécules Max Mousseron (IBMM) UMR 5247, CNRS, Université de
Montpellier, ENSCM, Bâtiment E, Faculté de Pharmacie 15, avenue Charles Flahault
BP14491 34093 Montpellier cedex 5, France.
Email: Frédéric Lamaty* - frederic.lamaty@umontpellier.fr
* Corresponding author
Abstract
Ring-closing metathesis (RCM) is a powerful tool for the preparation of cyclic organic
compounds. Yet, one of the major limitations of this method is the difficulty to prepare
large quantities of target molecules. Herein we describe a comprehensive study
regarding the gram-scale synthesis of 2-aryl-1H-pyrrole-3-carboxylates based on the
ring-closing metathesis of the corresponding β-amino esters as a key step. This
study includes evaluation of solvent and catalyst as well as reaction kinetics on the
RCM. After an aromatization step, this methodology allowed for an efficient
generation of variously substituted and unprecedented 2-aryl-1H-pyrrole-3-
1

ACCEPTED MANUSCRIPT
carboxylates in good yields and cost-effectiveness. The resulting molecules might
serve as key building blocks for the generation of CNS-oriented compound libraries.
Graphical abstract
Bridging Catalysis and Pharmaceutical Compounds
Ts
Ts
N
N
HN
NO2-Grela
NaOt-Bu
DMF
R
R
R
AcOEt
CO2Me
CO2Me
CO2Me
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Optimized catalyst loading
Scale up to 2.5g
Environmentally friendly solvent
Room temperature
ꢀ One-pot two-step
deprotection/aromatization
ꢀ Unprecedented pyrroles
ꢀ High value synthons
Short reaction time
Keywords
Ring-closing metathesis; pyrrole; ruthenium; microwaves; aromatization
Introduction
Olefin metathesis has become an efficient tool for the formation of carbon-carbon
double bonds. In particular, ring-closing metathesis (RCM) has a large impact on the
pharmaceutical industry because this reaction allows formation of medium-to-large
size carbocycles and heterocycles from acyclic dienes.1 One of the first applications
of RCM in the synthesis of biologically active compounds concerned the synthesis of
Ciluprevir (BILN-2061), a pseudopeptide inhibitor of HCV NS3 protease (Figure 1).2
This method stimulated intense generation of Ciluprevir analogs, among which
Vaniprevir (MH-7009) is now evaluated in phase III clinical trials.3 It is worth noting
that development of various Hepatitis C inhibitors is currently a subject of intense
research in medicinal chemistry.4 Another eminent example of biologically active
compound obtained by RCM process is represented by Tamiflu (oseltamivir
phosphate), which behaves as glycosidase inhibitor and is used for the treatment of
influenza.5 RCM was also applied as a central transformation in the synthesis of
2

ACCEPTED MANUSCRIPT
seven-member heterocyclic ring of SB-462795, a cathepsin K inhibitor, a drug
candidate for the treatment of osteoporosis.6
S
O
N
O
N
H
N
O
O
N
O O
OH
H
N
S
HN
N
HN
O
O
O
O
N
O
H
HN
O
N
O
O
O
O
Ciluprevir
Vaniprevir
O
N
NHAc
H
N
.
O
H2N
O
S
O
N
H3PO4
O
N
H
O
O
COOEt
SB-462795
Tamiflu
Figure 1: Selected biologically active compounds obtained via RCM method.
Since the first reports of phosphine-containing ruthenium complexes for metathesis
reaction,7 a number of new catalysts have been developed.8 A major breakthrough
was the replacement of the phosphine ligand with a N-heterocyclic carbene (NHC),
giving rise to second generation catalysts such as G-II (Figure 2).9 Such modification
increased air and moisture stability of the corresponding complexes. Replacement of
the benzylidene moiety with an indenylidene (Figure 2, M2 and M20)10a, 8b, 10b-d or 2-
isopropoxystyrene derivatives11 (Figure 2, NO2-Grela and M51) led to new catalyst
families with improved stability and activity. However, RCM is a highly substrate
depending reaction and despite the wide variety of catalysts, there is no universal
one applicable to all kind of dienes.12 Moreover, cost of the ruthenium complexes
constitutes a major limit of the process and studies for determining the proper
reaction conditions, which allow for minimal catalyst loading are an important
research area with regard to economical issues.
3

ACCEPTED MANUSCRIPT
SIMes
SIMes
Ru
Cl
Ph
Cl
Ru
Cl
Cl
O
NO2
PCy3
G-II
iPr
NO2-Grela
SIMes
Ru
SIMes
SIMes
Cl
Ph
Ph
Cl
Cl
Ru
Ru
PPh3
M20
Cl
Cl
Cl
O
PCy3
M2
O
M51
Figure 2: Structure of catalysts used in this study
The pyrrole scaffold has focused a special attention as a privileged structure in
medicinal chemistry, since several pyrrole-containing compounds displayed
antipsychotic, anxiolytic, anticancer and antibacterial activity.13 Among them, 2-
arylpyrrole core was present in a series of 5-phenyl pyrrole-3-carboxamides and 2,5-
disubstitued phenyl-1-H-pyrroles were classified as dopamine D2 receptor ligands14
and D3 receptor antagonists,15 respectively. Furthermore, compound TAK-438
(Venoprazan), displaying high H+/K+-ATP-ase inhibitory activity is currently evaluated
in phase III clinical trials for its efficacy in digestive disorders.16 Moreover, 2-
arylpyrrole derivatives behaved as potent progesterone receptor modulators.17
The synthetic procedures described for 2-arylpyrroles generally consist in C2
arylation of the heterocyclic core involving palladium catalyzed coupling18 or
cyclization of N-allylimine under oxidative conditions.19 Nevertheless, these methods
required either harsh conditions or prolonged reaction times. The metal-catalyzed
cyclization of homopropargyl azides, although highly efficient, needed either 24h
reaction time or the use of toxic mercury as catalyst.20
During our recent study on the synthesis of 1H-pyrrolo[3,2-c]quinolines as 5-
HT6 receptor antagonists,21 we found that RCM could be an efficient pathway to
obtain pyrroles. We thus decided to optimize a method for the generation of 2-aryl-
1H-pyrrole-3-carboxylates 4 involving RCM of 2 followed by base-induced
aromatization (Scheme 1). These scaffolds should represent key intermediates for
the synthesis of biologically active compounds targeted on CNS receptors. This
approach has already proven its efficiency in the preparation of aromatic and
heteroaromatic structures.22
4

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Ts
Ts
N
HN
N
Base
[Ru]
CO2CH3
R1
R1
R1
CO2CH3
CO2CH3
4
3
2
Scheme 1: Retrosynthetic approach for the formation of pyrrole derivatives 4.
Taking into account our interest in olefin metathesis23 as well as economic
limitations of this process, we wished to find optimal reaction conditions to obtain
differently substituted pyrroline derivatives 3 in a gram-scale, in satisfactory yields,
using a reduced catalyst loading. Herein we report a comparative study of selected
metathesis catalysts, as well as the influence of solvent and reaction kinetics on
RCM.
Results and Discussion
Compound 2a bearing a nitro-substituent in the C2 position of the phenyl ring was
selected as a model substrate for the preliminary RCM experiments. Indeed, this
substrate has already been used for the synthesis of pyrroloquinoline scaffolds, using
the NO2 moiety as an extra functional group for further transformations.23d In addition,
the RCM of 2a was found challenging since the nitro-substituent was suspected to
poison the ruthenium catalyst. At that time, RCM of 2a to yield 3a was performed in
dichloromethane, either at room temperature, in the presence of 10 mol% of G-II for
12 hours, or at 100°C with 4 mol% of G-II under microwave activation in a sealed
reactor for 2 hours. The latter strategy allowed the preparation of the desired product
3a in good yield (84%). It is worth noting, that microwave heating allows for the
24
acceleration of the RCM process.
Nevertheless, this method suffers from some
disadvantages with regard to the scale-up of the reaction. First of all, high catalyst
loading, 4 to 10 mol%, implicates high cost for the scaled-up synthesis. Furthermore,
microwave irradiation using sealed tubes is limiting in scale and thus would require
splitting of the reaction mixture into several batches, thus reducing the user-friendly
aspect of the whole process. The above observations prompted us to elaborate a
suitable method for larger scale synthesis.
5

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Table 1: Evaluation of the catalyst loading in the RCM of 2aa
0.5 g scale
Loading
2.5 g scale
Entry Cat.
Conv. (%)b
Conv. (%)b
Yield (%)c
TONd
18.8
18.5
24.7
24.3
59
(mol %)
1
2
3
4
5
G-II
4
100
100
99
98
94
94
86
72
77
75
74
74
73
59
65
NO2-Grela
G-II
3
1
NO2-Grela
G-II
94
96
6
NO2-Grela
77
65
a
Reaction conditions: 2a (0.5 or 2.5 g), Ru catalyst (1-4 mol%), CH2Cl2, reflux, MW
b
open vessel mode, 30 min.
Mean from two experiments, conversion was
c
determined by HPLC. Isolated yield upon crystallization from diethyl ether. d TON =
[(mmol of 3a/mmol of 2a)/mmol of [Ru]].
In order to optimize the catalyst loading, preliminary studies on the RCM of 2a
were performed under microwave irradiation, using an open-vessel mode, in the
presence of either G-II or NO2-Grela catalysts (Table 1).25 To directly find the best
catalyst loading for scalability, experiments were conducted on 0.5 g and 2.5 g of 2a.
Interestingly, on 0.5 g scale, while the decrease of G-II loading from 4 to 1 mol% did
not significantly affect the HPLC conversion, it was reduced from quantitative to 77%
in the presence of NO2-Grela (Table 1). However, the importance of scaling-up
reactions was demonstrated with experiments using 2.5g of 2a since G-II and NO2-
Grela behaved rather similarly on such scale, with a decrease in conversion
concomitant with the lowering of catalyst loading. At this scale, NO2-Grela performed
better than G-II when 1 mol% was used, and 3a could be isolated in 65% yield (Table
1, entry 6). The slightly lower yields compared to HPLC conversions were probably
due to isolation issues since no cross-metathesis side-products were observed.
Interestingly, only a 10% drop in the yield of isolated compound was observed when
changing NO2-Grela loading from 4 to 1 mol%. It is noteworthy that the obtained
6

ACCEPTED MANUSCRIPT
yields remained satisfactory from a preparative perspective. Indeed, TON (turn-over
number) values of 65 and 18.5 could be obtained with 1 mol% and 4 mol% of NO2-
Grela, respectively, proving that the cost-effectiveness (ratio of catalyst cost per
isolated yield of product) of the former reaction conditions was better than the latter
ones. A 1 mol% catalyst loading was thus kept for further experiments.
To further optimize the RCM process, two more parameters were explored: the
nature of the solvent and of the catalysts. One of the key considerations in industry is
the use of green solvents to replace environmentally unfriendly ones.26
Dichloromethane and toluene, which are both toxic, are the most widespread
solvents employed for RCM. Nevertheless, some reports describe application of
23a, 23c
alternative innocuous solvent in this reaction.27,
Among them, dimethyl
carbonate (DMC) and ethyl acetate (AcOEt) seemed to be the most practical greener
media for RCM transformation.28 Additionally, these environmentally friendly solvents
were reported in some cases to improve the reaction yields.27
Table 2: Evaluation of selected solvents in the RCM of 2aa
Entry Cat.
Solvent
CH2Cl2
AcOEt
DMC
HPLC Conv. (%)b NMR Yield (%)b,c
1
2
3
4
5
6
G-II
62
74
68
56
64
63
63
73
66
48
65
63
NO2-Grela
CH2Cl2
AcOEt
DMC
a Reaction conditions: 2a (50 mg), Ru catalyst (1 mol%), 30°C, 24 h. b Mean from two
experiments. c Based on CH2Br2 as internal standard.
Thus, the RCM of 2a was attempted in DCM, DMC and AcOEt on a 50 mg
scale using 1 mol% of G-II or NO2-Grela at 30 °C for 24 hours (Table 2). In order to
avoid the use of a microwave reactor that would represent a limit for scale-up, the
study was continued using traditional heating. Among the solvent tested, AcOEt gave
the best yields in the RCM reactions catalyzed by both G-II (Table 2, entry 2, 73%)
7

ACCEPTED MANUSCRIPT
and NO2-Grela (Table 2, entry 5, 65%). Nevertheless, NO2-Grela yielded
comparable results in DMC (63%) and AcOEt (Table 2, entries 5 and 6). In the
syntheses performed at the industrial scale, the choice of the solvent is of particular
importance and, among other issues, the costs of purchase, purification and drying
should be carefully considered. Taking into account the availability and low boiling
point of AcOEt, this solvent was selected for further study.
With these data in hands, additional catalysts, namely indenylidene-based
catalysts M2 and M20, and boomerang-type catalyst M51, featuring a N,N-bis[2,4,6-
(trimethyl)-phenyl]imidazolin-2-ylidene (SIMes) ligand, were investigated in the RCM
of 2a on a 2.5g scale (Figure 2). Moreover, the catalysts were added in three equal
portions over a period of 7 hours to maximize reaction yield by decreasing catalyst
decomposition.29 Although M2 catalyst gave the best HPLC results after 24 h, the
conversion measured after 4 h of stirring was significantly lower when compared with
other catalysts (Table 3, entry 3). This result might reflect the high stability and slow
initiation rate of M2. Even though no side-product was detected during the RCM, the
isolated yield obtained with this catalyst was the lowest. The best yields were
obtained using NO2-Grela and M20 catalysts (Table 3, entries 2 and 4). G-II and M51,
which are slightly less stable than the other catalysts tested, gave lower isolated
yields (Table 3, entries 1 and 5).
Table 3: Evaluation of selected ruthenium catalysts in the RCM of 2aa
Entry Cat.
HPLC Conv. (%)b
NMR Yield
(%)b,c
Yield
(%)b,d
47
4hb
30
34
9
7hb
48
52
48
50
54
24hb
1
2
3
4
G-II
63
71
NO2-Grela
M2
62
71
53
68
80
36
M20
34
37
62
65
52
5
M51
59
75
44
a
b
Reaction conditions: 2a (2.5 g), Ru catalyst (1 mol%), AcOEt, 30°C, 24 h. Mean
c
d
from two experiments. Based on CH2Br2 as internal standard. Isolated yield upon
crystallization from diethyl ether.
8

ACCEPTED MANUSCRIPT
The beneficial effect of the portionwise addition of the catalyst was monitored
on a 2.5 g scale experiment, using 1 mol% of NO2-Grela in AcOEt (Scheme 2).
When a single portion of NO2-Grela was added at the beginning of the reaction, the
conversion stabilized at 46% in less than 1h as shown by HPLC. With a two-portion
addition (second portion added after 45 min), the final conversion slightly increased
to 50%. Gratifyingly, the three-portion addition (second and third addition after 2h and
3h, respectively) gave the best result with 61% conversion after 4h of reaction. Such
condition allowed isolation of 3a in 54% yield.
Portion 3
0.33 mol%
Portion 2
0.33 mol%
Portion 2
0.5 mol%
Scheme 2: Kinetic study of RCM of 2a with portionwise addition of NO2-Grela
As already witnessed in the literature for G-II,30 kinetic data from Scheme 2
confirmed that the product concentration reached a constant level 30 min after each
catalyst addition. Thus, the best compromise for the experimental conditions and
catalyst loading, evaluated for the RCM reaction of 2-nitro-substituted substrate 2a
involved portionwise addition of 1 mol% of NO2-Grela catalyst (3 equal portions), with
30 min intervals, over a period of 1.5 h at 30°C in AcOEt.
In order to evaluate the influence of reaction scale-up on the outcome of RCM of 2a,
we next performed the experiment using 15 g of 2-nitro-substituted substrate,
maintaining 1 mol% of catalyst loading added in 3 portions in every 30 min, while
stirring the mixture in AcOEt at 30°C (Table 4). We were pleased to see that under
these conditions, the RCM product 3a was obtained with 53% isolated yield.
9

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Table 4: Evaluation of scale-up effect in the RCM of 2aa
Entry
Scale
2.5 g
15 g
HPLC Conv. (%)b NMR Yield (%)b,c Yield (%)b,d
1
2
61
63
70
60
54
53
a Reaction conditions: 2a (15 g), NO2-Grela (1 mol%), AcOEt, 30 °C, 1.5 h. Mean
b
c
d
from two experiments. Based on CH2Br2 as internal standard. Isolated yield upon
crystallization from diethyl ether.
Encouraged by these findings, we next investigated the synthetic utility of the
evaluated method for the RCM of variously substituted dienes 2a–2g, obtained
through a three-component aza-Baylis-Hillman reaction followed by allylation. It is
noteworthy that any substituent might modify biological activity of the final
compounds or could be used as a functional handle for further synthetic
transformations. In addition to 2a, non-substituted β-amino ester 2b as well as its
analogs bearing methoxy groups (2c–e) or chlorine atoms (2f–g) as substituents of
the phenyl ring were evaluated (Table 5). The reaction was performed on 0.5 g of
substrates using portionwise addition of 1 mol% of NO2-Grela while stirring the
mixture in AcOEt at 30 °C for 1.5 h.
10

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Table 5: Application of the optimized conditions to the synthesis of pyrrolines 3b-ga
HPLC Conv.
(%)b
NMR Yield
(%)b,c
Entry
Product
R
Yield (%)b,d
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
o-NO2
H
61
58
48
52
52
65
66
70
71
60
65
n.d.f
75
81
54
58
39
43
46
66
64
o-OMe
m-OMe
p-OMe
m-Cl
3g
p-Cl
a Reaction conditions: 2a-g (0.5 g), NO2-Grela (1 mol%), AcOEt, 30 °C, 1.5 h. b Mean
from two experiments. c Based on CH2Br2 as internal standard. d Isolated yield upon
crystallization from diethyl ether. e Reported in ref23d. f n.d. = not determined.
The RCM reaction was not affected by the position of the substituent on the phenyl
ring, as similar yields were obtained when the chloro or methoxy groups were either
in ortho, meta or para position (Table 5, entries 3-8). Compounds 3c–e, bearing a
methoxy group, were isolated in about 43% yield while their chloro congeners 3f–g
were obtained in more or less 64% yield. When no substituent was present on the
aromatic moiety, an intermediate yield of 54% for 3b was obtained (Table 5, entry 2).
It should be noted that in all cases, purification of compounds 3a–g was not
performed via column chromatography but simple crystallization in diethyl ether, thus
improving the feasibility of the whole process on a larger scale.
Pyrrolines 3a–g were then converted into corresponding pyrroles 4a–g using
NaOt-Bu in DMF, under air to promote deprotection and aromatization in a one-pot
sequence (Table 6). Corresponding pyrrole derivatives could be isolated efficiently,
with 60–70% yield, in solely 2 hours. It is important to highlight that this methodology,
involving RCM followed by base-mediated deprotection/aromatization, allowed to
synthesize new pyrrole derivatives 4c-f, which could serve as diversity platforms for
further transformations.
11

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Table 6: Deprotection-aromatization for the preparation of pyrroles 4a-g.a
Ts
N
HN
NaOt-Bu (3 equiv.)
R
R
DMF, rt, 2h
CO2Me
CO2Me
3a-g
4a-g
Entry
Product
4a
R
Yield (%)b,d
1
2
3
4
5
6
7
o-NO2
H
65
60
70
68
67
65
63
4b
4c
o-OMe
m-OMe
p-OMe
m-Cl
p-Cl
4d
4e
4f
4g
a Reaction conditions: 3a-g (0.3 mmol), NaOt-Bu (0.9 mmol), DMF, rt, 2h.
Conclusion
In conclusion, we developed a convenient protocol for the preparation of 2-arylpyrrole
derivatives based on a scaled-up RCM reaction, with reduced catalyst loading in a
non-toxic solvent. The study allowed to decrease the catalyst loading from 4 mol% to
1 mol% and to replace G-II catalyst with its NO2-Grela alternative. Dichloromethane,
which is commonly used in RCM, could also be changed for ethyl acetate, an
environmentally friendly solvent. Additionally, the optimized conditions were
successfully applied to differently substituted β-amino esters, providing the
corresponding pyrrolines in satisfactory yields. Finally, 2-aryl-1H-pyrrole-3-
carboxylates, which are important building blocks for the generation of CNS-oriented
compound
libraries,
were
obtained
through
a
one-pot
sequence
deprotection/aromatization.
Experimental Section
General remarks
Organic transformations were carried out at ambient temperature, unless indicated
otherwise. Organic solvents used in this study (from Sigma Aldrich and Chempur)
were of reagent grade and were used without purification. All other commercially
12

ACCEPTED MANUSCRIPT
available reagents were of the highest purity (from Sigma Aldrich, Alfa Aesar,
Fluorochem, TCI). Metathesis catalysts used were either purchased from Sigma
Aldrich, Apeiron-Synthesis (NO2-Grela) or given by Umicore AG & Co. All workup
and purification procedures were carried out with reagent-grade solvents under
ambient atmosphere.
Melting points were determined with a Büchi apparatus and are uncorrected.
Analytical HPLC analyses were run on an Alliance Waters 2695 Separations Module
equipped with a Chromolith Speed ROD RP 18.5 µm column (4.6 × 50 mm).
Standard conditions were as follows: eluent system A (water/0.1% TFA), system B
(MeCN/0.1% TFA). A flow rate of 5 ml/min with a gradient of (0–100)% B over 3 min
was used. Detection was performed with a Waters 2998 Photodiode Array Detector.
LC/MS analyses were carried out on a system consisting of a Waters Acquity UPLC
coupled with a Waters TQD mass spectrometer (electrospray ionization mode ESI-
tandem quadrupole). All of the analyses were carried out with an Acquity UPLC BEH
C18,50 × 2.1 mm column at 40 °C. A flow rate of 0.3 ml /min and a gradient of (5–
95)% B over 13 min was used. The mobile phase conditions were as follows: eluent
A: water/0.1% HCO2H; eluent B: MeCN/0.1% HCO2H. Retention times (tR) are
reported in minutes.
1H NMR and 13C NMR spectra were recorded either at 300 MHz and 75 MHz (Varian
BB 200 spectrometer) or 400 MHz and 100 MHz (Bruker Avance AM) using CDCl3 as
solvent. The J values are reported in Hertz (Hz), and the splitting patterns are
designated as follows: s (singlet), d (doublet), dd (doublet of doublet), t (triplet), m
(multiplet), bs (broad singlet).
General procedure for preparation of compounds 2a-2g
This procedure was similar to the one used in ref.21
In a dried flask p-toluenesulfonamide (18 g, 105 mmol, 1 eq) and 1,4-
diazabicyclo[2.2.2]octane (DABCO) (1.78 g, 15.7 mmol, 0.15 eq) were mixed
together with the previously activated molecular sieves (4 Å, 21 g). The mixture was
suspended in isopropanol (300 ml), followed by addition of benzaldehyde derivative
(105 mmol, 1 eq) and methyl acrylate (10.7 ml, 115 mmol, 1.1 eq). Subsequently,
titanium isopropoxide (Ti(iOPr)4) was added as a freshly prepared solution in
isopropanol (0.6 ml, 2.1 mmol, 0.02 eq). The flask was filled with nitrogen and the
mixture
was
stirred
at
room
temperature
for
36
h.
Then,
a mixture was filtered through Celite which was rinsed with CH2Cl2. The solvent was
13

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evaporated and the remaining crude was dissolved in AcOEt (400 ml), washed 3
times with 1M KHSO4, once with saturated NaHCO3, water and brine and dried over
Na2SO4. Evaporation of the solvent gave a yellow oil which was subsequently
dissolved in AcOEt (300 ml) and precipitated upon portionwise addition of n-hexane
(300 ml). The appearing white precipitate was filtered, dried under vacuum and was
pure enough to be directly engaged in the next step.
β-Aminoester (25.6 mmol, 1 eq) was dissolved in DMF (100 ml), followed by addition
of K2CO3 (76.5 mmol, 3 eq). Subsequently, allyl bromide (51.2 mmol, 2 eq) was
added dropwisely. The reaction was stirred at room temperature for 6 h. The mixture
was diluted with ethyl acetate (300 ml) and washed 5× with water and brine. The
organic phase was filtered and evaporated. The remaining yellow residue was
dissolved in AcOEt (70 ml) and precipitated upon portionwise addition of n-hexane
(70 ml). The obtained white solid was filtered and dried under vacuum.
Characterization of 2a-2g
Methyl-2-[(N-allyl-N-tosylamino)(2-nitrophenyl)-methyl]acrylate (2a)31, 23d
White solid, 95% yield, tR = 7.48, Mp 83–85 °C, C 21H22N2O6S, MW 430.47.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.40 (s, 3H), 3.52 (s, 3H), 3.92–4.23 (m, 2H),
4.89–5.01 (m, 2H), 5.42–5.57 (m, 2H), 6.42 (s, 1H), 6.80 (s, 1H), 7.19–7.27 (m, 2H),
7.41–7.50 (m, 1H), 7.59–7.69 (m, 3H), 7.76 (d, J = 7.62 Hz, 1H), 7.92 (dd, J = 7.91
Hz, 1.47 Hz, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 50.8, 52.1, 58.4, 118.7, 125.3, 127.7, 128.7,
129.3, 130.4, 133.2, 133.6, 134.4, 137.8, 138.3, 143.3, 148.0, 165.4.
Monoisotopic Mass 430.12, [M+H]+ 430.8. HRMS calcd for C21H23N2O6S 431.1277;
found: 431.1277.
Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](phenyl)methyl}acrylate (2b)32
White solid, 95% yield, tR = 7.90, Mp 67–69 °C, C 21H23NO4S, MW 385.46.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.43 (s, 3H), 3.60 (s, 3H), 3.77–3.85 (m, 2H),
4.78–4.88 (m, 2H), 5.19–5.35 (m, 1H), 5.73 (d, J = 1.76 Hz, 1H), 6.11 (s, 1H) 6.44 (s,
1H), 7.0 (dd, J = 6.45, 2.93 Hz, 2H), 7.19–7.30 (m, 5H) 7.69 (d, J = 8.21 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 48.7, 52.0, 61.8, 117.6, 127.5, 128.0, 128.5,
129.4, 134.3, 137.1, 137.9, 139.2, 143.2, 166.3.
Monoisotopic Mass 385.13, [M+H]+ 386.1.
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Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](2-
methoxyphenyl)methyl}acrylate (2c)
White solid, 90% yield, tR = 7.97, Mp 85–87 °C, C 21H25NO5S, MW 415.50.
1H NMR (300 MHz, CDCl3) δ ppm 2.39 (s, 3H), 3.51 (s, 3H), 3.60 (s, 3H), 3.74–3.98
(m, 2H), 4.76–4.85 (m, 2H), 5.30–5.47 (m, 1H), 5.96–6.00 (m, 1H), 6.25 (s, 1H),
6.49–6.53 (m, 1H), 6.66 (dd, J = 8.21, 0.77 Hz, 1H), 6.80–6.87 (m, 1H), 7.09 (dd,
J = 7.57, 1.67 Hz, 1H), 7.14–7.26 (m, 3H), 7.50–7.57 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 50.0, 51.9, 54.8, 56.9, 110.2, 117.3, 120.1,
124.8, 127.6, 128.9, 129.4, 129.7, 134.4, 138.4, 139.8, 142.4, 157.3, 166.4.
Monoisotopic Mass 415.15, [M+H]+416.2.
HRMS calcd for C21H25NO5S 416.1532; found: 416.1530.
Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](3-
methoxyphenyl)methyl}acrylate (2d)32
White solid, 90% yield, tR = 7.97, Mp 71–73 °C, C 21H25NO5S, MW 415.50.
1H NMR (300 MHz, CDCl3) δ ppm 2.42 (s, 3H), 3.63 (d, J = 8.98 Hz, 6H), 3.80 (d,
J = 6.16 Hz, 2H), 4.81–4.84 (m, 1H), 4.86–4.90 (m, 1H), 5.22–5.37 (m, 1H), 5.75 (d,
J = 1.28 Hz, 1H), 6.06 (s, 1H), 6.42–6.49 (m, 2H), 6.58–6.63 (m, 1H), 6.73–6.78 (m,
1H), 7.13 (t, J = 7.95 Hz, 1H), 7.23–7.31 (m, 2H), 7.67–7.74 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 48.7, 52.0, 55.0, 61.7, 113.9, 114.0, 117.6,
120.7, 127.6, 128.0, 129.4, 129.5, 134.4, 137.8, 138.5, 139.2, 143.2, 159.7, 166.3.
Monoisotopic Mass 415.15, [M+H]+416.3.
Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](4-
methoxyphenyl)methyl}acrylate (2e)32
White solid, 90% yield, tR = 7.97, Mp 91–92 °C, C 21H25NO5S, MW 415.50.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.42 (s, 3H), 3.60 (s, 3H), 3.75 (s, 3H), 3.77–3.81
(m, 2H), 4.81 (t, J = 1.28 Hz, 1H), 4.84–4.89 (m, 1H), 5.17–5.32 (m, 1H), 5.75 (dd,
J = 1.80, 0.51 Hz, 1H), 6.03 (s, 1H), 6.38–6.42 (m, 1H), 6.70–6.77 (m, 2H), 6.87–6.94
(m, 2H), 7.23–7.29 (m, 2H), 7.65–7.72 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 48.6, 52.0, 55.2, 61.3, 113.9, 117.6, 127.3,
127.5, 128.9, 129.4, 129.9, 134.4, 137.8, 139.4, 143.2, 159.3, 166.4.
Monoisotopic Mass 415.15. [M+H]+416.2.
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Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](3-
chlorophenyl)methyl}acrylate (2f)32
White solid, 93% yield, tR = 8.30, Mp 58–60 °C, C 21H22ClNO4S, MW 419.92.
1H NMR (300 MHz, CDCl3) δ ppm 2.43 (s, 3H), 3.60–3.64 (m, 3H), 3.83 (d, J = 6.41
Hz, 2H), 5.28–5.43 (m, 1H), 5.73 (d, J = 1.80 Hz, 1H), 6.04 (s, 1H), 6.47 (d, J = 1.03
Hz, 1H), 6.87 (t, J = 1.67 Hz, 2H), 6.92–6.97 (m, 2H), 7.13–7.29 (m, 4H), 7.62–7.70
(m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 49.0, 52.1, 61.2, 117.9, 126.7, 127.4, 128.2,
128.7, 129.5, 129.7, 134.1, 134.4, 137.6, 138.5, 139.3, 143.5, 166.0.
Monoisotopic Mass 419.10, [M+H]+ 420.2.
Methyl-2-{[(N-allyl-4-methylphenyl)sulfonamido](4-
chlorophenyl)methyl}acrylate (2g)32
White solid, 93% yield, tR = 8.30, Mp 87–89 °C, C 21H22ClNO4S, MW 419.92.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.43 (s, 3H), 3.58–3.63 (m, 3H), 3.78–3.84 (m,
2H), 4.81–4.90 (m, 2H), 5.22–5.40 (m, 1H), 5.72 (d, J = 1.80 Hz, 1H), 6.04 (s, 1H),
6.45 (d, J = 1.28 Hz, 1H), 6.93–7.00 (m, 2H), 7.23 (s, 4H), 7.63–7.68 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 49.0, 52.1, 61.1, 117.9, 128.5, 128.7, 129.5,
129.9, 133.9, 134.1, 136.0, 137.7, 139.0, 143.4, 166.1.
Monoisotopic Mass 419.10, [M+H]+ 420.3.
General procedure for preparation of compounds 3a-3g
Compound 2a-2g (2.5 g, 1 eq) was dissolved in AcOEt (25 mL) and NO2-Grela
catalyst (1 mol%) was added in three portions over a period of 1.5 h with 30 min time
intervals. The reaction was quenched with ethyl vinyl ether (50 eq/Ru) and stirred for
additional 1h. The solution was evaporated and the remaining residue was dissolved
in CH2Cl2 and filtered through a layer of silica gel. The obtained product was
triturated with diethyl ether to give white precipitate which was filtered and dried
under vacuum.
Characterization of 3a-3g
31,
Methyl 2,5-dihydro-2-(2-nitrophenyl)-1-tosyl-1H-pyrrole-3-carboxylate (3a)21,
23d
White solid, 54% yield, Mp 125–127 °C, tR = 6.83, C19H18N2O6S, MW 402.42.
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1H NMR (300 MHz, CDCl3) δ (ppm) 2.43 (s, 3H), 3.53 (s, 3H), 4.33–4.65 (m, 2H),
6.69–6.72 (m, 1H), 6.75-6.76 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.39–7.44 (m, 1H),
7.55–7.57 (m, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.7, 52.2, 55.8, 62.5, 124.7, 127.9, 128.7, 129.8,
130.2, 133.2, 133.5, 135.2, 135.8, 136.7, 144.4, 148.9, 161.7.
Monoisotopic Mass 402.09, [M+H]+ 403.3. HRMS calcd for C19H19N2O6S 403.0964;
found: 403.0967.
Methyl 2-phenyl-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3b)33
White solid, 58% yield, tR = 7.03, Mp 111–113 °C, C 19H19NO4S, MW 357.42.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.36 (s, 3H), 3.58 (s, 3H), 4.33– 4.43 (m, 1H),
4.47–4.57 (m, 1H), 5.72–5.75 (m, 1H), 6.76–6.80 (m, 1H), 7.14 (d, J = 8.21 Hz, 2H),
7.20–7.25 (m, 5H), 7.38–7.45 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.8, 54.9, 69.0, 127.1, 127.7, 128.3, 129.5,
135.6, 135.7, 139.4, 143.3, 162.2.
Monoisotopic Mass 457.10, [M+H]+ 358.2.
Methyl 2-(2-methoxyphenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3c)
White solid, 39% yield, tR = 6.93, Mp 115–117 °C, C 20H21NO5S, MW 387.45.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.38 (s, 3H) 3.56 (s, 6H) 4.30–4.56 (m, 2H) 5.99
(m, 1H) 6.66 (dd, J = 8.72, 0.77 Hz, 1H) 6.75 (m, 1H) 6.87 (m, 1H) 7.11 (d, J = 7.95
Hz, 2H) 7.16–7.27 (m, 2H) 7.33–7.41 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.4, 51.6, 55.2, 65.0, 111.0, 120.4, 126.8, 127.1,
129.1, 129.3, 130.4, 134.2, 135.7, 136.1, 142.8, 157.4, 162.4.
Monoisotopic Mass 387.11, [M+H]+388.3.
HRMS calcd for C20H21NO5S 388.1219, found 388.1217.
Methyl 2-(3-methoxyphenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3d)
White solid, 43% yield, tR = 6.93, Mp 79–81 °C, C 20H21NO5S, MW 387.45.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.36 (s, 3H), 3.55–3.64 (m, 3H), 3.71 (s, 3H),
4.31–4.56 (m, 2H), 5.68–5.74 (m, 1H), 6.64–6.69 (m, 1H), 6.71–6.89 (m, 3H), 7.08–
7.21 (m, 3H), 7.42 (d, J = 8.46 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 51.9, 55.0, 55.1, 68.9, 113.2, 133.5, 120.3,
127.1, 129.3, 129.4, 135.5, 135.8, 140.7, 143.3, 159.5, 162.2.
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Monoisotopic Mass 387.11, [M+H]+ 388.3.
HRMS calcd for C20H21NO5S 388.1219, found 388.1219.
Methyl 2-(4-methoxyphenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3e)
White solid, 46% yield, tR = 6.93, Mp 85–87 °C, C 20H21NO5S, MW 387.45.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.34 (s, 3H), 3.56 (s, 3H), 3.71–3.79 (m, 3H),
4.27–4.40 (m, 1H), 4.41–4.52 (m, 1H), 5.61–5.72 (m, 1H), 6.69–6.79 (m, 3H), 7.06–
7.18 (m, 4H), 7.42 (d, J = 8.21 Hz, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.4, 51.8, 54.8, 55.2, 68.5, 113.7, 127.1, 128.9,
129.5, 131.6, 135.5, 135.6, 143.2, 159.4, 162.3.
Monoisotopic Mass 387.11, [M+H]+ 388.3.
HRMS calcd for C20H21NO5S 388.1219, found 388.1216.
Methyl 2-(3-chlorophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3f)
White solid, 66% yield, tR = 7.49, Mp 112–114 °C, C 19H18ClNO4S, MW 391.87.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.41 (s, 3H), 3.53–3.66 (m, 3H), 4.32–4.60 (m,
2H), 5.68 (m, 1H), 6.75–6.85 (m, 1H), 7.04 (s, 1H), 7.09–7.28 (m, 5H), 7.34–7.51 (m,
2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 21.5, 51.9, 55.03, 68.4, 126.3, 127.0, 127.6,
128.2, 129.5, 134.2, 135.2, 135.4, 136.2, 141.3, 143.6, 162.0.
Monoisotopic Mass 391.06, [M+H]+ 392.2.
HRMS calcd for C19H18ClNO4S 392.0723, found 392.0727.
Methyl 2-(4-chlorophenyl)-1-tosyl-2,5-dihydro-1H-pyrrole-3-carboxylate (3g)
White solid, 64% yield, tR = 7.49, Mp 109–111 °C, C 19H18ClNO4S, MW 391.87.
1H NMR (300 MHz, CDCl3) δ (ppm) 2.39 (s, 3H), 3.59 (s, 3H), 4.33– 4.44 (m, 1H),
4.46–4.56 (m, 1H), 5.69 (dt, J = 5.57, 2.20 Hz, 1H), 6.78 (q, J = 2.15 Hz, 1H), 7.10–
7.23 (m, 6H), 7.41–7.49 (m, 2H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.9, 55.0, 68.3, 127.1, 128.5, 129.1, 129.6,
133.9, 135.3, 136.0, 138.1, 143.6, 162.0.
Monoisotopic Mass 391.06, [M+H]+ 392.2.
HRMS calcd for C19H18ClNO4S 392.0723, found 392.0722.
General procedure for preparation of compounds 4a-4g
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To a solution of 2,5-dihydropyrrole 3 (2.5 g, 6.2 mmol, 1 eq) in DMF (40 ml)
potassium tert-butoxide (2.09 g, 18.7 mmol, 3 eq) was added. The reaction was
carried for two hours under TLC monitoring. The mixture was diluted with ethyl
acetate, neutralized with 1 M KHSO4, washed with saturated solution of NaHCO3
(1×), water (3×) and brine (1×). The organic layer was dried under Na2SO4 and
evaporated. The obtained crude product was purified on silica gel with AcOEt/Hex
(4/6) as a developing solvent.
Characterization of 4a-4g
Methyl 2-(2-nitrophenyl)-1H-pyrrole-3-carboxylate (4a)21, 31, 23d
Yellow solid, 65% yield, tR = 5.72, C12H10N2O4, MW 246.22.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.63 (s, 3H), 6.74 (t, J = 2.95 Hz, 1H), 6.82–6.84
(m, 1H), 7.43–7.48 (m, 1H), 7.52–7.60 (m, 1H), 7.62–7.68 (m, 1H), 8.01 (dd,
J = 8.21, 1.28 Hz, 1H), 8.50–8.68 (m, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.0, 111.4, 113.5, 118.7, 124.4, 127.3, 129.5,
132.4, 149.5, 164.8.
Monoisotopic Mass 246.06, [M+H]+ 247.3.
Methyl 2-phenyl-1H-pyrrole-3-carboxylate (4b)23e
White oil, yield 60%, tR = 5.34, C12H11NO2, MW 201.23.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.71 (s, 3H), 6.66–6.74 (m, 2H), 7.31–7.37 (m,
2H), 7.38–7.41 (m, 1H), 7.52–7.55 (m, 1H), 7.56–7.58 (m, 1H), 8.68 (s, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.0, 111.7, 112.1, 117.8, 128.1, 128.9, 132.0,
137.2, 165.6.
Monoisotopic Mass 201.08, [M+H]+ 202.0.
Methyl 2-(2-methoxyphenyl)-1H-pyrrole-3-carboxylate (4c)
White oil, yield 70%, tR = 5.21, C13H13NO3, MW 231.25.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.72 (s, 3H), 3.81 (s, 3H), 6.69– 6.78 (m, 2H),
6.92– 7.07 (m, 2H), 7.26– 7.37 (m, 1H), 7.64 (dd, J = 7.62, 1.76Hz, 1H), 9.01 (bs,
1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 50.8, 55.7, 111.1, 111.5, 112.6, 117.2, 120.5,
120.2, 129.6, 132.3, 133.3, 156.4, 165.5.
Monoisotopic Mass 231.09, [M+H]+ 232.1.
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HRMS calcd for C13H13NO3 232.0974, found 232.0972.
Methyl 2-(3-methoxyphenyl)-1H-pyrrole-3-carboxylate (4d)
White oil, yield 68%, tR = 5.47, C13H13NO3, MW 231.25.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.64 (s, 3H), 3.78 (s, 3H), 6.52–6.56 (m, 1H),
6.82–6.87 (m, 1H), 6.88–6.94 (m, 1H), 7.14–7.22 (m, 2H), 7.26–7.34 (m, 1H), 11.50–
11.71 (m, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.0, 55.5, 111.4, 111.9, 113.8, 114.9, 119.0,
121.7, 129.3, 133.6, 136.5, 159.2, 165.1.
Monoisotopic Mass 231.09, [M+H]+ 232.1.
HRMS calcd for C13H13NO3 232.0974, found 232.0971.
Methyl 2-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (4e)
White oil, yield 67%, tR = 5.40, C13H13NO3, MW 231.25.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.72 (s, 3H), 3.82 (s, 3H), 6.69 (quin, J = 2.64
Hz, 2H), 6.87– 6.94 (m, 2H), 7.46– 7.53 (m, 2H), 8.46– 8.67 (m, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 50.5, 55.3, 111.2, 111.9, 113.6, 117.4, 124.5,
130.2, 137.3, 159.6, 165.6.
Monoisotopic Mass 231.09, [M+H]+ 232.1.
HRMS calcd for C13H13NO3 232.0974, found 232.0972.
Methyl 2-(3-chlorophenyl)-1H-pyrrole-3-carboxylate (4f)
White oil, yield 65%, tR = 6.21, C12H10ClNO2, MW 235.67.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.74 (s, 3H), 6.69– 6.76 (m, 2 H), 7.27– 7.34 (m,
2H), 7.42–7.49 (m, 1H), 7.53– 7.57 (m, 1H), 8.59– 8.78 (m, 1H).
13C NMR (75 MHz, CDCl3) δ (ppm) 51.1, 112.4, 118.3, 127.2, 128.2, 128.8, 129.4,
133.7, 165.3.
Monoisotopic Mass 235.04. [M+H]+ 236.0.
HRMS calcd for C12H10ClNO2 236.0478, found 236.0478.
Methyl 2-(4-chlorophenyl)-1H-pyrrole-3-carboxylate (4g)23e
White oil, yield 63%, tR = 6.18, C12H10ClNO2, MW 235.67.
1H NMR (300 MHz, CDCl3) δ (ppm) 3.73 (s, 3H), 6.69– 6.75 (m, 2H), 7.30–7.38 (m,
2H), 7.45–7.52 (m, 2H), 8.55–8.72 (m, 1H).
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13C NMR (75 MHz, CDCl3) δ (ppm) 51.0, 112.3, 118.1, 128.4, 130.2, 130.4, 134.2,
135.9, 165.4.
Monoisotopic Mass 235.04. [M+H]+ 236.0.
Supporting Information
Characterization of new compounds, 1H and 13C NMR spectra of all compounds.
Acknowledgements
The study was financially supported by the University Montpellier, CNRS, from
statutory funds from the Jagiellonian University Medical College. K.G. thanks the
French Embassy in Warsaw for the co-tutelle fellowship. Umicore AG & Co. KG is
gratefully acknowledged for the gift of catalysts M2, M20, M51.
References
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