New Efficient Eco-Friendly Supported Catalysts for the Synthesis of Amides with Antioxidant and Anti-Inflammatory Properties

Article abstract of DOI:10.1002/cmdc.201900641

A new environmentally friendly approach for the synthesis of idrocilamide (1), a marketed myorelaxant and anti-inflammatory agent, is reported herein. The synthetic strategy involves a solvent-free aminolysis reaction catalyzed by zinc-containing species

Full text of DOI:10.1002/cmdc.201900641

Accepted Article
Title: New efficient eco-friendly supported catalysts for the synthesis of
amides with antioxidant and anti-inflammatory properties
Authors: Pierrick Dufrénoy, Rogatien Charlet, Marie Hechelski, Adam
Daïch, Christophe Waterlot, Samir Jawhara, and ALINA
GHINET
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemMedChem 10.1002/cmdc.201900641
Link to VoR: http://dx.doi.org/10.1002/cmdc.201900641
A Journal of
www.chemmedchem.org

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
New efficient eco-friendly supported catalysts for the synthesis of amides with
antioxidant and anti-inflammatory properties
Pierrick Dufrénoy,[a] Rogatien Charlet,[b] Marie Hechelski,[c] Adam Daïch,[d] Christophe Waterlot,[c],[e]
Samir Jawhara,[b] and Alina Ghinet[a],[f],
*
[a]
[b]
[c]
Dr. Pierrick Dufrénoy
Dr. Alina Ghinet, corresponding author. E-mail: alina.ghinet@yncrea.fr; https://orcid.org/0000-0001-6468-4331
Yncréa Hauts-de-France, Hautes Etudes d’Ingénieur (HEI), UCLille, Health & Environment Department, Team Sustainable Chemistry, Laboratoire de chimie
durable et santé, 13 rue de Toul, F-56046 Lille, France.
Rogatien Charlet, PhD Student,
Dr. Samir Jawhara, https://orcid.org/0000-0002-2759-975X
LIRIC, UMR 995, Inserm, Université de Lille, CHU de Lille, Faculté de Médecine, Pôle Recherche, 4ème étage Epicentre Est, Place Verdun, F-59045 Lille
Cedex.
Dr. Marie Hechelski
Dr. Christophe Waterlot, https://orcid.org/0000-0002-4695-0082
Yncréa Hauts-de-France, Institut Supérieur d’Agriculture, UCLille, Health & Environment Department, Team Environment, Laboratoire Génie Civil et
géoEnvironnement, 48 boulevard Vauban, 59046 Lille Cedex, France.
[d]
[e]
[f]
Prof. Adam Daïch, https://orcid.org/0000-0002-6942-0519
Normandie Univ, UNILEHAVRE, URCOM EA 3221, INC3M CNRS-FR 3038, UFR des Sciences et Techniques, Université Le Havre Normandie, BP: 1123,
25 rue Philipe Lebon, F-76063 Le Havre Cedex, France.
Dr. Christophe Waterlot
Yncréa Hauts-de-France, Institut Supérieur d’Agriculture, UCLille, Equipe Biotechnologie et Gestion des Agents Pathogènes en agriculture, 48 boulevard
Vauban, 59046 Lille Cedex, France.
Dr. Alina Ghinet
‘Al. I. Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I, nr. 11, 700506 Iasi, Romania.
Supporting information for this article is given via a link at the end of the document.
1
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
Abstract: New environment friendly approach for the synthesis of
idrocilamide (1), the marketed myorelaxant and anti-inflammatory agent,
is reported. The synthetic strategy involves a solvent free aminolysis
reaction catalyzed by zinc-containing catalysts (ZnCl2, montmorillonite
K10 (MK10) impregnated with ZnCl2 or ecocatalysts). The latter have
been prepared from the aerial parts of Lolium perenne L. plants grown
on contaminated soils from North of France region without and with
thermal activation at 120°C and supported on MK10 (Ecocat1 and
Ecocat2, respectively). The best aminolysis catalysts in the current
study (ZnCl2 and Ecocat2) have been selected for additional
aminolyses. Compared to ZnCl2, Ecocat2 had the advantage of being
reusable over five tested runs and constituted a sustainable catalyst
allowing a green route to idrocilamide. Synthesized derivatives 1-4, 6
and 9 have been first evaluated for their effect on reactive oxygen
species (ROS) generation from macrophages and displayed
antioxidant properties by preventing ROS production. Next, the analysis
of the effect of molecules 1-4, 6 and 9 on macrophage migration
between epithelial cells to human opportunistic fungus Candida
albicans indicated that molecules 2-4, 6 and 9 exert anti-inflammatory
properties via reducing macrophage migration while parent idrocilamide
(1) did not show any significant effect. This work opens the way for the
discovery of new analogues of idrocilamide with improved properties.
literature for this compound, such as sedative effects, activity
against depression, rosacea, migraines and convulsions.3-7 The
marketing of the topical cream Srilane® was stopped in France
in December 2018, one of the causes being the mechanism of
action of idrocilamide (1) that remains unresolved.
Fig. 1 Structure of selected main ingredients of drugs bearing amide function A-D,
idrocilamide (1) and targeted idrocilamide derivatives in the current study.
The formation of the amide function is extremely well-
documented. More than forty research articles have been
dedicated this year only to the synthesis of amides.8,9 Classical
synthetic pathway to access amides include the use of activated
carboxylic acid derivatives such as activated esters, acyl halides
or anhydrides in the presence of various amounts of coupling
agents, generally expensive and/or toxic.8,10 Recent
developments in amide synthesis using nonactivated starting
materials have been described.10 These environmentally
friendly methodologies mainly include: i) direct amidation of
carboxylic acids with amines mediated by different catalysts,
the most employed being boric acid derivatives under heating,
or under microwave irradiation; ii) transamidation between
amides and amines in presence of transition metals catalysts
(iron, nickel and manganese derivatives being the most used);
iii) aminolysis reaction of esters with amines under different
catalytic conditions (e.g. transition metals derivatives11).
Introduction
The modern synthetic methodologies aim to use less toxic
reagents and solvents, produce less waste, limit halogenated
effluents particularly, proceed under milder conditions of
pressure
and
temperature
and
render
chemical
transformations faster than conventional kinetics by using often
catalytic conditions. For this purpose, green chemistry emerged
in the last decades and encourage to use new eco-friendly
conditions in organic syntheses. The construction of
conventional functional groups in organic chemistry, such as
esters, amides or carboxylic acids, etc… in greener conditions,
constitutes a contemporary challenge for increasing number of
research groups.
The amide moiety is an essential functional group in organic
chemistry. In fact, it is estimated that more than a quarter of
main ingredients of all marketed drugs contain at least one
amide group and are therefore found in all major therapeutic
The reported strategies for the synthesis of idrocilamide (1)
are depicted in Scheme 1. Eight different procedures were
described.12-21 The most documented is the treatment of
cinnamic acid with ethanolamine in different conditions: 1-i)
methylchloroformate, triethylamine in CH2Cl2 at room
classes of pharmaceuticals.
containing amide function that exhibit plethora of therapeutic
indications drugs is depicted in Figure 1 (compounds A-D and
A selection of some drugs
idrocilamide
1
). For instance, lidocaïne
A
is a local anesthetic
bearing an
temperature to provide idrocilamide
1
in 82% yield;12 1-ii)
from the amino-amides series. Oseltamivir
B
similar conditions have been also reported by Xiu, J.-H. and co-
workers13 and allowed to obtain the target idrocilamide in 75%
yield; 1-iii) the reaction between cinnamic acid and
ethanolamine conducted in presence of sulfuric acid furnished
68% of idrocilamide;14 1-iv) the two-step procedure described
by Zhang, J.-S.15 started from cinnamic acid which, upon
activation in presence of thionyl chloride to provide cinnamoyl
chloride, was treated with ethanolamine to obtain final
acetamide function is an antiviral molecule and is used in the
treatment and prevention of A and B influenzas. Another amide
derivative with different biological activity is the third-
generation cephalosporin antibiotic cefotiam
C. Ranolazine D,
mainly marketed under the brand name Ranexa®, is used to
treat heart related chest pain. Idrocilamide (1) was firstly
described as a precursor in the preparation of new penicillins.1
The anti-inflammatory and myorelaxant properties of
idrocilamide (
contributions describe the synthesis of compound
1
) without specifying the final yield. Two
by direct
idrocilamide (1
) have been described in the 2000s2 and
1
compound is being commercialized under different galenic
forms and commercial names (Srilane®, Talval® or Relaxnova®).
Other biological properties have been described in the
treatment of cinnamoyl chloride with ethanolamine in CH2Cl2
followed by alkaline treatment by using aqueous sodium
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
carbonate (4-vii)16 or triethylamine (4-viii)17 to furnish the target superficial reagents, which is problematic for industrial
amide in good yield. Another synthetic pathway (2) started from production.
an α,β-unsaturated ester that underwent methanolysis in the
presence of trimethylphosphine at room temperature and montmorillonite K-10 (MK10) have been conceived following
provided 49% of idrocilamide (
).18 In the same report, when 3- the methodology described by Waterlot et al. (2000)22 using
In the current contribution, new supported catalysts on
1
(trans-cinnamoyl)-2-oxazolidinone (α,β-unsaturated imide) was ZnCl2 as MK10-supported Lewis acid. To lead furthermore this
employed as a substrate, four products including idrocilamide project, new catalysts, called ecocatalysts have been prepared
(1
) (isolated as major product in 46% yield) were obtained (6).18 using aerial parts from Lolium perenne L. plants grown on
The nucleophilic substitution reaction (7) between 2,4- contaminated soils from the North-region of France.23 To test
dinitrophenyl cinnamate and ethanolamine in water containing the performance of these new catalysts, the aminolysis reaction
20 mol% of DMSO at 25°C was also reported to furnish has been selected as a model transformation to provide the
idrocilamide without yield indication.19 Another starting amide linkage. Chemical efforts were next directed on the
material used to provide idrocilamide was (E)-cinnamaldehyde synthesis of the bioactive idrocilamide (
1) and derivatives.
as shown in pathway (8).20 The reaction started by adding DBU
In order to obtain more information on the biological activity
to a solution of 1,3-dimethyltriazolium iodide and ethanolamine of idrocilamide and seek derivatives with improved efficiency,
in THF under argon atmosphere (8-xii). Cinnamaldehyde and the analysis of the effect of the molecules on reactive oxygen
3,3’,5,5’-tetra-tert-butyldiphenoquinone were next added and species (ROS) generation from macrophages and on
the mixture was stirred at room temperature for 2 hours to macrophage migration between epithelial cells to Candida
obtain idrocilamide in 63% yield.20 Two aminolysis reactions albicans have been conducted
have been reported starting from ethyl14 and methyl
cinnamates21 in presence of ethanolamine. The first (3)
.
Results and Discussion
provided the amide in 53% yield. The second method (2) used
methanol as solvent, large excess of aminoalcohol and an
equivalent of Na2CO3 as a base and constitute the best
transformation described in the literature to obtain
Chemistry
The study started with the evaluation of different catalysts,
including classical catalysts for comparison reasons, supported
idrocilamide (1
) in terms of final yield (87%).21
catalysts and ecocatalysts on the synthesis of idrocilamide (1)
and derivatives. Next, the efficiency and the recyclability in five
successive aminolysis reactions of the newly produced
supported catalysts and ecocatalysts after their first use were
assessed.
Table 1 Description of the catalysts used in the synthesis of idrocilamide (1).a
Catalyst
Na2CO3
ZnCl2
Description
Catalyst described in the literature21
Classical Lewis acid
Entry
1
2
ZnCl2 supported on montmorillonite K10 without
thermal activation
ZnCl2 supported on montmorillonite K10 with
thermal activation (120°C)
Metal salts contained in the aerial parts of plants
grown on contaminated soils and MK-10-supported
Metal salts contained in the aerial parts of plants
grown on contaminated soils and MK-10-supported
3
4
5
6
Cat1
Cat2
Ecocat1
Ecocat2
a All the catalysts were used dry.
The synthesis of idrocilamide (1) has been realized by reacting
Scheme 1 Reported synthetic procedures to access idrocilamide 1.12-21 Reagents and
conditions: i) CH2Cl2, Et3N, ClCO2Me, r.t, 2 h (82%); ii) Et3N, ClCO2Me, CH2Cl2, cooled to
r.t, 1 h, then CH2Cl2, cooled, 2 h, r.t then aq. HCl (75%); iii) SOCl2, THF, reflux, not indicated
yield ; iv) H2SO4 r.t (68%); v) Na2CO3, MeOH, 2 h, 80°C (87%); vi) r.t (53%); vii) CH2Cl2, then
aq. Na2CO3, r.t, 16 h (78%); viii) CH2Cl2, then Et3N, CH2Cl2, r.t, 4 h (78%); ix) Me3P, r.t (49%;
x) Me3P, 5 min, r.t (46%); xi) H2O, DMSO, 25°C (not indicated yield); xii) 3,3’,5,5’-tetra-
tert-butyldiphenoquinone, dimethyltriazolium iodide, DBU, r.t, 2 h (63%).
methyl cinnamate and ethanolamine in the presence of six
different catalysts described in the Table 1. These catalysts
include the sodium carbonate (Na2CO3), classical catalyst
mentioned in the literature for this reaction21 (Table 1 – entry
1
), the commercial zinc (II) chloride (ZnCl2) (Table 1 – entry
two supported catalysts (Cat1 and Cat2, respectively without
thermal activation and activation at 120°C – Table 1 – entries
and ). Two other new ecocatalysts produced from the aerial
parts of ryegrass grown on contaminated soils and MK10-
2),
3
Ultimately, from all these considerations, the major part of
these methods led to modest conversions, were often realized
in dichloromethane generating chlorinated effluents and used
4
3
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
supported (Ecocat1 and Ecocat2 – Table 1 – entries
catalyst’s efficiency may be explained by the thermal activation at
5 and 6)
120°C applied during the conception of Ecocat2.
were tested.
The different steps necessary for the preparation of
ecocatalysts Ecocat1 and Ecocat2 are presented in Figure 2.
Briefly, the fresh biomass (aerial parts of Lolium perenne L.) was
first dried, then mineralized at 500°C. The resulting ashes were
treated with concentrated hydrochloric acid to transform the
present metals into corresponding metal salts, which were
finally supported on montmorillonite K10 and thermally
activated at 120°C (Figure 2).23
120°C
120°C
Fig. 2 Schematization of the main steps to obtain ecocatalysts Ecocat1 and Ecocat2.
The reaction performed in different catalytic conditions is
illustrated in Scheme 2 and the results of the catalytic study
Fig. 3 Results obtained in the synthesis of idrocilamide (1) in different catalytic
conditions. Results represent mean and standard deviation of three independent
experiments.
reported in Figure 3. Idrocilamide (
1
) was obtained as the major
, Scheme
reaction product along with a by-product (compound
2
2) obtained from the double reaction of methyl cinnamate on
ethanolamine that was isolated in 5-15% yield, depending on
the nature of the catalyst (Scheme 2).
Indeed, differential calorimetric scanning of these
ecocatalysts showed two endothermic and exothermic pics
between 100 and 130°C in relation to the release of water, HCl
and physisorbed water23 which will contribute to decrease the
catalyst’s efficiency as it was highlighted in other study.24
The recyclability of the supported catalysts (Cat1 and Cat2)
and the ecocatalysts (Ecocat1 and Ecocat2) has been
investigated. For this purpose, the synthesis of idrocilamide was
realized in duplicate by repeating the operation five times by
using the same catalyst isolated from the previous reaction. The
results of the recyclability study have been illustrated on the
Figure 4.
Scheme 2 Reaction conditions: i) Neat or catalyst 5 w%, solvent free, 70°C, 24 h.
The most efficient catalyst for the studied transformation proved to
be the commercial zinc chloride (ZnCl2), which provided idrocilamide
(1) in 75% yield (red, Figure 3). The sodium carbonate (Na2CO3)
displayed slight decreased efficiency and allowed to obtain the title
molecule 1 in near 70% yield (yellow, Figure 3). The same conversion
was also induced by the Ecocat2 (green, Figure 3). The ZnCl2-
supported catalysts on MK10 (Cat1 and Cat2) were less efficient and
provided target idrocilamide (1) in moderate yields of 52 and 56%,
respectively (Figure 3). Neat conditions for the studied synthesis
furnished target compound in 54% yield (Figure 3). The less efficient
catalyst was the Ecocat1, which seemed to inhibit the conversion of
the reaction (45% yield) compared to the reaction conducted in the
absence of catalyst (54% yield). Interestingly, the catalytic
performance of Ecocat2 was the best since idrocilamide (1) was
obtained in 70% middle yield (Figure 3) and up to 78% yield (Figure
4). From our point of view the difference in the concentration of Zn
in ashes used to prepare Ecocat1 and Ecocat2 cannot explain the
different efficiencies of both catalysts since their conception was
based on the same Zn/MK10 ratio.23 So even if we cannot exclude
the effects of other cations (e.g. Fe, Al, Mn), the great difference in
Fig. 4 Chemical conversion according to the catalysts used: mean yields in presence of
different catalysts over 5 distinctive runs (experiences realized in duplicate).
The best supported catalyst in the current study for the
synthesis of idrocilamide (1), Ecocat2, proved to be reusable
conserving catalytic power and inducing 50% to 77% yield over
the 5 distinctive runs (Figure 4). The absence of the catalytic
activity of Ecocat1 has been proved again, the maximum yield
provided being 48% in the second and third run (Figure 4). In
4
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
comparative manner, the recyclability of supported catalysts
(Cat1 and Cat2) was also improved. Indeed, in comparison with
the efficiency and the recyclability of the ecocatalyst1, the
Table 2 Results obtained for the synthesis of amides 4, 5 and 6 using methyl cinnamate
and selected amines.
synthesis of idrocilamide (1) in presence of these catalysts is
operative with yields ranging from 52% up to 78% in presence
of Cat1 (Figure 4) and from 53% up to 71% in the presence of
Cat2 (Figure 4), respectively.
Entry
Amine
Product
Catalyst (Yield %)
Next, after having demonstrated the reactivity of the terminal
ZnCl2
22
Ecocat2
48
alcohol of idrocilamide (
1
) to obtain molecule
3
, the reaction
1
2
3
n-Propylamine
Aniline
(R)-(+)-Methylbenzylamine
4
5
6
NRb
11
NR
between idrocilamide
(1)
and the natural 5-methoxy-
40
pyrrolidone (pterolactam) using three different reaction
conditions (without catalyst, ZnCl2 and Ecocat2) was tested toa
Isolated yield in %. b Not determined.
provide a new potential prodrug of idrocilamide (compound 3)
but also compare the catalytic activity between ZnCl2 and
Ecocat2, the best catalysts in the current study (Scheme 3). It is
interesting to note that neat conditions allowed to obtain very
low transformation of starting reagents (yield inferior to 10%),
while the zinc chloride improved the condensation to 31% yield.
Finally, Ecocat2 proved to possess the best catalytic activity and
allowed to isolate compound 3 in 56% yield (Scheme 3).
Scheme 4 Synthesis of amide 9 bearing an oxicam moiety.
Biological evaluation
Analysis of the effect of the molecules 1-4, 6, and 9 on ROS
generation from macrophages
Scheme 3 Reagents and conditions: i) neat or catalyst 5 w%, solvent free, 80°C, 24 h.
Reactive oxygen species (ROS) are involved in the pathogenesis
of cardiovascular disease, and clinically related to pathologies
manifested by obesity, diabetes, and metabolic syndrome.26-28
Increased levels of ROS generation cause disruption of tissue
homeostasis leading to increased morbidity and risk of
mortality.29 To analyze the effect of newly synthesized
molecules on the ROS generation, macrophages were
New idrocilamide derivatives have been next synthesized in
the presence of the previously identified efficient catalysts
(ZnCl2 and Ecocat2) in order to compare their anti-inflammatory
properties with those of the parent compound
1. Methyl
cinnamate was submitted to aminolysis reaction with three
different amines (Scheme of Table 2). Selected amines except
less nucleophile aniline reacted with the methyl ester and
pretreated with the synthesized molecules (
1, 2, 3, 4, 6, and 9)
and then exposed to LPS in order to induce ROS production.
provided the expected amides
4 and 6. Interestingly, Ecocat2
The percentage of ROS significantly increased in the
macrophages exposed to LPS (10 µmol/L) and analyzed with a
kinetic chemiluminescent assay for 4 hours. In contrary the
pretreatment of macrophages with these molecules at a
concentration of 10-5 mol/L, and exposed to LPS, significantly
reduced the ROS production (Fig. 5A). We next used a
decreasing concentration of these molecules and observed that
displayed in all cases an improved catalytic power compared to
commercial Lewis acid (entries 1, 3 in Table 2).
In order to test the efficiency of Ecocat2 on the construction
of the amide bond in a different family of molecules with
potential anti-inflammatory activity, the reaction of an ester
function from the oxicam family (methyl 2-methyl-4-hydroxy-
2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide) with 2,4-
dichloroaniline was performed (Scheme 4). Solventless
conditions were not adapted for this transformation since
methyl ester was not soluble in the medium. For this reason, the
reaction has been conducted in refluxing o-xylene. Of interest,
in the absence of catalysts, only traces of final product have
been detected. The zinc chloride catalysis was slightly more
efficient and Ecocat2 permitted the obtention of oxicam
molecules
2-4, 6 and 9
at a concentration of 10-6 mol/L
significantly reduced ROS production. In contrast, the
pretreatment of macrophages with the reference idrocilamide
(1) did not inhibit the ROS production (Fig. 5B). This finding
indicates clearly that the tested molecules show antioxidant
properties in preventing ROS generation and that newly
synthesized derivatives
idrocilamide ( ).
2-4, 6, 9 are more active than parent
1
derivative
9 in 27% yield. The latter molecule has been
previously identified as anti-inflammatory agent in animals.25
5
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
Fig. 5 Effect of compounds 1-4, 6, 9 on the ROS generation from macrophages in a kinetic chemiluminescent assay. A, Analysis of ROS generation in the supernatant of macrophages
pretreated with molecules at a concentration 10-5 mol/L. B, Analysis of ROS generation in the supernatant of macrophages pretreated with molecules at a concentration 10-6 mol/L.
CTL- corresponds to macrophages alone. CTL+ corresponds to macrophages + LPS. H2O2 alone without macrophages at a concentration of 1.7 mol/L was used as a positive control.
Analysis of the effect of the molecules 1-4, 6, and 9 on macrophage molecules (2, 3, 4, 6, and 9
) at a concentration of 10-5 mol/L is
migration between epithelia cells to Candida albicans
observed when compared to those untreated with the
molecules (Fig. 6A). In contrast, no effect was detected for these
molecules on macrophage migration at a concentration of 10-6
mol/L (Fig. 6B).
A reduction of the intestinal epithelial barrier function is
observed during the intestinal inflammation that would
promote the migration of the immune cells including
macrophages.
The reference idrocilamide (
effect on macrophage migration. Overall, the present findings
suggest that idrocilamide derivatives (2, 3, 4, 6, and ) exert
1) did not show any significant
The effect of molecules
1-4, 6, 9 on the migration of
9
macrophages between Caco-2 cells to human opportunistic
fungus Candida albicans was assessed (Figure 6). A significant
decrease in the migration of macrophages pre-treated with
anti-inflammatory properties via reducing ROS production and
macrophage migration.
Fig. 6 Effects of the compounds 1-4, 6, 9 on macrophage migration between epithelial cells to C. albicans. A. Analysis of macrophage migration pre-treated with molecules at a
concentration of 10-5 mol/L. B. Analysis of macrophage migration pre-treated with molecules at a concentration of 10-6 mol/L. CTL- corresponds to macrophages alone. CTL+
corresponds to macrophage migration between epithelial cells to C. albicans without treatment with molecules.
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
doublet of doublet; t, triplet; m, multiplet; quint, quintuplet;
br s, broaden singlet; br t, broaden triplet. Coupling constants
(J) are reported in Hertz (Hz). Thin layer chromatography (TLC)
was realized on Macherey Nagel silica gel plates with
fluorescent indicator and were visualized under a UV-lamp at
254 nm and 365 nm. Column chromatography was performed
with a CombiFlash Rf Companion (Teledyne-Isco System) using
RediSep packed columns. IR spectra were recorded on a
Varian 640-IR FT-IR Spectrometer. Elemental analyses (C, H, N)
of new compounds were determined on a Thermo Electron
apparatus by “Pôle Chimie Moléculaire-Welience”, Faculté des
Sciences Mirande, Dijon, France.
Conclusions
In summary, zinc-containing catalysts (zinc chloride,
montmorillonite K10 impregnated with zinc (II) chloride-Cat1
and Cat2 and ecocatalysts Ecocat1 and Ecocat2) have been
identified for efficient green synthesis of idrocilamide (1),
marketed myorelaxant and anti-inflamatory agent. Ecocat2
was found to possess the best catalytic activity for the
aminolysis reaction between methyl cinnamate and
ethanolamine and provided the target molecule in 70% yield
in solventless conditions. In addition, the recyclability of
supported catalysts (Cat1, Cat2, Ecocat1 and Ecocat2) has
been investigated in the synthesis of idrocilamide (
distinctive runs.
1) over five
Synthesis of N-(2-hydroxyethyl)-3-phenyl-2-propenamide
(Idrocilamide, 1) without catalyst. A mixture of methyl
cinnamate (0.5 g, 3 mmol) and ethanolamine (0.19 mL, 3
mmol) was stirred at 70°C during 24h. After cooling to room
temperature, the crude was purified by flash chromatography
(EtOAc:n-heptane; 6:4) to provide pure N-(2-hydroxyethyl)-3-
phenyl-2-propenamide 1 as a white solid in 54% yield; mp 101-
102°C (EtOAc); Rf = 0.30 (EtOAc:n-Hept; 9:1); IR ν (cm-1): 3295,
Ecocat 2 has been further selected as privileged catalyst in
additional aminolysis reactions to produce amides , and
and in condensation of 5-methoxypyrrolidin-2-one with
idrocilamide ( ). The catalytic activity was systematically
4
,
6
9
1
compared to that of commercial zinc chloride and highlighted
the excellent catalytic power of ecocatalysts for amide linkage
construction.
1
1649, 1595, 1556, 1344, 1229. H NMR (400MHz, CDCl3) δ
Synthesized molecules 1-4, 6 and 9 have been submitted to
(ppm): 3.55 (q, J = 5.7 Hz, 2H, CH2CH2), 3.78 (dd, J = 5.3, 4.9 Hz,
2H, CH2CH2), 6.46 (d, J = 15.7 Hz, 1H, CHCHCO), 6.59 (br t, J =
6.2 Hz, 1H, NHCH2), 7.32-7.34 (m, 3H, ArH), 7.46-7.48 (m, 2H,
ArH), 7.63 (d, J = 15.7 Hz, 1H, CHCHCO). 13C NMR (100 MHz,
CDCl3) δ (ppm): 42.8 (CH2), 62.4 (CH2), 120.4 (CH), 128.0
(CHx2), 129.0 (CHx2), 129.9 (CH), 134.8 (C), 141.7 (CH), 167.3
(C).
Synthesis of N-(2-hydroxyethyl)-3-phenyl-2-propenamide
(Idrocilamide, 1) in presence of ZnCl2 as catalyst. A catalytic
amount of ZnCl2 (21 mg, 0.15 mmol) was added to a mixture
of methyl cinnamate (0.5 g, 3 mmol) and ethanolamine (0.19
g, 3 mmol) is added. The mixture was stirred at 70°C during
24h. After cooling to room temperature, the crude was solved
in CH2Cl2 (25mL) and washed with water (3x20mL). The
organic layers were concentrated under vacuum and the
resulting crude was purified by flash chromatography
(EtOAc:n-heptane; 6:4) to provide pure N-(2-hydroxyethyl)-3-
biological evaluation of their antioxidant and anti-
inflammatory potential in vitro in two assays: ROS generation
from macrophages and macrophage migration between
epithelia cells to Candida albicans. Interestingly, all molecules
displayed improved activity compared to parent idrocilamide
(
1
). The latter inhibited the ROS production at a concentration
of 10µM but lost the activity at a concentration of 1µM while
all other molecules 4, 6 and conserved the inhibitory
2
-
9
potential on ROS generation even at 1µM concentration. The
same tendency was observed also in the macrophage
migration between epithelial cells to C. albicans. Parent
idrocilamide did not display any inhibitory potential at tested
concentrations while molecules
migration of macrophages when applied at
concentration.
2
-
4, 6 and
9
decreased the
10µM
a
Ultimately, this work provides new environmentally friendly
methodology for the amide bond formation in organic
chemistry and opens the way for the discovery of new
phenyl-2-propenamide (1) in 75% yield.
Synthesis of N-(2-hydroxyethyl)-3-phenyl-2-propenamide
(Idrocilamide, 1) in presence of ZnCl2-impregnated MK10 (Zn-
MK10, Cat 1 and Cat2) or Ecocatalysts (Ecocat 1 and Ecocat 2)
as catalysts. A catalytic amount of catalyst (216 mg, 0.15
mmol) was added to a mixture of methyl cinnamate (0.5 g, 3
mmol) and ethanolamine (0.19 mL, 3 mmol). The medium was
stirred at 70°C during 24h. After cooling to room temperature,
the crude was solved in ethyl acetate (25mL) and filtered to
recover the supported catalyst. The filtrate was concentrated
under vacuum and the resulting crude was purified on flash
chromatography (EtOAc:n-heptane; 6:4) to provide pure N-(2-
hydroxyethyl)-3-phenyl-2-propenamide (1) in 46 to 70% yield.
Ethyl 3-phenyl-2-[(1-oxo-3-phenyl-2-propen-1-yl)amino]-2-
propenoate 2. By-product from the synthesis of idrocilamide
(1); 5% yield; white solid; mp 80-84°C (EtOAc); Rf = 0.88
(EtOAc:n-Hept; 9:1); IR ν (cm-1): 3371, 3288, 3026, 2953, 1708,
1622, 1532, 1165. 1H NMR (400MHz, CDCl3) δ (ppm): 3.75 (q, J
analogues of marketed controversial idrocilamide (
improved antioxidant and anti-inflammatory activity.
1) with
Experimental Section
Materials and methods
Starting materials are commercially available and were used
without further purification (suppliers: Carlo Erba Reagents
S.A.S., Tokyo Chemical Industry Co. Ltd. and Acros Organics).
Melting points were measured on a MPA 100 OptiMelt®
apparatus and are uncorrected. Nuclear Resonance Magnetic
(NMR) were acquired at 400 MHz for 1H NMR and at 100 MHz
for 13C NMR, on a Varian 400-MR spectrometer with
tetramethylsilane (TMS) as internal standard, at 25°C.
Chemical shifts (δ) are expressed in ppm relative to TMS.
Splitting patterns are designed: s, singlet; d, doublet; dd,
7
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
= 5.6 Hz, 2H, NHCH2CH2), 4.39 (t, J = 5.2 Hz, 2H, NHCH2CH2O), methylbenzylamine (0.39 mL, 3 mmol). The mixture was
6.09 (br t, J = 5.2 Hz, 1H, NHCH2CH2O), 6.42 (d, J = 15.6 Hz, 1H, stirred at 70°C during 24h. After cooling to room temperature,
CHCHCOO), 6.47 (d, J = 15.6 Hz, 1H, CHCHCONH), 7.29-7.43 (m, the crude was solved in ethyl acetate (50 mL) and filtered to
6H, ArH), 7.49-7.54 (m, 4H, ArH), 7.65 (d, J = 15.6 Hz, 1H, recover the ecocatalyst. The filtrate was concentrated under
CHCHCOO), 7.73 (d, J = 15.6 Hz, 1H, CHCHCONH).13C NMR (100 vacuum and the resulting crude was purified by flash
MHz, CDCl3) δ (ppm): 39.4 (CH2), 63.6 (CH2), 117.5 (CH), 120.4 chromatography (EtOAc:n-heptane, 50:50 to 100:0) to provide
(CH), 128.0 (CHx2), 128.3 (CHx2), 129.0 (CHx2), 129.1 (CHx2),
129.9 (CH), 130.7 (CH), 134.3 (C), 134.9 (C), 141.6 (CH), 145.8
pure (2E)-3-Phenyl-N-[(1R)-1-phenylethyl]-2-propenamide (6)
in 40% yield; white solid; mp 139-141°C (CH2Cl2); Rf = 0.57
(CH), 166.1 (C), 167.3 (C). Anal. Calcd. For C20H19NO3: C, 74.75; (EtOAc:n-Hept; 5:5); IR ν (cm-1): 3306, 1652, 1620, 1541, 1224.
H, 5.96; N, 4.36. Found: C, 74.58; H, 6.08; N, 4.54%.
N-(2-((5-Oxopyrrolidin-2-yl)oxy)ethyl)cinnamamide (3). 5- CHCH3), 5.05 (quint, J = 7.8 Hz, 1H, CHCH3), 6.71 (d, J = 15.6 Hz,
1H NMR (400MHz, CDCl3) δ (ppm): 1.41 (d, J = 6.8 Hz, 3H,
Methoxypyrrolidine (0.45 g, 4 mmol) was added to a mixture
of idrocilamide ( ) (0.75 g, 4 mmol) and zinc (II) chloride (26.7
mg, 0.20 mmol) and the resulting mixture was stirred at 80°C
1H, CHCHCO), 7.21-7.26 (m, 1H, ArH), 7.33 (d, J = 3.1 Hz, 2H,
ArH), 7.37-7.43 (m, 5H, ArH), 7.42 (d, J = 15.6 Hz, 1H, CHCHCO),
7.55 (d, J = 7.1 Hz, 2H, ArH), 8.55 (d, J = 8.4 Hz, 1H, CONHCH).
1
during 24h. After cooling to room temperature, the crude was 13C NMR (100 MHz, DMSO-d6) δ (ppm): 22.5 (CH3), 48.0 (CH),
solved in CH2Cl2 (25mL) and washed with water (3x20mL). The 122.3 (CH), 126.0 (CHx2), 126.7 (CH), 127.5 (CHx2), 128.3
organic layers were concentrated under vacuum and the (CHx2), 128.9 (CHx2), 129.4 (CH), 134.9 (C), 128.8 (CH), 144.5
resulting crude was purified by flash chromatography (C), 164.0 (C). The physico-chemical properties correspond to
(EtOAc:n-heptane; 5:5 to 100:0) to provide pure N-(2-((5- those described in the literature.31
oxopyrrolidin-2-yl)oxy)ethyl)cinnamamide ( ) in 31% yield; N-(2,4-dichlorophenyl)-4-hydroxy-2-methyl-2H-1,2-
3
white solid; mp 113-116°C (EtOAc); Rf = 0.09 (EtOAc:n-Hept; benzothiazine-3-carboxamide 1,1-dioxide (9). A catalytic
9:1); IR ν (cm-1): 3304, 3184, 2902, 1702, 1662, 1630, 1531, amount of Ecocat2 (45 mg, 0.055 mmol) and 2,4-
1
1284, 1213. H NMR (400MHz, CDCl3) δ (ppm): 1.99-2.07 (m, dichloroaniline (178 mg, 1.1 mmol) were added to a solution
1H, CH2CH2CH), 2.18-2.31 (m, 2H, CH2CH2CH), 2.45-2.55 (m, of
methyl
2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-
1H, CH2CH2CH), 3.51-3.66 (m, 4H, NHCH2CH2O), 4.99 (d, J = 5.8 carboxylate 1,1-dioxide (300 mg, 1.1 mmol) in o-xylene (5 mL).
Hz, 1H, CONHCH), 6.50 (d, J = 15.4 Hz, 1H, CHCHCO), 6.72 (br The mixture was stirred at reflux for 47h. After cooling to room
t, J = 4.8 Hz, 1H, CHCONHCH2), 7.32-7.34 (m, 3H, ArH), 7.47- temperature, the crude was filtered to recover the
7.50 (m, 2H, ArH), 7.63 (d, J = 15.4 Hz, 1H, CHCHCO), 8.06 (br ecocatalyst. The filtrate was concentrated under vacuum and
s, 1H, CONHCHCO). 13C NMR (100 MHz, CDCl3) δ (ppm): 28.0 the resulting crude was purified by flash chromatography
(CH2), 28.5 (CH2), 39.6 (CH2), 66.0 (CH2), 86.5 (CH), 120.1 (CH), (CH2Cl2:MeOH, 100:0 to 90:10) to provide pure N-(2,4-
127.9 (CHx2), 128.9 (CHx2), 129.8 (CH), 134.9 (C), 141.1 (CH), dichlorophenyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-
166.4 (C), 179.5 (C). Anal. Calcd. For C15H18N2O3: C, 65.68; H, carboxamide 1,1-dioxide (9) in 27% yield; orange solid; mp
6.61; N, 10.21. Found: C, 65.73; H, 6.70; N, 10.90%.
232-234°C (CH2Cl2); Rf = 0.53 (EtOAc:n-Hept; 65:35); IR ν (cm-
1
N-Propyl-3-phenyl-2-propenamide (4). A catalytic amount 1): 3365, 1633, 1580, 1520, 1344, 1178. H NMR (400MHz,
of Ecocat2 (252 mg, 0.3 mmol) was added to a mixture of CDCl3) δ (ppm): 2.92 (s, 3H, NCH3), 3.42 (br s, 1H, OH), 7.51 (dd,
methyl cinnamate (1.0 g, 6 mmol) and propylamine (0.36 g, 6
mmol). The mixture was stirred at 70°C during 24h. After
cooling to room temperature, the crude was solved in ethyl
acetate (50 mL) and filtered to recover the ecocatalyst. The
filtrate was concentrated under vacuum and the resulting
J = 8.4, 2.2 Hz, 1H, ArH), 7.65 (d, J = 8.6 Hz, 1H, ArH), 7.78 (d, J
= 2.3 Hz, 1H, ArH), 7.87-7.95 (m, 3H, ArH), 8.04 (d, J = 6.5 Hz,
1H, ArH), 10.41 (br s, 1H, NHAr). 13C NMR (100 MHz, DMSO-d6)
δ (ppm): 40.2 (CH3), 111.4 (CH), 124.2 (CH), 126.3 (CH), 127.8
(CH), 127.8 (C), 129.1 (CH), 129.9 (C), 130.9 (C), 131.8 (C),
crude was purified by flash chromatography (EtOAc:n- 132.7 (C), 133.2 (CH), 133.6 (CH), 134.2 (C), 157.2 (C), 167.3
heptane, 5:5 to 100:0) to provide pure N-propyl-3-phenyl-2- (C).
propenamide (4) in 48% yield; brown solid; mp 75-78°C
(EtOAc); Rf = 0.61 (EtOAc:n-Hept; 6:4); IR ν (cm-1): 3262, 2968, Cell lines and yeast culture.
2361, 1652, 1610, 1548, 1341, 1221. 1H NMR (400MHz, CDCl3) The human monocytic THP-1 cells were incubated in RPMI
δ (ppm): 0.96 (t, J = 7.2 Hz, 3H, CH2CH2CH3), 1.60 (sext, J = 6.8 1640 medium (Gibco by LifeTechnologies™, France)
Hz, 2H, CH2CH2CH3), 3.36 (q, J = 7.2 Hz, 2H, CH2CH2CH3), 5.81 supplemented with 10% fetal bovine serum (FBS; Gibco,
(br s, 1H, CONHCH2), 6.41 (d, J = 15.6 Hz, 1H, ArCHCHCO), 7.34- France), 50 IU/mL penicillin, and 50 IU/mL streptomycin. THP-
7.35 (m, 3H, ArH), 7.48-7.50 (m, 2H, ArH), 7.62 (d, J = 15.6 Hz, 1 cells were differentiated into macrophages in the presence
1H, ArCHCHCO). 13C NMR (100 MHz, CDCl3) δ (ppm): 11.6 of phorbol-12-myristate 13-acetate (PMA, 25 nmol/L, Sigma-
(CH3), 23.1 (CH2), 41.6 (CH2), 121.0 (CH), 127.9 (CHx2), 128.9 Aldrich, France) at 37°C and 5% CO2. Caco-2 cells were grown
(CHx2), 129.7 (CH), 135.0 (C), 140.9 (CH), 166.0 (C). The
physico-chemical properties correspond to those described in
the literature.30
in Dulbecco's modified Eagle medium (DMEM) (Sigma-Aldrich,
France), supplemented with 20% FBS, 50 IU/mL penicillin and
50 IU/mL streptomycin at 37 °C and 5% CO2. C. albicans strain
(2E)-3-Phenyl-N-[(1R)-1-phenylethyl]-2-propenamide (6). A SC5314 was used in this study and maintained at 4ꢀ°C in yeast
catalytic amount of Ecocat2 (126 mg, 0.15 mmol) was added peptone dextrose broth (YPD; 1% yeast extract, 2% peptone,
to a mixture of methyl cinnamate (0.5 g, 3 mmol) and (R)-(+)- 2% dextrose). To prepare the yeast suspension, C. albicans
8
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
2
3
R. Aung-Din, 2004, WO 2004/112723 A2.
R. B. Moffet, A. R. Hanz and P. H. Seay, J. Med. Chem., 1963
7, 319–325.
E. Van Heyningen, C. N. Brown, F. José, J. K. Henderson and
P. Stark, J. Med. Chem., 1966, 9, 675–681.
A. Balsamo, P. L. Barili, P. Crotti, B. Macchia, A. Pecchia, A.
Cuttica and N. Passerini, J. Med. Chem., 1975, 18, 842–846.
F. Folfi and W. R. Pilgrim, 2005, FR 2862538-A.
X.-Q. Deng, D. Wu, C.-X. Wei and Z.-S. Quan, Med. Chem.
Res., 2011, 20, 1273–1279.
T. N. Reddy and D. P. de Lima, Asian J. Org. Chem., 2019, 8,
1227–1262 and references cited therein.
cells were cultured in Sabouraud dextrose broth (Sigma-
Aldrich, St. Quentin Fallavier, France) for 24 h at 37°C in a
rotary shaker.32
,
4
5
Migration assay.
A migration assay was performed as described previously.33,34
Caco-2 cells were grown to confluence at a cell density of
200,000 cells/mL in upper chamber of the transwell devices
(Costar Transwell inserts in a 96-well plate format) for 48 h in
DMEM (Sigma-Aldrich, France) and 20% FBS. After 48h
incubation, DMEM was removed, and 150 µL containing 5x105
6
7
8
9
For a selection see: (a) M. R. Petchey and G. Grogan, Adv.
Synth. Catal., 2019, doi: 10.1002/adsc.201900694; (b) J. S.
Derasp and A. M. Beauchemin, ACS Catal., 2019, doi:
10.1021/acscatal.9b02641; (c) P. E. Piszel, A. Vasilopoulos
and S. S. Stahl, Angew. Chem. Int. Edd., 2019, 58, 12211–
12215; (d) S. Jamalifard, J. Mokhtari and Z. Mirjafary, RSC
Adv., 2019, doi:10.1039/c9ra04216d; (e) F. Ke, Y. Xu, S. Zhu,
X. Lin, C. Lin, S. Zhou and H. Su, Green Chem., 2019, 21,
4329–4333; (f) P. Daw, A. Kumar, N. A. Espinosa-Jalapa, Y.
Ben-David and D. Milstein, J. Am. Chem. Soc., 2019, 141,
12202–12206; (g) A. Dandia, S. Parihar, P. Saini, K. S. Rathore
and V. Parewa, Catal. Lett., 2019, doi: 10.1007/s10562-019-
02878-5; (h) T. W. Bousfield, K. P. R. Pearce, S. B. Nyamini, A.
Angelis-Dimakis and J. E. Camp, Green Chem., 2019, 21,
3675–3681; (i) G. Li, C.-L. Ji, X. Hong and M. Szostak, J. Am.
Chem. Soc., 2019, 141, 11161–11172; (j) B. T. Sargent and E.
J. Alexanian, Angew. Chem., Int. Ed., 2019, 58, 9533–9536;
calcein-labeled
washed
PMA-differentiated
THP-1
macrophage cells and pre-treated with the molecules (at
concentration of 10-5 or 10-6 mol/L) were added to Caco-2 cells
in the upper chamber of the transwell devices. A volume of
150 μL RPMI containing 105 C. albicans yeast cells was added
to the lower chamber. Plates were placed in a humidified
incubator at 37°C and 5% CO2 for 8h. After migration, non-
migrated cells were removed from upper chamber of
transwell inserts, and the migrated macrophages present on
C. albicans strains were assessed by measuring fluorescence
using a fluorometer (FLUOstar® Omega (BMG Labtech).
ROS Assay.
Macrophages (5x105 cells) were plated in 96-well plates,
(k) J.-B. Peng, D. Li, H.-Q. Geng and X.-F. Wu, Org. Lett., 2019
,
pretreated with molecules 1-4,6, and 9
at concentration 10-5
21, 4878–4881; (l) M. Subramani and S. K. Rajendran, Eur. J.
Org. Chem., 2019, 22, 3677–3686; (m) H. A. Swarup, N.
Chaithra, N. C. Sandhya, S. Rangappa, K. Mantelingu and K.
S. Rangappa, Synth. Commun., 2019, 49, 2106–2116; (n) D.
M. M. M. Dissanayake, A. D. Melville and A. K. Vannucci,
Green Chem., 2019, 21, 3165–3171; (o) Y.-L. Zheng and S. G.
Newman, ACS Catal. 2019, 9, 4426–4433; (p) F. Zhang, L. Li,
J. Zhang and H. Gong, Sci. Rep., 2019, 9, 1–6; (q) S.-M. Wang,
or 10-6 mol/L and exposed to 10 μmol/L of LPS recruiting a
signaling pathways through TLR4 to induce ROS (Sigma-
Aldrich, France), incubated at 37°C and 5% CO2 in 100 µL RPMI
1640 medium supplemented with 10% fetal bovine serum. A
volume of 50 μL of a mixture of 50 μg/mL horseradish
peroxidase and 50 µM luminol were added to each well. The
chemiluminescence was measured at different incubation
times, 0h, 1h, 2h, 3h, and 4h in a FLUOstar Omega Fluorometer
(BMG Labtech). H2O2 alone without macrophages at a low
concentration 1.7 mol/L was used as a positive control.
C. Zhao, X. Zhang and H.-L. Qin, Org. Biomol. Chem., 2019
,
17, 4087–4101; (r) K. Singh, N. K. Pal, C. Guha and J. K. Bera,
J. Organometal. Chem., 2019, 886, 1–8; (s) C. Bal Reddy, S.
Ram, A. Kumar, R. Bharti and P. Das, Chem. Eur. J., 2019, 25,
4067–4071; (t) Y. Moglie, E. Buxaderas, A. Mancini, F. Alonso
and G. Radivoy, ChemCatChem, 2019, 11, 1487–1494; (u) T.
Narendar Reddy, A. Beatriz, V. Jayathirtha Rao and D. Pires
de Lima, Chem. Asian J., 2019, 14, 344–388; (v) G. Laconde,
M. Amblard and J. Martinez, Eur. J. Org. Chem., 2019, 85–90;
(w) S. K. Rath, S. Singh, S. Kumar, N. A. Wani, R. Rai, S. Koul,
I. A. Khan and P. L. Sangwan, Bioorg. Med. Chem., 2019, 27,
343–353; (x) J. Zhang, Y. Hou, Y. Ma and M. Szostak, J. Org.
Chem., 2019, 84, 338–345; (y) M. B. Chaudhari and B.
Gnanaprakasam, Chem. Asian J., 2019, 14, 76–93; (z) A. R.
Makhmutov, Russ. Chem. Bull., 2019, 68, 68–73.
Acknowledgements
The authors warmly thank the ‘Fondation de la Catho de Lille,
France’, Yncréa Hauts-de-France and University of Le Havre
Normandy for the financial support of this work and technical
help and facilities.
10 A. Ojeda-Porras and D. Gamba-Sánchez, J. Org. Chem., 2016
81, 11548–11555 and references cited therein.
,
11 G. Homerin, D. Baudelet, P. Dufrénoy, B. Rigo, E. Lipka, X.
Dezitter, C. Furman, R. Millet and A. Ghinet, Tetrahedron
Lett., 2016, 57, 1165–1170.
Conflict of Interest
12 L.-P. Guan, C.-X. Wei, X.-Q. Deng, X. Sui, H.-R. Piao and Z.-S.
Quan, Eur. J. Med. Chem., 2009, 44, 3654–3657.
The authors declare no conflict of interest.
13 J.-H. Xiu, Y.-C. Quan, G.-H. Zheng and L.-P. Guan, Huaxue
Shiji, 2009, 31, 663–666. Chem. Abstr. 2019, 152, 262340.
14 T. Yan, Y. Wu, F. Yuan, H. Pan, W. Guo and Z. Gao, Zhongguo
Keywords: ecocatalyst • idrocilamide • amide • antioxidant •
green chemistry
Yiyao Gongye Zazhi, 1991, 22, 443–444; Chem. Abstr. 1992
116, 151267.
,
15 J.-S. Zhang, Shanxi Daxue Xuebao, Ziran Kexueban, 2001, 24,
244–245. Chem. Abstr. 2001, 136, 355043.
References:
1
O. K. Behrens, J. Corse, D. E. Huff, R. G. Jones, Q. F. Soper and
C. W. Whitehead, J. Biol. Chem., 1948, 175, 771–792.
9
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
16 A. Beutler, C. D. Davies, M. C. Elliott, N. M. Galea, M. S. Long,
D. J. Willock and J. L. Wood, Eur. J. Org. Chem., 2005, 3791–
3800.
17 V. Chauhan, D. Chaudhary, U. Pathak, N. Saxena and R. K.
Dhaked, J. Med. Chem., 2016, 59, 10763–10773.
18 H. Sato and S. Hosokawa, Synthesis, 2018, 50, 1343–1349.
19 I.-H. Um, A.-R. Bae and J. M. Dust, Can. J. Chem., 2019, 97,
7–12.
20 S. De Sarkar, S. Grimme and A. Studer, J. Am. Chem. Soc.,
2010, 132, 1190–1191.
21 P. Garg and M. D. Milton, Tetrahedron Lett., 2013, 54, 7074–
7077.
22 C. Waterlot, D. Couturier and B. Hasiak, J. Chem. Res. 2000
3, 417–429.
,
23 For full physico-chemical characterization and descriptions
of contaminated soils used to obtain ecocatalysts see: C.
Waterlot, P. Dufrénoy, M. Hechelski, B. Duchemin, A. Daïch and
A. Ghinet, Publication pending.
24 C. Waterlot, D. Couturier, B. Rigo, A. Ghinet and M. De
Backer, Chem. Pap., 2013, 65, 873–882.
25 J. G. Lombardino, E. H. Wiseman and W. M. McLamore, J.
Med. Chem., 1971, 14, 1171–1175.
26 J. Kuroda, T. Ago, S. Matsushima, P. Zhai, M. D. Schneider
and J. Sadoshima, Proc. Natl. Acad. Sci. U. S. A., 2010, 107,
15565–15570.
27 C. Gummersbach, K. Hemmrich, K. D. Kroncke, C. V. Suschek,
K. Fehsel and N. Pallua, Differentiation, 2009, 77, 115–120.
28 A. Sturza, O. M. Duicu, A. Vaduva, M. D. Danila, L. Noveanu,
A. Varro and D. M. Muntean, Can. J. Physiol. Pharm., 2015
93, 555–561.
,
29 E. De Vallance, Y. Li, M. Jurczak, E. Cifuentes-Pagano and P.
J. Pagano, Antioxid. Redox Sign., 2019, 31, 687–709.
30 S. De Sarkar and A. Studer, Org. Lett. 2010, 12, 1992–1995.
31 J. G. H. Barajas, L. Y. V. Mendez, V. V. Kouznetsov and E. E.
Stashenko, Synthesis, 2008, 377–382.
32 S. Jawhara, X. Thuru, A. Standaert-Vitse, T. Jouault, S.
Mordon, B. Sendid, P. Desreumaux and D. Poulain, J. Infect.
Dis., 2008, 197, 972–980.
33 L. Choteau, H. Vancraeyneste, D. Le Roy, L. Dubuquoy, L.
Romani, T. Jouault, D. Poulain, B. Sendid, T. Calandra, T.
Roger and S. Jawhara, Gut Pathog., 2017
doi:10.1186/s13099-017-0158-0.
, 9, 9.
34 S. Jawhara, E. Pluskota, D. Verbovetskiy, O. Skomorovska-
Prokvolit, E. F. Plow and D. A. Soloviev, J. Immunol. 2012
189, 2468–2477.
,
10
This article is protected by copyright. All rights reserved.

10.1002/cmdc.201900641
ChemMedChem
FULL PAPER
Entry for the Table of Contents
Insert graphic for Table of Contents here.
Green amidation
P. Dufrénoy, R. Charlet, M.
Hechelski,A. Daïch, C. Waterlot, S.
Jawhara and A. Ghinet*
Page No. – Page No.
New efficient eco-friendly supported
catalysts for the synthesis of amides
The work given herein involves new environmental eco-friendly approach
for the synthesis of amide function tethered to idrocilamide and derivatives
with improved antioxidant and anti-inflammatory activity. Interesting
idrocilamide prodrug was also explored under these greener conditions
using intramolecular trapping of the N-acyliminium species.
with
antioxidant
and
anti-
inflammatory properties
11
This article is protected by copyright. All rights reserved.