Microwave-Assisted condensation reactions of acetophenone derivatives and activated methylene compounds with aldehydes catalyzed by boric acid under solvent-free conditions

Article abstract of DOI:10.3390/molecules200611617

We here disclosed a new protocol for the condensation of acetophenone derivatives and active methylene compounds with aldehydes in the presence of boric acid under microwave conditions. Implementation of the reaction is simple, healthy and environmentally

Full text of DOI:10.3390/molecules200611617

Molecules 2015, 20, 11617-11631; doi:10.3390/molecules200611617
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Microwave-Assisted Condensation Reactions of Acetophenone
Derivatives and Activated Methylene Compounds with
Aldehydes Catalyzed by Boric Acid under
Solvent-Free Conditions
Elodie Brun 1,†, Abdelmounaim Safer 2,†, François Carreaux 1,*, Khadidja Bourahla 1,
Jean-Martial L’helgoua’ch 1, Jean-Pierre Bazureau 1 and Jose Manuel Villalgordo 3
1
Institut des Sciences Chimiques de Rennes, Université de Rennes 1, Campus de Beaulieu,
UMR 6226 CNRS, 35042 Rennes Cedex, France; E-Mails: brun_elodie@hotmail.com (E.B.);
bkhadije@yahoo.fr (K.B.); jm.lhelgoualch@gmail.com (J.-M.L.);
jean-pierre.bazureau@univ-rennes1.fr (J.-P.B.)
2
LSOA—Laboratoire de Synthèse Organique Appliquée, Department of chemistry,
Oran 1 University, 1524 Oran, Algeria; E-Mail: asafer2001@yahoo.fr
3
Villapharma Research, Parque Tecnologico de Fuente Alamo, E-30320 Murcia, Spain;
E-Mail: jmvillalgordo@villapharma.com
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: francois.carreaux@univ-rennes1.fr;
Tel.: +33-2-23-23-57-34.
Academic Editors: Marilena Radoiu, Jean Jacques Vanden Eynde and Annie Mayence
Received: 28 May 2015 / Accepted: 15 June 2015 / Published: 23 June 2015
Abstract: We here disclosed a new protocol for the condensation of acetophenone derivatives
and active methylene compounds with aldehydes in the presence of boric acid under
microwave conditions. Implementation of the reaction is simple, healthy and environmentally
friendly owing to the use of a non-toxic catalyst coupled to a solvent-free procedure. A large
variety of known or novel compounds have thus been prepared, including with substrates
bearing acid or base-sensitive functional groups.
Keywords: condensation reaction; boric acid; catalysis; solvent-free; microwave

Molecules 2015, 20
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1. Introduction
The development of new methodologies employing oxygenated boron compounds (i.e., borinic
acids R1R2B(OH), boronic acids RB(OH)2 and boric acid H3BO3) as reaction catalysts has received
a lot of attention from the organic chemistry community during these past few years [1]. Beside their
stability to air and moisture, the growing interest for this class of compounds can also be attributed to
the different modes of catalytic reactivity achieved depending on their electronic nature. They can
indeed act as Lewis acids but also as activators of functional groups such as hydroxyl and carboxylic
groups by reversible covalent interactions [2]. Among them, boric acid was found to be an efficient
catalyst in numerous reactions such as selective esterification of α-hydroxycarboxylic and malonic
acids [3–5], amide formation from carboxylic acids [6–8], transamidation of carboxamides [9],
trimethylsilylation of alcohols and phenols [10], decarboxylation of cyclic β-enaminoketoesters [11],
ipso-hydroxylation of aryl boronic acids [12], aza [13] and thia-Michael addition [14], Friedel-Crafts
alkylation of indoles [15] as well as in diverse multicomponent reactions [16–19].
Condensation reactions of aldehydes with active methylene compounds are very useful to prepare
molecules with potential therapeutic relevance such as, for instance, the 1,3-diphenylpropenones also
called chalcones. They exhibit diverse pharmacological activities [20–22] and more particularly, as
anticancer agents [23,24]. Many other drugs as well as pharmacological tools with heterocyclic structures
can also include an aldol-type condensation step in their synthesis [25,26], as illustrated in Figure 1.
O
O
OH
N
OCH3
S
HO
NH2, MeSO3H
F
potent
antitumor activity
[24]
Darbufelone mesilate,
anti-inflammatory drug
[25]
O
O
O
H
N
N
N
H
Leucettine L-41,
neuroprotective effect
[26]
Figure 1. Selected molecules with high biological value.
These condensation reactions can be promoted by a large array of catalysts including Lewis bases
and acids but can suffer from limitations related, among other factors, to waste elimination and use of
toxic products [27]. Therefore, the development of new methods involving the environmentally benign
and cost-efficient catalysts still remains a major challenge. In this context, the use of boric acid as a
catalyst in these reactions should be particularly adapted due to its lack of apparent toxicity and its
easy removal from a reaction mixture [28]. To the best of our knowledge, only a limited number of
articles report the use of boric acid acting as the sole catalyst for aldol condensation and subsequent
dehydration to form α,β-unsaturated ketones [29,30]. However, the described conditions require long
reaction times at reflux of m-xylene in presence of 50 mol % of catalyst and water removal through
a Dean-Stark trap.

Molecules 2015, 20
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As part of our program focused on the development of novel green methods based on organoboron
chemistry for the synthesis of molecules with a high biological profile [31–35], we here report our
efforts to develop a general procedure for condensation reactions employing boric acid as catalyst. The
application of microwave technology as non-conventional energy source was crucial for the
implementation of this methodology. Under solvent-free conditions, we have shown that the
condensation protocol was efficient from various substrates bearing an activated methylene group. In
addition, we found that the condensation reaction with an aldehyde possessing a boronic acid group
proceeds without the need to an additional catalyst.
2. Results and Discussion
For the experimental protocol development, we selected the 4-methoxyacetophenone 1a (1 equiv.)
and the 4-methoxybenzaldehyde (1.2 equiv.) as model substrates due to the fact that, from a biological
point of view, the chalcones bearing electron rich groups are part of the most interesting molecules [20].
After observing very low formation of the expected product 2a, under thermal heating in presence of
boric acid for 4 h (Table 1, entry 1), we tried different conditions using microwave irradiation as energy
source and without adding any solvent. For a first attempt, we employed 50 mol % of boric acid at 160 °C
for 20 min. Under these conditions, chalcone 2a is formed stereoselectively (only E) with an almost
complete conversion (95%) compared to 4-methoxyacetophenone (entry 2). Improvement of the reaction
conversion when phenyl boronic acid is used instead of boric acid confirms that the catalyst has to act
as a Lewis acid during the condensation reaction (entry 3).
Table 1. Optimization of the condensation reaction catalyzed by boric acid a.
Entry
Catalyst (mol %)
B(OH)3 (50 mol %)
B(OH)3 (50 mol %)
PhB(OH)2 (50 mol %)
B(OH)3 (10 mol %)
B(OH)3 (20 mol %)
Conditions
2a (Conv. %) c
5%
2a (yield %) d
1
2
3
4
Toluene, reflux (4 h)
MWI, 160 °C (20 min) b
MWI, 160 °C (20 min) b
MWI, 160 °C (40 min) b
MWI, 160 °C (40 min) b
-
-
-
-
95%
100%
75%
5
93%
70%
a
b
Reaction condition: 4-methoxyacetophenone (1 mmol), 4-methoxybenzaldehyde (1.2 mmol); Microwave
irradiation of the reaction mixture was carried out in a glass tube sealed with a snap cap using the
c
Explorer®24 CEM apparatus (CEM µ Waves, Saclay, France) (P = 300 W); Conversion based on
4-methoxyacetophenone 1a as the limiting reagent; d Isolated pure product.
Even though phenyl boronic acid is a stronger Lewis acid than boric acid and is easy to handle, we
continued our study using boric acid because of its low cost and the fact that it is a more
environmentally friendly reagent [36]. Eventually, by changing the irradiation time, we found that it
was possible to reduce the quantity of catalyst down to 20 mol % while keeping a good conversion
(entry 5). The desired compound 2a has been obtained in a pure form in an acceptable yield (70%) by
mere addition, after heating, of a mixture of solvent (H2O/EtOH) and filtration.

Molecules 2015, 20
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The next goal was to extend this protocol to other acetophenone derivatives 1 and aldehydes in
order to show the scope and limitations of this process. In all cases described in Scheme 1, chalcones 2
were obtained in a stereoselective manner (>95%) in favor of E isomer as confirmed by the magnitude
of the coupling constant between the two vinyl protons (range from 15.5 to 15.8 Hz). The obtained
yields after precipitation and filtration were not optimized but we observed slightly better results when
bromo group was present on the aromatic ring of aldehydes (2e compared to 2a, 2n compared to 2o).
Undoubtedly, the solvent-free conditions are relatively mild compared to basic or acidic media generally
implemented in conventional methods to prepare the 1,3-diaryl-2-propen-1-ones. As demonstrated by the
synthesis of unknown compounds 2n–p, this new process tolerates the presence of an ester functional
group and allows access to functionalized chalcones which may be difficult to prepare by traditional
methods. Typically, the aldol condensations in basic media are carried out in the appropriate alcoholic
solvent to prevent the transesterification side-reaction. In this regard, our metal-free process can be
considered as a complementary methodology of the catalyzed coupling reactions requiring any base
such as the oxidative carbonylative vinylation reactions of aryl boronic acids with styrenes which is
described in particular as compatible with the carbonyl groups [37].
R4
O
R4
O
R5
R6
R1
R5
R6
R1
R2
CHO
R8
B(OH)3 (20 mol%)
+
2
R
R8
MW, 160 °C, 40 min.
R7
R3
R7
R3
1
2
O
O
O
O
O
N
O
O
O
O
O
O
2b, 65%
2a, 70%
2c, 61%
O
O
Br
O
O
O
O
Br
O
O
2d, 66%
2e, 75%
2f, 58%
O
O
O
O
O
O
O
O
Br
O
2i, 69%
2g, 64%
2h, 68%
O
O
O
O
O
O
Br
O
Br
N
2l, 59%
2k, 60%
2j, 64%
O
O
O
O
O
O2N
O
N
Br
2m, 65%
2o, 58%
2n, 62%
O
O
O
O
O
O
2p, 57%
Scheme 1. Synthesis of various functionalized chalcones.
Despite the lack of evidence for the postulated mechanism, we can speculate that, under these
microwave irradiation conditions, the ketone first reacts with boric acid to form a boron enolate
(Scheme 2). The aldol reaction between this species and an aldehyde might then proceed via a

Molecules 2015, 20
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six-membered chair-like transition state. Finally, the resulting adduct may undergo a dehydration step
assisted by a possible intramolecular coordination of the boron atom with the carbonyl group.
Scheme 2. Proposed catalytic cycle for the formation of α,β-unsatured ketones.
Five-membered heterocyclic rings such as the thiohydantoin (X = S, Y = NH), hydantoin (X = O,
Y = NH), rhodanine or 2-thioxo-1,3-thiazolidin-4-one (X = S, Y = S) and 1,3-thiazolidin-2,4-dione (X = O,
Y = S) have attracted our attention as potential substrates in our condensation protocol since they
appear as interesting scaffolds for drug discovery [38]. To our delight, in all cases the expected
products 3 were obtained in moderate to good yields (Scheme 3).
X
HN
X
HN
ArCHO (1.2 equiv.), B(OH)3 (20 mol%)
MW, 160 °C, 40 min.
Y
Y
Ar
3
O
O
O
O
O
S
O
HN
S
HN
NH
NH
O
NH
HN
O
O
O
3c, 180 °C, 49%
3b, 87%
3a, 75%
Cl
O
O
S
S
S
S
S
S
O
HN
HN
HN
O
O
O
3e, 95%
3f, 91%
3d, 90%
NO2
OH
OMe
N
S
O
S
S
S
O
S
S
S
HN
HN
HN
HN
O
O
O
O
3g, 90%
3j, 44%
3h, 93%
3i, 79%
Scheme 3. Condensation reaction with five-membered heterocyclic rings.

Molecules 2015, 20
11622
After microwave heating in the presence of 1.2 equivalent of aldehyde, the addition of ethanol in
the crude reaction mixture allowed the formation of a precipitate that is filtered to give the 5-arylidene
derivatives 3 as a sole isomer whose Z stereochemistry was assigned, in accordance with the literature.
In the case of hydantoin, an adjustment of the experimental protocol was necessary to obtain
compound 3c in a suitable yield (49%). In a similar way, an increased temperature (180 °C) with
thiazolidinedione as substrate was envisaged but without any substantial effect on yield (3j, 44%).
In these last two decades, boronic acid derivatives have become a significant class of compounds
with important biological applications [39]. On this basis, we put forth the idea that the condensation
reaction involving an aldehyde bearing a boronic group on the aromatic ring might constitute a new
route to these organoboron compounds. Without the supplementary addition of catalyst, the reaction
between thyohydantoin and 4-formylphenylboronic acid under microwave irradiation afforded the
expected product 4 (Scheme 4).
Scheme 4. Condensation reactions involving the 4-formylboronic acid.
The work-up is a simple filtration of the formed precipitate following the addition of a H2O/EtOH
mixture in the crude mixture. Unfortunately and unexpectedly, when the reaction was achieved with
4-methoxyacetophenone using the same experimental conditions, product 5 rather than the chalcone
containing the boronic acid function was isolated probably as a result of a protonolysis of the C-B
bond. Other attempts were made with similar substrates though without any more success showing the
difficulty to overcome this side reaction.
3. Experimental Section
All reagents were purchased from Acros (Geel, Belgium), Aldrich (Saint Louis, MI, USA) and were
used without further purification. Melting points were determined on a Kofler melting point apparatus
1
(Wagner & Munz, Munich, Germany), and were uncorrected. H-NMR spectra were recorded on
BRUKER AC 300 P (300 MHz) spectrometer (Bruker, Bremen, Germany), 13C-NMR spectra on
11
BRUKER AC 300 P (75 MHz, Bruker) spectrometer and B-NMR spectra on BRUKER AC 300 P
(96 MHz, Bruker). Chemical shifts are expressed in part per million downfield from tetramethylsilane
as an internal standard. Data are given in the following order: δ value, multiplicity (s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad), number of protons, coupling constants J is given

Molecules 2015, 20
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in Hz. Reactions under microwave irradiations were realized in the Explorer®24 CEM microwave
reactor (CEM France, CEM µ Waves) using borosilicate glass vials of 10 mL equipped with snap caps
(at the end of the irradiation, cooling reaction was realized by compressed air). The microwave
instrument consists of a continuous focused microwave power output from 0 to 300 W. All the
experiments were performed using a stirring option. The target temperature was reached with a ramp
of 2 min. and the chosen microwave power stayed constant to hold the mixture at this temperature. The
reaction temperature is monitored using calibrated infrared sensor and the reaction time included the
ramp period. The microwave irradiation parameters (power and temperature) were monitored by the
ChemDriver software package (Version 2.0, CEM µ Waves). High-resolution mass sprectra (HMRS)
were recorded on a Bruker Micro-Tof-Q II (Bruker) or on a Waters Q-Tof 2 at the CRMPO (Centre
Régional de Mesures Physiques de l’Ouest, Rennes, France) using positive ion Electro-Spray Ionization
(ESI, Waters, Manchester, UK). Purifications by column chromatography were all carried out on silica
gel by using Acros silica 0.060–0.200 mm, 60 Å. Thin layer chromatography analyses were performed
on Merck Silica Gel 60 F254 plates (Merck, Darmstadt, Germany).
3.1. General Procedure for the Condensation Reaction
A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in
a cylindrical quartz reactor (Ø = 4 cm). The reactor was introduced into an Explorer®24 CEM apparatus.
The stirred mixture was heated at 160 °C (P = 300 W) for 40 min, except for 3c (180 °C). After
microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature
and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz
reactor. The resulting precipitated product was filtered off and was purified by recrystallization from
ethanol if necessary.
3.2. Physical and Spectroscopic Data of Products
(E)-1,3-Bis-(4-methoxyphenyl)-prop-2-en-1-one (2a) [40]. Pale cream powder, 70% yield,
m.p. = 96–98 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.95 (d, 2H,
J = 8.7 Hz, Ar-), 7.00 (d, 2H, J = 8.8 Hz, Ar-), 7.45 (d, 1H, J = 15.6 Hz, CH=), 7.62 (d, 2H, J = 8.7 Hz,
Ar-), 7.80 (d, 1H, J = 15.6 Hz, CH=), 8.05 (d, 2H, J = 8.8 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz):
δ = 55.4, 55.5, 113.8, 114.4, 119.6, 127.8, 130.1, 130.7, 131.4, 143.8, 161.5, 163.3, 188.7 ppm; HRMS
(ESI+): m/z calcd for C17H16O3 [M + Na]+ 291.0997; found 291.0996.
(E)-3-(4-(Dimethylamino)phenyl)-1-(4-methoxyphenyl)-prop-2-en-1-one (2b) [40]. light yellow powder,
1
65% yield, m.p. = 128–130 °C; H-NMR (CDCl3, 300 MHz): δ = 3.05 (s, 6H, N(CH3)2), 3.89 (s, 3H,
OCH3), 6.71 (d, 2H, J = 8.7 Hz, Ar-), 6.99 (d, 2H, J = 8.4 Hz, Ar-), 7.37 (d, 1H, J = 15.4 Hz, CH=),
7.57 (d, 2H, J = 8.4 Hz, Ar-), 7.80 (d, 1H, J = 15.4 Hz, CH=), 8.01 (d, 2H, J = 8.7 Hz, Ar-) ppm;
13C-NMR (CDCl3, 75 MHz): δ = 40.2, 55.5, 111.8, 113.7, 116.6, 122.8, 130.3, 130.6, 131.9, 145.0,
151.9, 163.0, 188.9 ppm; HRMS (ESI+): m/z calcd for C18H19NO2 [M + Na]+ 304.1313; found 304.1313.

Molecules 2015, 20
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(E)-1-(4-Methoxyphenyl)-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one (2c) [41]. Yellow powder, 61%
yield, m.p. = 128–130 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OCH3), 3.90 (s, 3H, OCH3),
3.93 (s, 6H, OCH3), 6.16 (s, 2H, Ar-), 6.98 (d, 2H, J = 8.8 Hz, Ar-), 7.90 (d, 2H, J = 15.8 Hz, CH=),
13
8.04 (d, 2H, J = 8.8 Hz, Ar-), 8.24 (d, 1H, J = 15.8 Hz, CH=) ppm; C-NMR (CDCl3, 75 MHz):
δ = 55.8, 56.5, 56.8, 57.3, 97.5, 112.1, 114.1, 116.2, 120.6, 131.1, 132.1, 139.7, 143.7, 152.7, 154.9,
163.5, 189.7 ppm; HRMS (ESI+): m/z calcd for C19H20O5 [M + Na]+ 351.1208; found 351.1208.
(E)-1-(4-Methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)-prop-2-en-1-one (2d) [42]. Pale yellow powder,
1
66% yield, m.p. = 138–140 °C; H-NMR (CDCl3, 300 MHz): δ = 3.92 (s, 6H, OCH3), 3.95 (s, 6H,
OCH3), 6.88 (s, 2H, Ar-), 7.01 (d, 2H, J = 8.7 Hz, Ar-), 7.43 (d, 1H, J = 15.8 Hz, CH=), 7.73 (d, 1H,
13
J = 15.8 Hz, CH=), 8.05 (d, 2H, J = 8.7 Hz, Ar-) ppm; C-NMR (CDCl3, 75 MHz): δ = 55.9, 56.6,
61.4, 106.0, 114.2, 121.7, 131.0, 131.2, 131.5, 140.7, 144.5, 153.9, 163.8, 189.1 ppm; HRMS (ESI+):
m/z calcd for C19H20O5 [M + Na]+ 351.1208; found 351.1209.
(E)-3-(4-Bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (2e) [43]. Pale yellow powder, 75%
yield, m.p. = 157–159 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.92 (s, 3H, OCH3), 7.00 (d, 2H, J = 8.9 Hz,
Ar-), 7.49–7.61 (m, 5H, Ar, CH=), 7.75 (d, 1H, J = 15.6 Hz, CH=), 8.05 (d, 2H, J = 8.9 Hz, Ar-) ppm;
13C-NMR (CDCl3, 75 MHz): δ = 55.5, 113.9, 122.4, 124.5, 129.7, 130.8, 130.9, 132.1, 134.0, 142.5,
163.5, 188.3 ppm; HRMS (ESI+): m/z calcd for C16H13BrO2 [M + Na]+ 338.9997; found 338.9996.
(E)-3-(5-Bromobenzo[d][1,3]dioxol-4-yl)-1-(4-methoxyphenyl)prop-2-en-1-one (2f). Pale green powder,
1
58% yield, m.p. = 120–122 °C; H-NMR (CDCl3, 300 MHz) δ= 3.89 (s, 3H, OCH3), 6.16 (s, 2H,
OCH2O), 6.72 (d, 1H, J = 8.3 Hz, Ar-), 7.01 (d, 2H, J = 8.9 Hz, Ar-), 7.15 (d, 1H, J = 8.3 Hz, Ar-),
7.90 (d, 1H, J = 15.8 Hz, CH=), 8.01 (d, 1H, J = 15.8 Hz, CH=), 8.07 (d, 2H, J = 8.9 Hz, Ar-) ppm;
13C-NMR (CDCl3, 75 MHz): δ = 55.4, 102.1, 110.1, 113.8, 117.0, 118.2, 125.9, 127.2, 130.9, 137.4,
147.3, 147.5, 163.5, 188.8 ppm; HRMS (ESI+): m/z calcd for C17H13BrO4 [M + Na]+ 382.9895;
found 382.9895.
(E)-3-(4-Bromophenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (2g) [44]. Pale yellow powder,
1
64% yield, m.p. = 123–124 °C; H-NMR (CDCl3, 300 MHz): δ: 3.92 (s, 3H, OCH3), 3.93 (s, 6H, 2 ×
OCH3), 7.22 (s, 2H, Ar-), 7.42 (d, 1H, J = 15.6 Hz, CH=), 7.48 (d, 2H, J = 8.0 Hz, Ar-), 7.54 (d, 2H,
13
J = 8.0 Hz, Ar-), 7.72 (d, 1H, J = 15.6 Hz, CH=) ppm; C-NMR (CDCl3, 75 MHz): δ = 56.6, 56.7,
61.2, 106.4, 122.5, 125.0, 130.0, 131.7, 132.5, 133.5, 134.0, 143.5, 153.4, 189.3 ppm; HRMS (ESI+):
m/z calcd for C18H17BrO4 [M + Na]+ 399.0208; found 399.0208.
(E)-3-(4-Methoxyphenyl)-1-phenylprop-2-en-1-one (2h) [43]. Pale yellow powder, 68% yield,
1
m.p. = 74–76 °C; H-NMR (CDCl3, 300 MHz): δ: 3.83 (s, 3H, OCH3), 6.96 (d, 2H, J = 8.8 Hz, Ar-),
7.44 (d, 1H, J = 15.7 Hz, CH=), 7.49–7.58 (m, 3H, Ar-), 7.63 (d, 2H, J = 8.8 Hz, Ar-), 7.80 (d, 1H,
13
J = 15.7 Hz, CH=), 8.03 (d, 2H, J = 8.1 Hz, Ar-) ppm; C-NMR (CDCl3, 75 MHz): δ = 55.4, 119.8,
127.7, 128.5, 128.6, 130.2, 130.3, 132.6, 138.5, 144.7, 161.6, 190.6 ppm. HRMS (ESI+): m/z calcd for
C16H14O2 [M + Na]+ 261.0891; found 261.0893.

Molecules 2015, 20
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(E)-3-(2,3-Dihydrobenzofuran-5-yl)-1-phenylprop-2-en-1-one (2i). Pale yellow powder, 69% yield,
1
m.p. = 110–112 °C; H-NMR (CDCl3, 300 MHz): δ= 3.26 (t, 2H, J = 8.7 Hz, ArCH2), 4.65 (t, 2H,
J = 8.7 Hz, CH2O), 6.82 (d, 1H, J = 8.3 Hz, Ar-), 7.31 (d, 1H, J = 15.6 Hz, CH=), 7.41–7.61 (m, 5H,
13
Ar-), 7.79 (d, 1H, J = 15.6 Hz, Ar-), 8.01 (dd, 2H, J = 1.6, 8.5 Hz, Ar-) ppm; C-NMR (CDCl3,
75 MHz): δ= 29.1, 71.8, 109.7, 118.9, 124.8, 127.6, 128.1, 128.2, 128.4, 130.0, 132.4, 138.4, 145.1,
162.5, 190.4 ppm. HRMS (ESI+): m/z calcd for C17H14O2 [M + Na]+ 273.0891; found 273.0891.
(E)-3-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-prop-2-en-1-one (2j) [45]. Yellow powder,
64% yield, m.p. = 82–84 °C; 1H-NMR (CDCl3, 300 MHz): δ = 4.30 (m, 4H, OCH2CH2O), 6.90 (d, 1H,
J = 8.2 Hz, Ar-), 7.14–7.20 (m, 2H, Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.47–7.6 (m, 3H, Ar-), 7.71
13
(d, 1H, J = 15.6 Hz, CH=), 8.00 (dd, 2H, J = 1.6, 8.5 Hz, Ar-) ppm; C-NMR (CDCl3, 75 MHz):
δ = 64.2, 64.6, 116.7, 117.0, 117.8, 120.4, 121.2, 122.6, 128.0, 128.4, 128.6, 132.6, 138.5, 143.8,
144.6, 146.0, 190.5 ppm; HRMS (ESI+): m/z calcd for C17H14O3 [M + Na]+ 289.0841; found 289.0841.
(E)-1-(4-Bromophenyl)-3-(4-dimethylamino)phenylprop-2-en-1-one (2k) [46]. Pale yellow powder,
1
60% yield, m.p. = 140–142 °C; H-NMR (CDCl3, 300 MHz): δ = 3.07 (s, 6H, N(CH3)2), 6.72 (d, 2H,
J = 8.7 Hz, Ar-), 7.30 (d, 1H, J = 15.4 Hz, CH=), 7.54 (d, 2H, J = 8.7 Hz, Ar-), 7.62 (d, 2H, J = 8.7 Hz,
Ar-), 7.74 (d, 1H, J = 15.4 Hz, CH=), 7.89 (d, 2H, J = 8.7 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz):
δ = 40.1, 111.8, 116.2, 122.4, 127.1, 129.9, 130.6, 131.7, 137.9, 146.4, 152.2, 189.4 ppm; HRMS
(ESI+): m/z calcd for C17H16BrNO [M + Na]+ 352.0313; found 352.0314.
(E)-1-(4-Bromophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (2l) [46]. Pale cream powder, 59% yield,
1
m.p. = 148–150 °C; H-NMR (CDCl3, 300 MHz): δ = 3.88 (s, 3H, OCH3), 6.97 (d, 2H, J = 8.8 Hz,
Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.63 (d, 2H, J = 8.8 Hz, Ar-), 7.66 (d, 2H, J = 8.6 Hz, Ar-), 7.82
(d, 1H, J = 15.6 Hz, CH=), 7.90 (d, 2H, J = 8.6 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.7,
114.7, 119.3, 127.6, 127.8, 130.2, 130.6, 132.1, 137.4, 145.5, 162.1, 189.6 ppm; HRMS (ESI+): m/z
calcd for C16H13BrO2 [M + Na]+ 338.9997; found 338.9997.
(E)-3-(4-Methoxyphenyl)-1-(4-nitrophenyl)prop-2-en-1-one (2m) [43]. Yellow powder, 65% yield,
1
m.p. = 183–185 °C; H-NMR (CDCl3, 300 MHz): δ = 3.89 (s, 3H, OCH3), 6.97 (d, 2H, J = 8.7 Hz,
Ar-), 7.37 (d, 1H, J = 15.6 Hz, CH=), 7.64 (d, 2H, J = 8.7 Hz, Ar-), 7.84 (d, 1H, J = 15.6 Hz, CH=),
8.14 (d, 2H, J = 8.9 Hz, Ar-), 8.36 (d, 2H, J = 8.9 Hz, Ar-) ppm; 13C-NMR (CDCl3, 75 MHz): δ = 55.5,
114.6, 118.9, 123.9, 127.0, 129.3, 130.5, 143.5, 146.7, 149.9, 162.3, 189.1 ppm. HRMS (ESI+): m/z
calcd for C16H13NO4 [M + Na]+ 306.0742; found 306.0742.
Methyl (E)-4-(3-(4-bromophenyl)acryloyl)benzoate (2n). Pale yellow powder, 62% yield,
1
m.p. = 212–214 °C; H-NMR (CDCl3, 300 MHz): δ = 3.96 (s, 3H, OCH3), 7.40–7.51 (m, 5H, CH=,
Ar-), 7.68 (d, 1H, J = 15.7 Hz, CH=), 7.97 (d, 2H, J = 8.5 Hz, Ar-), 8.10 (d, 2H, J = 8.5 Hz, Ar-) ppm;
13C-NMR (CDCl3, 75 MHz): δ = 52.5, 122.3, 125.2, 128.1, 128.4, 129.9, 132.3, 133.5, 133.7, 141.4,
144.3, 189.8 ppm. HRMS (ESI+): m/z calcd for C17H13BrO3 [M + Na]+ 366.9946; found 366.9946.
Methyl (E)-4-(3-(4-dimethylamino)phenyl)acryloyl)-benzoate (2o). Orange powder, 58% yield,
m.p. = 164–166 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.10 (s, 3H, N(CH3)2), 3.96 (s, 3H, OCH3), 6.71

Molecules 2015, 20
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(d, 2H, J = 8.8 Hz, Ar-), 7.30 (d, 1H, J = 15.5 Hz, CH=), 7.55 (d, 2H, J = 8.8 Hz, Ar-), 7.79 (d, 1H,
J = 15.5 Hz, CH=), 8.02 (d, 2H, J = 8.6 Hz, Ar-), 8.14 (d, 2H, J = 8.6 Hz, Ar-) ppm; 13C-NMR (CDCl3,
75 MHz): δ = 40.0, 52.3, 111.7, 116.4, 122.2, 128.1, 129.6, 130.6, 132.8, 142.6, 146.8, 152.2, 166.4,
190.0 ppm. HRMS (ESI+): m/z calcd for C19H19NO3 [M + Na]+ 322.1263; found 322.1262.
Methyl (E)-4-(3-methoxyphenyl)acryloyl)-benzoate (2p). Pale yellow powder, 57% yield,
m.p. = 144–146 °C; 1H-NMR (CDCl3, 300 MHz): δ = 3.83 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 6.94 (d,
2H, J = 8.7 Hz, Ar-), 7.38 (d, 1H, J = 15.6 Hz, CH=), 7.61 (d, 2H, J = 8.7 Hz, Ar-), 7.79 (d, 1H,
J = 15.6 Hz, CH=), 8.03 (d, 2H, J = 8.4 Hz, Ar-), 8.15 (d, 2H, J = 8.4 Hz, Ar-) ppm; 13C-NMR (CDCl3,
75 MHz): δ = 52.3, 55.3, 114.3, 119.4, 127.2, 128.1, 129.6, 130.3, 133.1, 141.8, 145.5, 161.8, 166.2,
190.0 ppm; HRMS (ESI+): m/z calcd for C18H16O4 [M + Na]+ 319.0946; found 319.0945.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxo-imidazolidin-4-one (3a) [47]. Yellow powder,
1
75% yield, m.p. ≥ 260 °C; H-NMR (DMSO-d6, 300 MHz): δ = 6.09 (s, 2H, OCH2O), 6.43 (s, 1H,
CH=), 6.97 (d, 1H, J = 8.1 Hz, Ar-), 7.27 (d, 1H, J = 8.1 Hz, Ar-), 7.44 (s, 1H, Ar-), 12.08 (br s, 1H,
NH), 12.31 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz): δ = 102.1, 109.2, 109.7, 112.6, 126.5,
126.7, 126.9, 148.4, 148.9, 166.2, 179.1 ppm; HRMS (ESI+): m/z calcd for C11H8N2O3S [M + Na]+
271.0153; found 271.0152.
(Z)-5-(4-Methoxybenzylidene)-2-thioxoimidazolidin-4-one (3b) [48]. Yellow powder, 67% yield,
m.p. = 211–213 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.81 (s, 3H, OCH3), 6.47 (s, 1H, CH=), 6.98
(d, 2H, J = 8.8 Hz, Ar-), 7.74 (d, 2H, J = 8.8 Hz), 12.07 (br s, 1H, NH), 12.30 (s, 1H, NH) ppm;
13C-NMR (DMSO-d6, 75 MHz): δ = 55.4, 113.9, 114.4, 124.0, 124.7, 127.4, 128.3, 132.3, 160.4,
163.9, 177.9 ppm; HRMS (ESI+): m/z calcd for C11H10N2O2S [M + Na]+ 257.0361; found 257.0361.
(Z)-5-(4-Methoxybenzylidene)imidazolidine-2,4-dione (3c) [38]. Yellow powder, 49% yield,
m.p. = 202–204 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.79 (s, 3H, OCH3), 6.38 (s, 1H, CH=), 6.95
(d, 2H, J = 8.8 Hz, Ar-), 7.58 (d, 2H, J = 8.8 Hz, Ar-), 10.42 (br s, 1H, NH), 11.16 (br s, 1H, NH) ppm;
13C-NMR (DMSO-d6, 75 MHz): δ = 55.2, 108.6, 114.1, 125.4, 131.0, 155.6, 159.4, 165.5, 173.9 ppm;
HRMS (ESI+): m/z calcd for C11H10N2O3 [M + Na]+ 241.0589; found 241.0591.
(Z)-5-(4-Methoxybenzylidene)-2-thioxothiazolidin-4-one (3d) [38]. Yellow powder, 90% yield,
m.p. = 263–265 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.84 (s, 3H, OCH3), 7.11 (d, 2H, J = 8.7 Hz,
Ar-), 7.57 (d, 2H, J = 8.7 Hz, Ar-), 7.60 (s, 1H, CH=), 13.75 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6,
75 MHz): δ = 55.4, 114.9, 124.9, 125.8, 129.7, 132.2, 160.8, 172.9, 197.2 ppm; HRMS (ESI+): m/z
calcd for C11H9NO2S2 [M + Na]+ 273.9972; found 273.9972.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-thioxo-thiazolidin-4-one (3e) [49]. Yellow powder, 95%
yield, m.p. = 248–250 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 6.13 (s, 2H, OCH2O), 7.11 (m, 3H, Ar-),
13
7.54 (s, 1H, CH=), 13.74 (br s, 1H, NH) ppm; C-NMR (DMSO-d6, 75 MHz): δ = 102.5, 109.6,
121.4, 126.3, 127.6, 132.4, 148.6, 149.7, 167.8, 195.3 ppm; HRMS (ESI+): m/z calcd for C11H7NO3S2
[M + Na]+ 287.9765; found 287.9765.

Molecules 2015, 20
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(Z)-5-(4-Chlorobenzylidene)-2-thioxothiazolidin-4-one (3f) [50]. Pale orange powder, 91% yield,
1
m.p. = 230–232 °C; H-NMR (DMSO-d6, 300 MHz): δ = 7.60–7.64 (m, 5H, CH=, Ar-), 13.89 (br s,
13
1H, NH) ppm; C-NMR (DMSO-d6, 75 MHz): δ = 126.2, 129.5, 130.1, 131.8, 132.0, 135.3, 169.3,
195.4 ppm; HRMS (ESI+): m/z calcd for C10H6ClNOS2 [M + Na]+ 277.9477; found 277.9476.
(Z)-5-(4-(Dimethylamino)benzylidene)-2-thioxo-thiazolidin-4-one (3g) [51]. Orange powder, 90%
1
yield, m.p. = 270–272 °C; H-NMR (DMSO-d6, 300 MHz): δ = 3.04 (s, 6H, N(CH3)2), 6.83 (d, 2H,
J = 8.7 Hz, Ar-), 7.43 (d, 2H, J = 8.7 Hz, Ar-), 7.54 (s, 1H, CH=), 13.59 (br s, 1H, NH) ppm;
13C-NMR (DMSO-d6, 75 MHz): δ = 40.3, 112.5, 117.7, 120.1, 133.3, 133.7, 152.1, 169.8, 195.4 ppm;
HRMS (ESI+): m/z calcd for C12H12N2OS2 [M + Na]+ 287.0289; found 287.0287.
(Z)-5-(4-Nitrobenzylidene)-2-thioxothiazolidin-4-one (3h) [52]. Yellow powder, 93% yield,
m.p. = 254–256 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 7.75 (s, 1H, CH=), 7.87 (d, 2H, J = 8.6 Hz,
13
Ar-), 8.35 (d, 2H, J = 8.6 Hz, Ar-), 14.03 (br s, 1H, NH) ppm; C-NMR (DMSO-d6, 75 MHz):
δ = 124.7, 128.7, 130.3, 131.7, 139.6, 147.9, 169.6, 196.7 ppm; HRMS (ESI+): m/z calcd for
C10H6N2O3S2 [M + Na]+ 288.9718; found 288.9719.
(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-2-thioxothiazolidin-4-one (3i) [38]. Yellow powder, 79% yield,
m.p. = 228–230 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.85 (s, 3H, OCH3), 6.94–7.17 (m, 3H, Ar-),
13
7.60 (s, 1H, CH=), 10.13 (br s, 1H, OH), 13.75 (br s, 1H, NH) ppm; C-NMR (DMSO-d6, 75 MHz):
δ = 56.1, 114.8, 116.8, 121.6, 124.8, 125.5, 133.2, 148.6, 150.4, 169.9, 195.9 ppm; HRMS (ESI+): m/z
calcd for C11H9NO3S2 [M + Na]+ 299.9922; found 299.9923.
(Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione (3j) [53]. Yellow powder, 44% yield,
m.p. = 214–216 °C; 1H-NMR (DMSO-d6, 300 MHz): δ = 3.22 (s, 3H, OCH3), 7.10 (d, 2H, J = 8.7 Hz,
Ar-), 7.56 (d, 2H, J = 8.7 Hz, Ar-), 7.75 (s, 1H, CH=), 12.51 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6,
75 MHz): δ = 55.5, 114.9, 125.6, 131.6, 132.0, 160.9, 168.1, 168.3 ppm; HRMS (ESI+): m/z calcd for
C11H9NO3S [M + Na]+ 258.0211; found 258.0212.
(Z)-5-(4-Benzilydene-4-boronic acid)-2-thioxo-imidazolidin-4-one (4). Pale Brown powder, 65% yield,
1
m.p. = 242–244 °C; H-NMR (DMSO-d6, 300 MHz): δ = 7.54 (d, 2H, J = 8.1 Hz, Ar-), 7.62 (s, 1H,
CH=), 7.91 (d, 2H, J = 8.1 Hz, Ar-), 13.85 (s, 1H, NH) ppm; 13C-NMR (DMSO-d6, 75 MHz):
δ = 126.3, 129.8, 132.1, 134.7, 135.4, 169.8, 196.2 ppm (Carbon atoms in α to boron are often
non visible in 13C-NMR); 11B NMR (96 MHz, DMSO-d6): 28.30; HRMS (ESI+): m/z calcd for
C10H8BNO3S2 [M + Na]+ 287.9936; found 287.9939.
(E)-1-(4-Methoxyphenyl)-3-phenylprop-2-en-1-one (5) [40]. Pale yellow powder, 50% yield,
1
m.p. = 106–108 °C; H-NMR (CDCl3, 300 MHz): δ = 3.90 (s, 3H, OCH3), 6.98 (d, 2H, J = 8.8 Hz,
Ar-), 7.40–7.45 (m, 3H, Ar-), 7.55 (d, 1H, J = 15.7 Hz, CH=), 7.62–7.64 (m, 2H, Ar-), 7.80 (d, 1H,
13
J = 15.7 Hz, CH=), 8.03 (d, 2H, J = 8.8 Hz, Ar-) ppm; C-NMR (CDCl3, 75 MHz): δ = 55.5, 113.8,
121.9, 128.2, 128.3, 128.9, 130.3, 130.8, 144.0, 163.4, 188.8 ppm. HRMS (ESI+): m/z calcd for
C16H14O2 [M + Na]+ 261.0891; found 261.0892.

Molecules 2015, 20
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4. Conclusions
We described here an environmentally friendly protocol under microwave irradiation conditions for
the preparation of several condensation products. The reaction time is short and non-toxic and cheap
boric acid is employed as catalyst. These conditions can be considered as an alternative method to
those traditionally described by their compatibility to base-sensitive functional groups. Our preliminary
attempts to develop an auto-catalyzed reaction with a substrate bearing a boronic acid function have
partly failed. Work is ongoing in our laboratory.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/06/11617/s1.
Acknowledgments
We are grateful to the University of Rennes 1 and CNRS for their financial support. Thanks to
Ludovic Paquin for his help concerning the use of the microwave apparatus. We are thankful to
Laurent Meijer (Manros Therapeutics) for continuous support.
Author Contributions
E.B., A.S., K.B., J.-M.L. performed the experiments. J.-P.B., J.M.V. and F.C. designed research and
analyzed the data. F.C. wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2c–f, 2j–l, 2o–p, 3b,d,j are available from the authors.
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