Montmorillonite clay-promoted, solvent-free cross-aldol condensations under focused microwave irradiation

Article abstract of DOI:10.3390/molecules19067317

An environmentally benign, clean and general protocol was developed for the synthesis of aryl and heteroaryl trans-chalcones. This method involved solvent-free reaction conditions under microwave irradiation in the presence of a clay-based catalyst, and afforded the target compounds in good yields and short reaction times. Furthermore, the same conditions allowed the synthesis of symmetrical, diarylmethylene-a,a-unsaturated ketones from aromatic aldehydes and ketones.

Full text of DOI:10.3390/molecules19067317

Molecules 2014, 19, 7317-7326; doi:10.3390/molecules19067317
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Montmorillonite Clay-Promoted, Solvent-Free Cross-Aldol
Condensations under Focused Microwave Irradiation
Damiano Rocchi, Juan F. González and J. Carlos Menéndez *
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense,
Madrid 28040, Spain; E-Mails: rocchid83@gmail.com (D.R.); juanfrangn@ucm.es (J.F.G.)
* Author to whom correspondence should be addressed; E-Mail: josecm@ucm.es;
Tel.: +34-91-394-1840; Fax: +34-91-394-1822.
Received: 27 March 2014; in revised form: 14 May 2014 / Accepted: 26 May 2014 /
Published: 4 June 2014
Abstract: An environmentally benign, clean and general protocol was developed for the
synthesis of aryl and heteroaryl trans-chalcones. This method involved solvent-free
reaction conditions under microwave irradiation in the presence of a clay-based catalyst,
and afforded the target compounds in good yields and short reaction times. Furthermore,
the same conditions allowed the synthesis of symmetrical, diarylmethylene-α,β-unsaturated
ketones from aromatic aldehydes and ketones.
Keywords: heterogenous catalysis; clays as catalysts; Lewis acids; condensation reactions;
green chemistry; aldehydes; enones
1. Introduction
Chalcones (trans-1,3-diaryl-2-propen-1-ones) are a very important class of compounds due to
their occurrence in Nature and their interesting and versatile pharmacological properties, as summarized
in several reviews [1–5]. These properties include antineoplastic [5–7], antimalarial [8], antiviral
(HIV) [9,10], antibacterial [4,11,12], antioxidant [12] and anti-inflammatory [4,13] activities, among
others. These compounds are also flexible scaffolds for the construction of five- and six-membered
rings or their subsequent elaboration into polycyclic systems [14,15]. Chalcones are traditionally
accessed by cross-aldol condensations of aryl methyl ketones and aromatic aldehydes in the presence
of alkali [16–18], a reaction that requires the use of an organic solvent and a highly polluting alkaline
base and in most cases needs to be followed by purification by column chromatography, leading

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again to waste generation in the form of volatile organic solvents and discarded chromatographic
stationary phases.
Economic and environmental concerns connected to the practice of organic synthesis have received
especial attention in recent years. In this context, a particularly important area is the development of
synthetic processes in the absence of solvents [19–22]. Microwave-assisted organic synthesis (MAOS)
has emerged as an efficient and powerful tool in this area [23–28] and often leads to simple protocols,
short processing times, increased product yields, energy savings [29] and lower costs, thereby enabling
environmentally friendly processes [30]. On the other hand, methods based on the use of
heterogeneous catalysts are widely used in industrial fine and pharmaceutical chemistry, and play an
important role in the current bid for the development of green synthetic processes. In particular, there
is much interest in the use of clays as solid acid catalysts because of their desirable properties such as
environmental compatibility, non-corrosive and non-toxic nature, low cost and, furthermore, because
they often allow very simple isolation procedures. To summarize, heterogeneous catalysis is crucial to
chemical technology, and clays in particular are finding increasing applications as catalysts [31–34].
In this paper, we describe a method that combines the desirable features of both approaches and its
application to the preparation of chalcones. The need for this research became apparent in the course of
our program on the use of aryl and heteroaryl trans-chalcones in heterocyclic synthesis [35–38], when
we noticed the shortcomings of the currently available protocols for the synthesis of the required
starting materials. Thus, we present here our studies on a solvent-free protocol for their synthesis under
microwave irradiation conditions in the presence of a montmorillonite clay catalyst, its application to a
large number of examples in order to establish its scope and a brief study of its subsequent
generalization to other types of substrates.
2. Results and Discussion
We started our study by examining the model cross aldol condensation reaction between
acetophenone (1a) and benzaldehyde (2a) at a relatively large scale (8.6 mmol) in the presence of
montmorillonite KSF (MKSF). The choice of catalyst was based on literature precedent for the thermal
cross-condensation of acetophenone and benzaldehyde in the presence of clay although we were
concerned about its generality, since the scope of this literature method was quite narrow [39]. Thus,
we set out to optimize conditions for this model reaction by varying the following experimental
parameters: temperature, time, stoichiometry, and amount of clay. In order to study the influence of
temperature, an equimolecular mixture of 1a and 2a with 0.3 g/mol of the clay catalyst was irradiated
under focused microwave for 1 hour. When the reaction mixture was heated at 100 °C or 120 °C, poor
conversions were observed (Table 1, entries 1 and 2), but a further increase in the reaction temperature
to 150 °C afforded chalcone 3a in a very good 88% yield (Table 1, entry 3). The next parameter that
we investigated was the amount of catalyst, and to this end we performed the reaction with an
equimolecular mixture of 1a and 2a, for 1 hour at 150 °C, in the presence of MKSF 0.06, 0.12, 0.24
and 0.30 gram of clay per mol of 1a. These experiments led us to select 0.24 g/mol as the optimal
clay/substrate ratio (Table 1, entries 5 to 8). Under these conditions, reaction times below 1 h (entries 9
and 10) proved to be detrimental to conversion and were therefore avoided in further experiments.
We also observed that an increase of the 1a/2a ratio led to decreased yield (Table 1, entry 11). When

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the reaction was carried out in a multigram scale, an increase in the temperature was required in order
to obtain chalcone 3a in a good yield (Table 1, entry 12). Finally, in order to compare the performance
of microwave irradiation versus conventional heating, the reaction was performed at 150 °C in an oil
bath using the optimal 1a/2a ratio and amount of clay. In this experiment, a very long reaction time
(20 h) was needed for the reaction to achieve completion, and 3a was isolated in a poor 16% yield,
together with many unidentified by-products (Table 1, entry 13). To summarize these experiments, it
can be concluded that focused microwave irradiation has a highly beneficial effect on the reaction,
both in terms of yields and reaction times.
Table 1. Optimization of the synthesis of model chalcone 3a.
O
3a
KSF/substrate
Entry
1a/2a
T (°C)
Time
Yield (%) a
ratio (g/mol)
0.30
1
2
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
2/1
1/1
1/1
100 °C
120 °C
150 °C
160 °C
150 °C
150 °C
150 °C
150 °C
150 °C
150 °C
150 °C
160 °C
150 °C
60 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
40 min
20 min
60 min
60 min
20 h
8
23
88
88
5
0.30
3
0.30
4
0.30
5
0.06
6
0.12
81
97
88
74
50
86
78 b
16 c
7
0.24
8
0.30
9
0.24
10
11
12
13
0.24
0.24
0.24
0.29
a
Isolated yields, when the reaction was performed under microwave irradiation at 0.86 mmol scale, except
b
where noted otherwise; Isolated yields, when the reaction was performed under microwave irradiation in a
30 mmol scale; c Isolated yield under reflux conditions.
The substrate scope of the cross aldol condensation reaction in the presence of the MKSF clay catalyst
was explored with a variety of substituted acetophenone substrates containing either electron donating or
electron withdrawing groups, with the results shown in Scheme 1 and Table 2. As expected,
the presence of electron-releasing substituents in the acetophenone component, which acts as the
nucleophile, is slightly beneficial to yield (compare, for instance, the yields in entries 1, 10, 19, 23 and 26).
The reaction was not sensitive to steric hindrance in the aldehyde, since it tolerates well the presence
of ortho substituents (compare the yields in entries 4–5, 7–9 and 15–16). Generally speaking, the
substituents at the aromatic ring of the aldehyde component did not have a significant influence
in the yield, but it is remarkable that some of the best results corresponded to reactions with
methoxybenzaldehyde derivatives (entries 2, 11, 15, 20), in spite of the fact that the electron-releasing
nature of the methoxy substituent should lead to a lower reactivity as electrophiles.

Molecules 2014, 19
Scheme 1. Clay-promoted synthesis of chalcones under microwave irradiation.
7320
MKSF 0.24 g/mol,
MW, 150 °C, 1h or
170 °C, 3 h
O
H
O
+
Ar1
CH3
O
Ar2
Ar1
Ar2
Solvent-free
3
2
1
Table 2. Scope and yields in the synthesis of chalcones 3.
Entry
1
Ar1
Ar2
Compound
3a
Yield (%) a
97
C6H5
C6H5
2
C6H5
4-MeOC6H4
4-MeC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
C6H5
3b
85
3
C6H5
3c
55
4
C6H5
3d
74
5
C6H5
3e
77
6
C6H5
3f
69
7
C6H5
3g
51
8
C6H5
3h
44
9
C6H5
3i
43 (57) b
91
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
3j
4-MeOC6H4
4-BrC6H4
C6H5
3k
83
3l
73
3m
3n
95
4-NO2C6H4
2-MeOC6H4
4-MeC6H4
4-BrC6H4
2-NO2C6H4
C6H5
55
3o
93
3p
77
3q
76
3r
66
3s
54
3-OMeC6H4
4-BrC6H4
2-NO2C6H4
C6H5
3t
78
3u
64
3v
48
3w
3x
60
4-BrC6H4
4-NO2C6H4
C6H5
86
3y
49
3z
65 c
64 c
77 c
68 c
60 c
4-OMeC6H4
4-MeC6H4
4-BrC6H4
4-NO2C6H4
3aa
3ab
3ac
3ad
31
32
33
34
C6H5
C6H5
3ae
3af
3ag
3ah
57
63
54
64
4-MeC6H4
4-MeC6H4

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Table 2. Cont.
Entry
Ar1
4-BrC6H4
C6H5
Ar2
Compound
Yield (%) a
35
3ai
48
36
37
38
39
40
41
42
3aj
3ak
3al
85
60
97
45
54
78
92
C6H5
2-NO2C6H4
C6H5
3am
3an
3ao
3ap
C6H5
a
General reaction conditions: A mixture of aldehyde 2 (0.86 mmol), ketone 1 (0.86 mmol) and MKSF
b
(200 mg) in a sealed tube, was heated under microwave irradiation at 150 °C for 1 h; Reaction conditions
for the reaction proceeding in 57% yield: 170 °C, 3 h; c Reaction conditions for entries 26–30: A mixture of
aldehyde 2 (0.86 mmol), ketone 1 (0.86 mmol) and MKSF (200 mg) in a sealed tube, was heated under
microwave irradiation at 170 °C for 3 h.
Since the catalytic affect of the clay can be attributed to the Lewis acid activity of its metallic
centers (Scheme 2a), the good reactivity of the methoxy derivatives can be explained by accepting that
coordination of the oxygen atom in the OMe group with cationic centers in the clay attenuates its
electron-releasing effect (Scheme 2b) [40]. Another special case was that of nitrobenzaldehyde
derivatives which, again unexpectedly, gave relatively low yields (entries 7, 8, 9, 13, 18, 22, 25, 30–35).
In this case, we propose that the lower reactivity is due to an increased activation energy associated to
stabilizing interactions of the aldehyde with the clay by coordinating two of the cationic centers
(Scheme 2c). In agreement to this explanation, we found an increase in yield from 43% to 57% for the
case of compound 3i when changing the conditions from 150 °C, 1 h to 170 °C, 3 h (enthy 9).
Unfortunately, higher temperatures could not be used because they led to the decomposition of
p-nitrobenzaldehyde. Finally, in order to demonstrate the wide application of this methodology, the
reaction was carried out with selected examples of heteroaromatic aldehydes and ketones, to give good
yields of compounds 3aj to 3ap (entries 36–42).
Scheme 2. Explanation proposed for the observed substituent effects on yield.
c)
b)
a)
Clay
Clay
Clay
Mn+
Mn+
Mn+
OH
OH
OH
O
O
O
Mn+
O
H3C
O
N
Mn+
O Mn+

Molecules 2014, 19
7322
In order to further demonstrate the generality of this methodology, the pseudo three-component,
double aldol reactions of representative aliphatic ketones with two equivalents of benzaldehyde were
briefly examined under the optimal microwave conditions previously developed, leading to
compounds 5–7 in good to excellent yields. Also, one example of a Knoevenagel reaction was carried
out, affording compound 8 [41] in an excellent 92% yield (Scheme 3).
Scheme 3. Additional examples showing the generality of the clay-promoted condensations.
PhCHO
MKSF 0.24 g/mol
O
O
MWI, 150 ˚C, 1h
5, 92 %
PhCHO
MKSF 0.24 g/mol
O
O
MWI, 150 ˚C, 2.5 h
6, 86 %
PhCHO
MKSF 0.24 g/mol
MWI, 150 ˚C, 1h
O
O
N
N
CH3
CH3
7, 74%
PhCHO
MKSF 0.24 g/mol
MWI, 150 ˚C, 2 h
O
O
O
O
H3C
CH3
H3C
CH3
8, 92%
3. Experimental Section
3.1. General Information
Melting points were measured in open capillary tubes and are uncorrected. A CEM Discover
focused microwave synthesizer with a maximum microwave power level of 400 W and microwave
1
frequency of 2,444 MHz was employed. The H-NMR and 13C-NMR spectra were recorded on a
Bruker (Avance) 250 MHz NMR instrument maintained by the CAI de Resonancia Magnética,
Universidad Complutense, using unless indicated otherwise CDCl3 as solvent and the residual CHCl3
as reference. Chemical shifts are given in parts per million (δ scale) and the coupling constants are
given in Hertz. Silica gel-G plates (Merck) were used for TLC analysis. Elemental analyses were
measured by the CAI de Microanálisis Elemental, Universidad Complutense, on a Leco 932 CHNS
analyser. IR spectra were recorded on a Perkin Elmer Paragon 1000 FT IR instrument (neat samples on
a NaCl window). Montmorillonite KSF (product number 28,153-0) was purchased from Sigma-Aldrich
(Madrid, Spain) and used as received. This particular clay has 20–25 μm particle size and a surface
area of 20–40 m2/g.

Molecules 2014, 19
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3.2. General Procedure for Cross Aldol Condensations
A mixture of the suitable aldehyde (1.0 mmol), acetophenone (1.0 mmol) and clay catalyst
(240 mg) was warmed at 150 °C in a sealed tube under microwave irradiation, for 1 h. In the reactions
involving solid starting materials, they were thoroughly mixed by grinding in a mortar before
irradiation. The reaction mixture was diluted with hot ethanol (20 mL), the catalyst was filtered off, the
solvent was evaporated and the residue was purified by crystallization (EtOH) for solid chalcones
(compounds 3a–3d, 3f–3m, 3p–3ar) or by column chromatography (silica gel, ethyl acetate/hexanes)
for oily chalcones (compounds 3e, 3o), to afford the pure final products. All yields were calculated
from isolated products. Characterization data for previously unknown compounds are given below. For
full characterization data, see the Supporting Information.
(E)-3-(5-Bromo-2-nitrophenyl)-1-(p-tolyl)-2-propen-1-one (3ag). White solid (54%). M.p. 164–166 °C.
IR νmax (KBr): 1663, 1598, 1520 cm−1. 1H-NMR δ: 8.08 (1H, d, J = 15.7 Hz), 8.00–7.83 (4H, m), 7.68
13
(1H, dd, J = 9.0, 2.8 Hz), 7.32 (3H, m), 2.45 (3H, s). C-NMR δ: 189.6, 147.2, 144.5, 138.5, 134.8,
133.6, 133.3, 132.3, 129.7, 129.1, 128.6, 128.3, 126.7, 21.9. Anal. Calcd. for C16H12BrNO3: C, 55.51;
H, 3.49; N, 4.05. Found: C, 55.28; H, 3.21 N, 3.95.
(E)-3-(4,5-Dimethoxy-2-nitrophenyl)-1-(p-tolyl)-2-propen-1-one (3ah). White solid (64%). M.p.
1
180–182 °C. H-NMR δ 8.20 (d, J = 15.7 Hz, 1H), 7.97–7.91 (m, 2H), 7.67 (s, 1H), 7.36–7.29 (m,
2H), 7.20 (d, J = 15.7 Hz, 1H), 7.07 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H), 2.45 (s, 3H). 13C-NMR δ 190.8,
153.3, 150.0, 144.0, 141.4, 141.1, 135.0, 129.5, 129.1, 126.7, 126.2, 110.2, 108.1, 56.7, 56.6, 21.8.
Anal. Calcd. for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C, 59.93; H, 5.09; N, 4.15.
(E)-3-(5-Bromo-2-nitrophenyl)-1-(4-bromophenyl)-2-propen-1-one (3ai). White solid (48%). M.p.
191–193 °C. 1H-NMR, DMSO-d6) δ: 8.49 (1H, d, J = 2.7 Hz), 8.16 (2H, d, J = 9.0 Hz), 8.05 (1H, d, J
= 9.0 Hz), 7.98 (2H, d, J = 3.8 Hz), 7.92 (1H, dd, J = 9.0, 2.7 Hz), 7.82 (2H, d, J = 9.0 Hz). 13C-NMR (63
13
MHz, DMSO-d6) δ: C-NMR (63 MHz, DMSO) δ 188.0, 147.8, 137.7, 135.9, 133.7, 132.0, 131.8,
130.9, 127.9, 127.6, 126.9, 126.8. Anal. Calcd. for C15H9Br2NO3: C, 43.83; H, 2.21; N, 3.41. Found:
C, 43.57; H, 2.39; N, 3.17.
4. Conclusions
In conclusion, we have developed a solvent-free, inexpensive and fast microwave-assisted method
for cross aldol condensations, catalysed by the acidic clay montmorillonite KSF, with a broad scope of
application. In comparison to previously reported methods, where strong acids or bases are normally
required, the protocol reported here constitutes a user- and environment-friendly alternative that
proceeds normally in good to excellent yields.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/6/7317/s1.

Molecules 2014, 19
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Acknowledgments
Financial support from Ministerio de Economía y Competitividad (MINECO) is gratefully
acknowledged (grant CTQ-2012-33272-BQU).
Author Contributions
D.R., J.F.G. and J.C.M. conceived the research and designed the experiments. D.R. and J.F.G.
carried out the experiments. J.F.G. and J.C.M. wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds described in this paper are available from the authors.
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