Multicomponent Cascade Synthesis of Biaryl-Based Chalcones in Pure Water and in an Aqueous Micellar Environment

Article abstract of DOI:10.1002/ejoc.201600095

The challenging multicomponent cascade synthesis of biaryl-based chalcones was carried out in pure water and in an aqueous micellar system. The first step of the protocol was a simple Pd-catalysed, ligand-free, and aerobic Suzuki–Miyaura reaction in aqueous medium. This proved to be extremely efficient for the coupling of aryl and heteroaryl bromides with different arylboronic acids. Subsequently, the resulting intermediates underwent an in-situ aldol condensation reaction to give biaryl(hetero)chalcones in good to excellent yields. When the protocol was applied to highly lipophilic or less reactive reagents, micellar catalysis was required for good results. To achieve this, we successfully used a new surfactant obtained from renewable resources that we recently designed. Furthermore, using this additive, the catalytic system can be repeatedly recycled without significant loss of activity.

Full text of DOI:10.1002/ejoc.201600095

DOI: 10.1002/ejoc.201600095
Full Paper
Multicomponent Reactions
Multicomponent Cascade Synthesis of Biaryl-Based Chalcones in
Pure Water and in an Aqueous Micellar Environment
Nicola Armenise,*[a] Danilo Malferrari,[b] Sara Ricciardulli,[a] Paola Galletti,[a,b] and
Emilio Tagliavini[a,b]
Dedicated to Professor Achille Umani-Ronchi in occasion of his 80th birthday.
Abstract: The challenging multicomponent cascade synthesis biaryl(hetero)chalcones in good to excellent yields. When the
of biaryl-based chalcones was carried out in pure water and in
an aqueous micellar system. The first step of the protocol was
a simple Pd-catalysed, ligand-free, and aerobic Suzuki–Miyaura
reaction in aqueous medium. This proved to be extremely effi-
cient for the coupling of aryl and heteroaryl bromides with dif-
ferent arylboronic acids. Subsequently, the resulting intermedi-
ates underwent an in-situ aldol condensation reaction to give
protocol was applied to highly lipophilic or less reactive rea-
gents, micellar catalysis was required for good results. To
achieve this, we successfully used a new surfactant obtained
from renewable resources that we recently designed. Further-
more, using this additive, the catalytic system can be repeatedly
recycled without significant loss of activity.
Introduction
Multicomponent reactions (MCRs) allow several chemical
bonds to be generated in a single synthetic operation, and offer
notable advantages such as convergence, operational simplic-
ity, and a decrease of the number of work-up and purification
steps, thus minimizing the generation of waste. Generally, one-
pot MCRs decrease the overall reaction time, and give higher
yields than standard multistep syntheses. MCRs are useful for
the development of libraries of potential drugs and lead com-
pounds with high levels of molecular complexity and diversity.
Therefore, the design of new MCRs that can be run in water[6]
has attracted great attention, especially in the areas of drug
discovery and materials science.
From an environmental point of view, the massive use of sol-
vents is highly concerning, since it gives rise to toxicity, hazard,
and pollution issues. Moreover, solvents generally account for
the major source of waste mass in chemical processes or syn-
thetic routes.[1] Consequently, much effort has been put into
the search for sustainable reaction media.[2] In this context, the
use of water as solvent has attracted much interest in recent
years. In fact, water offers many advantages because it is a
cheap, readily available, nontoxic and nonflammable solvent.
This makes it very attractive from both an economical and an
environmental point of view.[3]
In the literature, there are a lot of examples involving a
Suzuki–Miyaura cross-coupling reaction followed by an aldol or
Knoevenagel condensation as the final steps of longer synthetic
routes. These synthetic routes are aimed towards the total syn-
thesis of different classes of natural products, such as alkaloids,
fungal metabolites, and hetero-polycyclic compounds that
show manifold biological activities.[7]
Of the organic reactions that can be conducted in water,
cross-coupling[4] and aldol condensation reactions[5] are partic-
ularly significant; moreover, these reactions can be coupled to-
gether in one-pot and sequential procedures.
The traditional multistep design of complex molecules gen-
erally involves several operations, including extraction and puri-
fication processes for each single synthetic step. This leads to
synthetic inefficiency, and also generates large amounts of
waste.
In particular, the one-pot synthesis of biarylchalcones in
aqueous medium, through sequential Suzuki–Miyaura coupling
and aldol condensation reactions, is a challenging but attractive
synthetic route. Unfortunately, the poor solubility of many sub-
strates in water, the incompatibility of some of these with differ-
ent catalysts, and the formation of ꢀ-arylated ketones as side-
products still limit the use of this strategy.[8]
[a] Department of Chemistry “G. Ciamician”,
University of Bologna,
2, Via Selmi, 40126 Bologna, Italy
E-mail: nicola.armenise2@unibo.it
www.ciam.unibo.it/greenchemistry
Chalcones are relevant natural products, and they are pivotal
intermediates in the synthesis of flavonoids and isoflavonoids.
Because of their importance, numerous procedures for their
preparation have been developed.[9] Chalcones show a wide
range of biological activities; some of them show anti-inflam-
[b] Interdepartmental Centre for Industrial Research “Energy and
Environment” (CIRI EA), University of Bologna,
163, Via S. Alberto, 48123 Ravenna, Italy
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600095.
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matory, antimicrobial (antibacterial, antifungal), antimalarial, an- micellar system, overcoming the existing drawbacks. The first
timitotic, antioxidant, and anticancer properties.
step of our protocol is a simple Pd-catalysed, ligand-free, aero-
bic Suzuki–Miyaura reaction in aqueous medium,[12] which
proved to be extremely efficient for the coupling of aryl and
heteroaryl bromides bearing a carbonyl moiety with different
arylboronic acids. In the second step, the third substrate (the
appropriate ketone or aldehyde) is added, and this then under-
goes an in situ aldol condensation reaction.
A major limitation that is sometimes encountered in this pro-
tocol comes from the poor solubility of some substrates, which
prevented good results from being obtained. We found an envi-
ronmentally sustainable solution to this issue by using a new
ionic surfactant recently developed by our group.[13] This am-
In the chalcone structure, two phenyl rings are linked to a 2-
propenone moiety; any alteration of this arrangement is known
to result in the loss of their biological activity. Therefore, the
two aromatic rings have been extensively modified by append-
ing different hydrophilic or hydrophobic substituents to give a
variety of biologically active chalcone-based compounds.[10] As
a consequence, biarylchalcones and more complex chalcone
derivatives have become important in the field of medicinal
chemistry. However, their syntheses are still carried out by two
distinct steps using water/organic cosolvents mixtures as reac-
tion media.[11]
Aiming for environmentally sustainable synthetic processes, phiphilic compound allows the system to undergo micellar ca-
in this paper we report a highly efficient protocol for the multi- talysis; furthermore, the catalytic system composed of Pd, base,
component cascade synthesis of biaryl(hetero)chalcones and water, and surfactant proved to be highly recyclable without
their functionalized derivatives, in pure water or in aqueous significant loss of activity.
Table 1. Screening of bases and catalysts for the synthesis of biarylchalcone 5aa in pure water.[a]
Entry
Catalyst
(amount)
Base
Equiv.
Conv.
[%][b]
Yield
[%][d]
4a
5aa
1
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(3 mol-%)
Pd(OAc)2
(1.5 mol-%)
Pd/C
Et3N
3
3
3
3
6
3
3
3
3
3
6
9
6
6
6
100
100
100
100
98
100
100
100
97
98
0
0
2
nPr3N
nBu3N
DMCHA
DMCHA
DMAP
DBU
0
3
0
4
3
5
0
6
59[c]
100[c]
99
0
7
5
4
8
pyrrolidine
K2CO3
KOH
56
82
96
4
35
0
9
85
10
11
12
13
14
15
100
100
100
100
100
100
4
KOH
88
(83)[e]
81
KOH
2
KOH
15
0
60
13
25
KOH
(3 wt.-%)
Pd/C
KOH
0
(4 wt.-%)
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), phenylboronic acid (2a; 0.32 mmol), Pd catalyst, base, H2O (3 mL), 80 °C, 1 h;
2) acetophenone (3a; 0.30 mmol), 80 °C, 5 h. [b] Conversion determined by GC–MS [1,3,5-tri(tert-butyl)benzene as the internal standard] is referred to 1a. [c]
For characterization of the crude reaction mixtures and identification of the by-products obtained, see the Supporting Information. [d] Yield of product 5aa
determined by GC–MS. [e] Yield of isolated 5aa.
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Results and Discussion
erated in the substrates: 4′-hydroxy-3′-methoxyacetophenone
(3b), 2-acetylfuran (3f), and 2-acetylthiophene (3g) successfully
gave the corresponding hetero-biarylchalcones (i.e., 5ab, 5af,
and 5ag, respectively) in good to excellent yields.
Optimization of Reaction Conditions
The optimal reaction conditions were determined by carrying
out a set of experiments. In a model reaction, the Suzuki cross-
coupling of 4-bromobenzaldehyde (1a; 0.27 mmol) with phen-
ylboronic acid (2a; 0.32 mmol), catalysed by Pd(OAc)2 (3 mol-
%) was carried out at 80 °C for 1 h in pure water (3 mL) to
give biphenyl-4-carbaldehyde (4a). This was followed by the
addition of acetophenone (3a; 0.30 mmol) for an in situ aldol
condensation at 80 °C for 5 h, which gave biarylchalcone 5aa
(see Table 1).
Table 2. Cascade Suzuki–aldol reaction of 4-bromobenzaldehyde and phenyl-
boronic acid with different aromatic ketones in water.[a]
Firstly, we screened different bases: tertiary amines such as
Et3N, nPr3N, nBu3N, and N,N-dimethylcyclohexylamine (DMCHA)
promoted the Suzuki coupling reaction very effectively, and re-
sulted in the quantitative formation of intermediate 4a. How-
ever, they were completely ineffective for the aldol condensa-
tion, and we did not observe the formation of the desired prod-
uct (i.e., 5aa; Table 1, entries 1–4), even when the amount of
DMCHA was increased from 3 to 6 equiv. (Table 1, entry 5).
When we moved to 4-dimethylaminopyridine (DMAP) and di-
azabicycloundecene (DBU), only by-products were formed
(Table 1, entries 6 and 7).[14] The secondary amine pyrrolidine
performed better, and the desired product (i.e., 5aa) was ob-
tained in 35 % yield (Table 1, entry 8). We realized that strong
bases were required at least to promote the aldol condensation,
and so we screened some inorganic bases. K2CO3 (3 equiv.) was
completely ineffective for this reaction (Table 1, entry 9), and
when we used 3 equiv. of KOH we obtained only 4 % of 5aa
along with 96 % of intermediate 4a (Table 1, entry 10). Increas-
ing the amount of KOH to 6 equiv. was, however, successful,
and gave 88 % of 5aa (Table 1, entry 11). Further increasing the
amount of KOH did not result in further improvements in the
yield (Table 1, entry 12). Although it is still not completely clear
why such an excess of base is required to achieve a good yield,
we are aware that 2 equiv. of KOH is consumed in the catalytic
cycle of the Suzuki cross-coupling reaction.[15] Next, we
screened different quantities and types of Pd catalysts: decreas-
ing the amount of Pd(OAc)2 from 3 to 1.5 mol-% gave a lower
yield (Table 1, entry 13). Lower yields were also obtained when
Pd/C (3 wt.-% and 4 wt.-%) was used (Table 1, entries 14 and
15). Thus, we chose Pd(OAc)2 (3 mol-%) and KOH (6 equiv.) as
the optimal conditions for the synthetic protocol.
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), phenylbor-
onic acid (2a; 0.32 mmol), Pd(OAc)2 (3 mol-%), KOH (6 equiv.), H2O (3 mL),
80 °C, 1 h; 2) aromatic ketone 3a–3i (0.30 mmol), 80 °C, 5 h. [b] Yield deter-
mined by GC–MS (internal standard). [c] KOH (7.1 equiv.) was used. [d] H2O
(2 mL) was used for 15 h in the second step.
Sharpless et al. used the term “on water” to describe the
substantial rate acceleration that is observed when some insol-
uble organic reactants are stirred in aqueous suspension.[16]
McErlean et al. recently proposed a mechanism that explains
the phenomenon of on-water catalysis.[17] The protonation of
organic substrates at the oil–water interface is driven by the
strong adsorption of hydroxide ions to the interface.[18] The pro-
tonated species can then undergo acid-catalysed reactions,
while the hydroxide ion is sequestered in a deep thermody-
namic well. It was also demonstrated that the rate of on-water
catalysis was the same in pure water and in water containing
NaCl, acid, or NaOH.
Later, we focussed on improving the greenness of the work-
up procedure. After extracting the crude reaction mixture with
ethyl acetate, we isolated pure product 5aa in very good yield
(83 %) by simple recrystallization from methanol, avoiding puri-
fication by flash chromatography.
Screening of Different Aromatic Ketones and Additives
After the optimization of the reaction conditions, we explored
Based on this new understanding of acid catalysis on water,
the scope and limitations of this protocol (Table 2). Therefore, we expected that in all cases, the rate of the aldol condensation
4-bromobenzaldehyde (1a) and phenylboronic acid (2a) were of intermediate 4a with aromatic ketones could be accelerated
coupled in water and subsequently condensed with different by carrying out the reaction as a heterogeneous suspension of
aromatic ketones 3a–3g to give biarylchalcones 5aa–5ag in organic droplets in water (the reaction conditions described by
65–93 % yield. Interestingly, several functional groups were tol- Sharpless et al. as “on water”). On the other hand, two highly
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lipophilic ketones, 2-acetonaphthone (3h) and α-tetralone (3i), pling reaction of 1a with 2a, the addition of C18-OPC had only
were poorly reactive under the optimized reaction conditions, a minor beneficial effect on the cross-coupling step, in which
and gave low yields of the expected products [i.e., 5ah (42 %) smaller and less lipophilic molecules are involved. In contrast,
and 5ai (44 %)] only at higher concentrations and after longer C18-OPC was found to be crucial for providing a suitable reac-
reaction times.
tion medium for the subsequent aldol condensation with bulky
ketone 3h.
Therefore, we tested different additives to improve the per-
formance of lipophilic ketones in the reaction (Table 3). The
Encouraged by this result, we compared our surfactant with
addition of 0.5 equiv. of each selected additive gave different Triton X-100 also in the presence of α-tetralone (3i). By using
results: we observed lower yields of 5ah, along with increased C18-OPC, we obtained 5ai in higher yield (67 %; Table 3, en-
amounts of by-products in the presence of tetra-n-butylammo- try 4).
nium bromide (TBAB) or sodium dodecyl sulfate (SDS) (Table 3,
entries 1 and 3). In contrast, we obtained the desired product
(i.e., 5ah) in 87 % yield in the presence of Triton X-100 (Table 3,
entry 2). Next, we tested the new surfactant C18-OPC (Figure 1),
developed by our research group, and synthesized from ita-
conic acid.[19] Given that the carboxylic acid moiety of this sur-
factant is converted into a carboxylate anion under the basic
reaction conditions, we slightly increased the amount of KOH,
and pleasingly we obtained 5ah in a comparably high yield
(89 %; Table 3, entry 4).
Subsequently, we tested the generality of the previously op-
timized work-up procedure. Pleasingly, after extracting the
crude reaction mixtures with ethyl acetate, we were able to
isolate pure products 5ab–5ai by simple recrystallization from
methanol without appreciable loss of yield, which confirms the
robustness of our work-up procedure.
To the best of our knowledge, there are no reports of the
isolation of biaryl-based chalcone derivatives by similar proce-
dures, in which tedious and solvent-consuming chromato-
graphic purifications are avoided.
Table 3. Cascade Suzuki–aldol reaction of 4-bromobenzaldehyde and phenyl-
boronic acid with lipophilic aromatic ketones in water, in the presence of
different additives.[a]
Screening of Different Arylboronic Acids
Next, the influence of the electronic properties of the arylbor-
onic acid derivatives on the reaction with 4-bromobenz-
aldehyde was investigated, by carrying out the Suzuki coupling
reaction of 1a with different arylboronic acids (Table 4). (4-Me-
thoxyphenyl)boronic acid (2b), bearing a para electron-donat-
ing group, gave the desired products (i.e., 5bc–5bg) in pure
water in excellent yields. On the other hand, [4-(trifluoro-
methyl)phenyl]boronic acid (2c) showed a much lower reactiv-
ity in the Suzuki coupling reaction with 1a in pure water, but
Entry
Additive
Yield [%][b]
5ah
Table 4. Cascade Suzuki–aldol reaction of 4-bromobenzaldehyde and arylbor-
onic acids with different aromatic ketones in water.[a]
5ai
1
2
3
4
5
TBAB
21
87
73
89
86
–
54
–
67
–
Triton X-100[c]
SDS
C18-OPC[c]
C18-OPC[c,d]
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), phenylbor-
onic acid (2a; 0.32 mmol), Pd(OAc)2 (3 mol-%), KOH (6 equiv.), additive
(0.5 equiv.), H2O (3 mL), 80 °C, 1 h; 2) aromatic ketone 3h or 3i (0.30 mmol),
80 °C, 5 h. [b] Yield determined by GC–MS (internal standard). [c] KOH
(6.5 equiv.) was used. [d] C18-OPC (0.5 equiv.) was added during the second
step.
Figure 1. 1-Octadecyl-5-oxopyrrolidine-3-carboxylic acid (C18-OPC).
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), arylbor-
onic acid 2b or 2c (0.32 mmol), Pd(OAc)2 (3 mol-%), KOH (6 equiv.), H2O
(3 mL), 80 °C, 1 h; 2) aromatic ketone 3c, 3f, 3g, or 3h (0.30 mmol), 80 °C,
Moreover, we studied the effect of adding C18-OPC only dur-
ing the second synthetic step, and we obtained a comparable
result; compound 5ah was obtained in 86 % yield (Table 3, en-
try 5). This means that in the specific case of the Suzuki cou-
5
h. [b] Yield determined by GC–MS (internal standard). [c] C18-OPC
(0.5 equiv.) and KOH (6.5 equiv.) were used for 2 h in the first step.
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we obtained the expected products (i.e., 5cc and 5ch) in high
yields under the micellar catalysis conditions (C18-OPC,
0.5 equiv.).
Table 5. Cascade Suzuki–aldol reaction of 4-bromoacetophenone and phenyl-
boronic acid with different aromatic aldehydes in water.[a]
Suzuki Coupling Reaction on the Ketone Moiety Followed
by Aldol Condensation
To further extend the flexibility of our synthetic protocol, and
to synthesize new biaryl-based chalcones, we changed the hal-
ogenated partner in the Suzuki coupling reaction from 4-
bromobenzaldehyde (1a) to 4-bromoacetophenone (3e). The
resulting 4-biphenyl methyl ketone can then react with various
aromatic aldehydes (Table 5).
In this case, we found that pure water was an unsuitable
reaction medium both for the synthesis and for the further
aldol condensation of such a nonpolar intermediate ketone (the
final yields of 6ab, 6ac, and 6ae in pure water were about
10 %). Therefore, micellar catalysis conditions were used by
adding C18-OPC (0.5 equiv.), and this gave the desired products
(i.e., 6ab–6ag) in very high to excellent yields. To the best of our
knowledge, no deep studies have been published on micellar
catalysis (mediated by an environmentally sustainable surfac-
tant) for the synthesis of new biaryl-based chalcone derivatives
with such promising results. We also observed that when the
micellar catalysis conditions were required, we were able to use
the previously optimized work-up procedure and isolate pure
products 6ab–6ag without appreciable loss of yield.
[a] Reaction conditions: 1) 4-bromoacetophenone (3e; 0.25 mmol), phenyl-
boronic acid (2a; 0.30 mmol), Pd(OAc)2 (3 mol-%), KOH (6.5 equiv.), C18-OPC
(0.5 equiv.), H2O (3 mL), 80 °C, 1 h; 2) aromatic aldehyde 1b–1g (0.28 mmol),
80 °C, 5 h. [b] Yield determined by GC–MS (internal standard). [c] KOH
(6 equiv.) and pure water (3 mL) were used.
and antifungal activities.[20,21] In particular, a biarylchalcone
containing a thiophene nucleus flanked by a phenyl ring on
one side and a phenylpropenone on the other side is a scaffold
that is found in specific classes of DNA-binding anticancer
drugs.[21b]
Synthesis of Thiophene-Centred Biarylchalcones
Thiophene-containing biarylchalcones are intriguing structures
for medicinal chemistry, because thiophene nuclei are found in
There are many reports dealing with the synthesis of thio-
many natural products with promising anticancer, antibacterial, phene-containing biarylchalcones[22] through Suzuki-coupling–
Table 6. Cascade Suzuki–aldol reaction of 5-bromo-2-thiophenecarbaldehyde and arylboronic acids with different aromatic ketones in water.[a]
[a] Reaction conditions: 1) 5-bromo-2-thiophenecarbaldehyde (1h; 0.26 mmol), arylboronic acid 2a or 2b (0.31 mmol), Pd(OAc)2 (3 mol-%), KOH (6 equiv.),
H2O (3 mL), 80 °C, 1 h; 2) aromatic ketone 3c, 3f, or 3g (0.29 mmol), 80 °C, 5 h. [b] Yield determined by GC–MS (internal standard).
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Wittig-olefination reactions,[22a] Vilsmeier–Haack chloroformyla-
tion–cyclization reactions,[22b] direct arylation of thiophene-
containing alkenes,[22c] and Pd-catalysed C–H olefination of
(hetero)arenes with (hetero)aryl ethyl ketones[22e] in the litera-
ture. However, some of these methods have drawbacks, such
as a requirement for harsh reaction conditions (phosphine rea-
gents, hazardous organic solvents, high temperatures, etc.), and
very long reaction times. In particular, (hetero)biarylcarbalde-
hydes,[23] the key intermediates for the synthesis of (hetero)aryl-
centred biarylchalcones, are commonly obtained through cross-
coupling reactions that exploit various Pd catalysts containing
expensive ligands, such as dialkylbiphenylphosphinyl[23a,23b] or
1,1′-bis(diphenylphosphanyl)ferrocene.[23d]
Bearing in mind the importance of these scaffolds, we tested
whether our new protocol could be used for the synthesis of
thiophene-centred biarylchalcones (Table 6). 5-Bromo-2-thio-
phenecarbaldehyde (1h) was successfully coupled with phenyl-
boronic acid (2a), and a subsequent condensation with selected
aromatic ketones (3c, 3f, or 3g) gave (hetero)biarylchalcones
7ac–7ag in very high yields. We then examined (4-methoxy-
phenyl)boronic acid (2b) as a Suzuki coupling partner for 1h;
the resulting (hetero)biarylcarbaldehyde intermediate con-
densed with selected aromatic ketones to give the desired
products (i.e., 7bc–7bg) in very high to excellent yields.
Table 7. Synthesis of bischalcone 8g by cascade aldol–Suzuki–aldol reaction
in water.[a]
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), (4-formyl-
phenyl)boronic acid (2d; 0.32 mmol), Pd(OAc)2 (3 mol-%), KOH (10.75 equiv.),
C18-OPC (0.75 equiv.), H2O (4 mL), 80 °C, 2 h; 2) 2-acetylthiophene (3g;
0.59 mmol), 80 °C, 5 h. [b] Yield determined by GC–MS (internal standard).
(3e), followed by a double Suzuki coupling reaction between
the intermediate 4,4′-dibromochalcone and (4-methoxy-
phenyl)boronic acid (2b), we obtained the expected product
(i.e., 9b) in 93 % yield.
Table 8. Synthesis of (bis)biarylated chalcone 9b by cascade Suzuki–aldol–
Suzuki reaction in water.[a]
To the best of our knowledge, there are no reports of Suzuki
coupling and aldol condensation reactions being carried out in
a cascade manner, using pure water as the reaction medium,
for the synthesis of bisthiophene-substituted enone derivatives.
Synthesis of Bischalcones and (Bis)Biarylated-Chalcones
As a final implementation of the synthetic strategy described
above, we investigated aldol–Suzuki–aldol and Suzuki–aldol–
Suzuki cascade reactions in water, in order to obtain more com-
plex biaryl-based chalcone derivatives. Bischalcones show a
wide range of pharmacological properties,[24] including antibac-
terial activity,[24b,24d] cytotoxic activity against a number of hu-
man cancer cell lines,[24a,24e,24f] and anti-inflammatory activity
by inhibiting the production of NO.[24c]
[a] Reaction conditions: 1) 4-bromobenzaldehyde (1a; 0.27 mmol), 4-bromo-
acetophenone (3e; 0.30 mmol), KOH (8.75 equiv.), C18-OPC (0.75 equiv.), H2O
(5 mL), 80 °C, 2 h; 2) (4-methoxyphenyl)boronic acid (2b; 0.65 mmol),
Pd(OAc)2 (6 mol-%), 80 °C, 2 h. [b] Yield determined by GC–MS (internal
standard). [c] One-pot, 80 °C, 4 h.
We were pleased to obtain the desired products (i.e., 8g and
9b) in good to excellent yields, confirming the versatility of our
new surfactant C18-OPC in promoting both Suzuki coupling
and aldol condensation reactions directed towards the synthe-
sis of highly functionalized biaryl-based chalcone derivatives.
We synthesized bischalcone 8g through an aldol–Suzuki–
aldol cascade approach under micellar catalysis conditions
achieved by the addition of C18-OPC (0.75 equiv.). We carried
out the Suzuki coupling reaction of 4-bromobenzaldehyde (1a)
with (4-formylphenyl)boronic acid (2d), and then a double aldol
condensation between the (1,1′-biphenyl)-4,4′-dicarbaldehyde
intermediate and aromatic ketone 3g to give bischalcone 8g in
good yield (Table 7).
Recycling Tests of Catalytic Systems
The recycling of solvents, additives, and catalysts is one of the
main goals of sustainable chemistry. It not only reduces the
overall cost of the synthetic process, but it also avoids the gen-
eration of waste and potentially polluting materials.
We went on to develop a strategy for the synthesis of (bis)bi-
arylated-chalcones.[25] These interesting scaffolds not only have
wide-ranging pharmacological properties, including anticancer,
antimicrobial, analgesic, and DPPH (2,2-diphenyl-1-picryl-
hydrazyl) scavenging activities,[25a,25c] but also some of their de-
To evaluate the lifetime and reusability of the Pd catalyst,
rivatives are essential components of organic-based electrolu- recycling experiments were carried out. First of all, we carried
minescent devices.[25b] However, an attempted one-pot Suzuki– out recycling tests using as a model reaction the synthesis of
aldol–Suzuki reaction gave 9b in only 18 % yield (Table 8). In 5aa under the best conditions found. When the reaction was
contrast, when the aldol condensation was carried out first be- complete (i.e., complete consumption of starting material), the
tween 4-bromobenzaldehyde (1a) and 4-bromoacetophenone product was extracted with ethyl acetate. Further 4-bromo-
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benzaldehyde (1a), phenylboronic acid (2a), KOH, and aceto- extended to allow the multiple construction of carbon–carbon
phenone (3a) were then added to the remaining aqueous bonds through aldol–Suzuki–aldol and Suzuki–aldol–Suzuki
phase. The yields of 5aa for the first three cycles were 88, 46, cascade reactions carried out in a micellar environment, to ob-
and 35 %, respectively, clearly indicating a worsening of the tain more complex biarylchalcones derivatives. This demon-
catalyst performance. Next, we investigated whether micellar strates the generality and robustness of the developed syn-
catalysis conditions (water/C18-OPC) would give better results thetic routes.
in the synthesis of 6af. After the first cycle, the catalytic system
composed of Pd, C18-OPC, and H2O was used in the next run
by adding 4-bromoacetophenone (3e), phenylboronic acid (2a),
KOH, and 4-chlorobenzaldehyde (1f). In this case, we ran five
cycles without any significant loss in activity; the yield of each
cycle is shown in Figure 2.
Besides the green reaction medium, our catalytic system
showed other sustainable features such as the fact that a Pd
catalyst without phosphine ligands was used, and the fact that
no significant amount of metal or additive was found in the
final product. The most important feature is that the Pd(OAc)2/
C18-OPC/H2O catalytic system could be recycled at least five
times without significant loss in activity. Finally, due to the high
yields and the fact that few by-products were formed, the pure
products could be isolated without a significant loss of material
by simple recrystallization from methanol, avoiding chromato-
graphic separation.
The design of similar new catalytic systems and the develop-
ment of multicomponent tandem/cascade cross-coupling reac-
tions are in progress at our laboratory.
Figure 2. Recycling of the Pd/C18-OPC/H2O system in the synthesis of biaryl-
chalcone 6af.
As extensively described in the literature, Pd(OAc)2 in the
aqueous phase acts as a catalyst precursor. In fact, it is reduced
in situ to give catalytically active Pd0 species in molecular, col-
loidal, and nanoparticle forms. Further aggregation of these
species occurs in pure water to form larger and less reactive
particles, eventually leading to the deposition of Pd black.[26]
The addition of additives/stabilizers can prevent this aggrega-
tion, significantly prolonging the catalyst's lifespan and making
recycling more successful.[27]
Our new surfactant C18-OPC proved to be highly effective
for this purpose, probably interacting with the in-situ-generated
Pd nanoparticles through its carboxylic moiety. Careful analysis
of the extraction medium allowed us to exclude the possibility
of any appreciable loss of C18-OPC during the work-up of the
reaction; as a result, the whole micellar catalytic system can be
used for different cycles, as reported below (Figure 2).
The loss of the Pd catalyst was determined by atomic absorp-
tion measurements (GFAAS), and it was found that at the end
of each synthetic cycle, the extraction solvent contained ap-
proximately 3–7 ppm of Pd (see Table S3 in the Supporting
Information). This means that a significant amount of Pd cata-
lyst remained in the aqueous micellar environment, so it could
be reused in the next cycle maintaining its high activity.
Experimental Section
General Procedures for the Synthesis of Compounds 5aa–9b
Synthesis of Compounds 5aa–5ag: 4-Bromobenzaldehyde (1a;
0.27 mmol), phenylboronic acid (2a; 0.32 mmol), Pd(OAc)2 (3 mol-
%), and KOH (6 equiv.) were dissolved in H2O (3 mL), and the mix-
ture was stirred at 80 °C for 1 h (until complete conversion of 1a).
Then aromatic ketone 3a–3g (0.30 mmol) was added, and the mix-
ture was stirred at 80 °C for 5 h. The progress of reaction was moni-
tored by TLC and GC–MS. When the reaction was complete, the
mixture was cooled to room temp., diluted with water (2 mL), and
extracted with ethyl acetate (3 × 5 mL).[28] The combined organic
phases were washed with brine, and dried with Na2SO4. The solvent
was removed under reduced pressure, and the solid residue was
purified by recrystallization from methanol to give pure 5aa–5ag.
Synthesis of Compounds 5ah and 5ai: 4-Bromobenzaldehyde (1a;
0.27 mmol), phenylboronic acid (2a; 0.32 mmol), Pd(OAc)2 (3 mol-
%), KOH (6.5 equiv.), and C18-OPC (0.5 equiv.) were dissolved in
H2O (3 mL), and the mixture was stirred at 80 °C for 1 h (until
complete conversion of 1a). Then aromatic ketone 3h or 3i
(0.30 mmol) was added, and the mixture was stirred at 80 °C for
5 h. The progress of reaction was monitored by TLC and GC–MS.
When the reaction was complete, the same work-up procedure de-
scribed above was adopted to give pure 5ah and 5ai.
Synthesis of Compounds 5bc–5bg: 4-Bromobenzaldehyde (1a;
0.27 mmol), (4-methoxyphenyl)boronic acid (2b; 0.32 mmol),
Pd(OAc)2 (3 mol-%), and KOH (6 equiv.) were dissolved in H2O
(3 mL), and the mixture was stirred at 80 °C for 1 h (until complete
conversion of 1a). Then aromatic ketone 3c, 3f, or 3g (0.30 mmol)
was added, and the mixture was stirred at 80 °C for 5 h. The
progress of reaction was monitored by TLC and GC–MS. When the
reaction was complete, the same work-up procedure described
above was adopted to give pure 5bc–5bg.
Conclusions
We have developed a highly efficient synthetic protocol for
multicomponent cascade Suzuki–aldol reactions aimed at the
synthesis of (hetero)biarylchalcone derivatives in water. In some
cases, micellar catalysis gave much better results, when carried
out using the new surfactant C18-OPC, developed by our re-
search group and accessible through manipulation of itaconic
acid (industrially produced from renewable resources).
Synthesis of Compounds 5cc and 5ch: 4-Bromobenzaldehyde (1a;
0.27 mmol), [4-(trifluoromethyl)phenyl]boronic acid (2c; 0.32 mmol),
Pd(OAc)2 (3 mol-%), KOH (6.5 equiv.), and C18-OPC (0.5 equiv.) were
dissolved in H2O (3 mL), and the mixture was stirred at 80 °C for
A wide range of functional groups were tolerated in the reac-
tants, and good to excellent yields were obtained under the
optimized conditions. Furthermore, this synthetic protocol was 2 h (until complete conversion of 1a). Then aromatic ketone 3c or
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3h (0.30 mmol) was added, and the mixture was stirred at 80 °C for
catalyst and the base was subjected to the next run by adding 4-
5 h. The progress of reaction was monitored by TLC and GC–MS. bromobenzaldehyde (1a; 0.27 mmol), phenylboronic acid (2a;
After the reaction was complete, the same work-up procedure de-
scribed above was adopted to give pure 5cc and 5ch.
0.30 mmol), KOH (2 equiv.), and acetophenone (3a; 0.30 mmol) un-
der the same reaction conditions. At the end of each of the later
runs, the same work-up procedure described above was adopted.
The solid residues obtained at the end of the three runs, each con-
taining the product (i.e., 5aa), were stored separately for subse-
quent determination of the amount of Pd catalyst lost during the
work-up procedure.
Synthesis of Compounds 6ab–6ag: 4-Bromoacetophenone (3e;
0.25 mmol), phenylboronic acid (2a; 0.30 mmol), Pd(OAc)2 (3 mol-
%), KOH (6.5 equiv.), and C18-OPC (0.5 equiv.) were dissolved in
H2O (3 mL), and the mixture was stirred at 80 °C for 1 h (until
complete conversion of 3e). Then aromatic aldehyde 1b–1g
(0.28 mmol) was added, and the mixture was stirred at 80 °C for
5 h. The progress of reaction was monitored by TLC and GC–MS.
When the reaction was complete, the same work-up procedure de-
scribed above was adopted to give pure 6ab–6ag.
General Procedure for Recycling Test of the Pd/C18-OPC/H2O
Catalytic System: 4-Bromoacetophenone (3e; 0.25 mmol), phenyl-
boronic acid (2a; 0.30 mmol), Pd(OAc)2 (3 mol-%), KOH (6.5 equiv.),
and C18-OPC (0.5 equiv.) were dissolved in H2O (3 mL), and the
mixture was stirred at 80 °C for 1 h (until complete conversion of
3e). Then 4-chlorobenzaldehyde (1f; 0.28 mmol) was added, and
the mixture was stirred at 80 °C for 5 h. The progress of reaction
was monitored by TLC and GC–MS. When the reaction was com-
plete, the mixture was cooled to room temp., diluted with water
(2 mL), and extracted with ethyl acetate (3 × 5 mL). The combined
organic phases were washed with brine, and dried with Na2SO4.
The solvent was removed under reduced pressure, and the solid
residue containing the product (i.e., 6af) was stored. After the first
cycle, the aqueous phase containing the Pd catalyst, C18-OPC, and
the base was subjected to the next run by adding 4-bromoaceto-
phenone (3e; 0.25 mmol), phenylboronic acid (2a; 0.30 mmol), KOH
(2 equiv.), and 4-chlorobenzaldehyde (1f; 0.28 mmol) under the
same reaction conditions. At the end of each of the later runs, the
same work-up procedure described above was adopted. H2O
(0.5 mL) was added to the catalytic system in the third run. The
solid residues obtained at the end of the five runs, each containing
the product (i.e., 6af), were stored separately for subsequent deter-
mination of the amount of Pd catalyst lost during the work-up pro-
cedure.
Synthesis of Compounds 7ac–7bg: 5-Bromothiophene-2-carbal-
dehyde (1h; 0.26 mmol), arylboronic acid 2a or 2b (0.31 mmol),
Pd(OAc)2 (3 mol-%), and KOH (6 equiv.) were dissolved in H2O
(3 mL), and the mixture was stirred at 80 °C for 1 h (until complete
conversion of 1h). Then aromatic ketone 3c, 3f, or 3g (0.29 mmol)
was added, and the mixture was stirred at 80 °C for 5 h. The
progress of reaction was monitored by TLC and GC–MS. When the
reaction was complete, the same work-up procedure described
above was adopted to give pure 7ac–7bg.
Synthesis of Compound 8g: 4-Bromobenzaldehyde (1a;
0.27 mmol), (4-formylphenyl)boronic acid (2d; 0.32 mmol), Pd(OAc)2
(3 mol-%), KOH (10.75 equiv.), and C18-OPC (0.75 equiv.) was dis-
solved in H2O (4 mL), and the mixture was stirred at 80 °C for 2 h
(until complete conversion of 1a). Then 2-acetylthiophene (3g;
0.59 mmol) was added, and the mixture was stirred at 80 °C for 5 h.
The progress of reaction was monitored by TLC and GC–MS. When
the reaction was complete, the mixture was cooled to room temp.,
diluted with water (2 mL), and extracted with ethyl acetate (3 ×
6 mL). The combined organic phases were washed with brine, and
dried with Na2SO4. The solvent was removed under reduced pres-
sure, and the solid residue was purified by recrystallization from
methanol to give pure 8g.
Acknowledgments
The authors acknowledge the University of Bologna, Italy for
funding. This work was carried out by CIRI Energia e Ambiente
with the cooperation of the Emilia-Romagna High Technology
Network within the “Programma Operativo Regionale – Fondo
Europeo di Sviluppo Regionale 2007–2013” (European funding).
Synthesis of Compound 9b: 4-Bromobenzaldehyde (1a;
0.27 mmol), 4-bromoacetophenone (3e; 0.30 mmol), KOH
(8.75 equiv.), and C18-OPC (0.75 equiv.) were dissolved in H2O
(5 mL), and the mixture was stirred at 80 °C for 2 h (until complete
conversion of 1a). Then (4-methoxyphenyl)boronic acid (2b;
0.65 mmol) and Pd(OAc)2 (6 mol-%) were added, and the mixture
was stirred at 80 °C for 2 h. The progress of reaction was monitored
by TLC and GC–MS. When the reaction was complete, the mixture
was cooled to room temp., diluted with water (2 mL), and extracted
with ethyl acetate (3 × 7 mL). The combined organic phases were
washed with brine, and dried with Na2SO4. The solvent was re-
moved under reduced pressure, and the solid residue was purified
by recrystallization from methanol to give pure 9b.
Keywords: Multicomponent reactions · Cross-coupling ·
Water chemistry · Micelles · Nanoparticles · Palladium
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Received: January 26, 2016
Published Online: ■
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Full Paper
Multicomponent Reactions
N. Armenise,* D. Malferrari,
S. Ricciardulli, P. Galletti,
E. Tagliavini ....................................... 1–10
Multicomponent Cascade Synthesis
of Biaryl-Based Chalcones in Pure
Water and in an Aqueous Micellar
Environment
The multicomponent cascade synthe- Miyaura reaction in aqueous medium.
sis of biaryl-based chalcones was car- The resulting intermediates then un-
ried out in pure water and in an aque- derwent an in-situ aldol condensation
ous micellar system. The first step of reaction to give biaryl(hetero)chal-
the protocol was a simple Pd-cata- cones in good to excellent yields.
lysed, ligand-free, and aerobic Suzuki–
DOI: 10.1002/ejoc.201600095
Eur. J. Org. Chem. 0000, 0–0
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10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim