molecules

Article
Synthesis of Chalcones: An Improved High-Yield and
Substituent-Independent Protocol for an Old Structure
Ana Donaire-Arias , Martin L. Poulsen, Jaime Ramón-Costa , Ana Maria Montagut , Roger Estrada-Tejedor
and José I. Borrell *

Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390,
E-08017 Barcelona, Spain; [email protected] (A.D.-A.); [email protected] (M.L.P.);
[email protected] (J.R.-C.); [email protected] (A.M.M.); [email protected] (R.E.-T.)
* Correspondence: [email protected]; Tel.: +34-935-756-069

Abstract: Chalcones are a type of molecule that can be considered as easily synthesizable through
aldol condensation or that can be readily purchased from habitual commercial vendors. However, on
reviewing the literature, one realizes that there are no standard procedures for such aldol conden-
sations, that there exists a wide range of alternative methods for the aldol condensation (indicating
that such a condensation is not always simple), and that, in many cases, low yields are obtained that
involve purifications by recrystallization or column chromatography. To develop a robust standard
protocol independent of the nature of the substituents present on the acetophenone or the benzalde-
hyde involved in the aldol condensation leading to the chalcone, we made a comparison between
an aldol condensation in KOH/EtOH and a Wittig reaction between the corresponding ylide and
benzaldehyde in water. We describe an improved procedure for the Wittig reaction and a protocol
for the elimination of the Ph3 P=O byproduct (and the excess of ylide used) by filtration of the crude
reaction product through a silica gel plug. We thus demonstrate that such an improved procedure
can be a general method for the synthesis of chalcones in high yield and excellent purity and is clearly
Citation: Donaire-Arias, A.; Poulsen, an improvement on the classical aldol condensation.
M.L.; Ramón-Costa, J.; Montagut,
A.M.; Estrada-Tejedor, R.; Borrell, J.I. Keywords: chalcones; aldol condensation; Wittig reaction
Synthesis of Chalcones: An Improved
High-Yield and Substituent-
Independent Protocol for an Old
Structure. Molecules 2023, 28, 7576. 1. Introduction
https://doi.org/10.3390/
Since the synthesis of chalcone (1{1,1}, Ar1 = Ar2 = Ph, Scheme 1) by Claisen and
molecules28227576
Claperède in 1881 [1] from acetophenone (2{1}, Ar1 = Ph) and benzaldehyde (3{1}, Ar2
Academic Editors: Julio A. Seijas = Ph), such 1,3-diaryl substituted 2-propen-1-ones have attracted the interest of organic
Vázquez, Alejandro Baeza Carratalá chemists as more than 48,000 compounds 1 included in SciFinder [2] (only considering
and José C. González-Gómez those presenting phenyl or phenyl fused rings at Ar1 and Ar2 ) and numerous reviews [3–5]
(more than 20 on the synthesis and applications of chalcones) clearly show.
Received: 26 October 2023
Revised: 8 November 2023
Chalcones 1 have been used as starting products for the synthesis of Michael adducts 4
Accepted: 12 November 2023
(Scheme 1), with more than 6800 reactions in SciFinder, using active methylene compounds
Published: 14 November 2023 such as dialkyl malonates, alkyl cyanoacetates, malononitrile, or nitroalkanes including,
more recently, enantioselective versions of such reactions [6–8]. Compounds 1 have also
been used as starting compounds for the synthesis of heterocyclic compounds (Scheme 1)
such as pyrazoles 5, upon reaction with hydrazine or substituted hydrazines [9–11]; pyrim-
Copyright: © 2023 by the authors. idines 6 [12] by reaction with urea, thiourea or guanidines (more than 3300 reactions in
Licensee MDPI, Basel, Switzerland. SciFinder) [13–16]; or 3-cyanopyridines 7 by the Michael addition of malononitrile fol-
This article is an open access article lowed by an intramolecular cyclization [17]. Diels–Alder adducts 8 (Scheme 1) have also
distributed under the terms and
been obtained from chalcones 1 and dienes (more than 2000 compounds obtained in this
conditions of the Creative Commons
way) [18–20] and, finally, the stereoselective epoxidation of chalcone (1, Ar1 = Ar2 = Ph) in
Attribution (CC BY) license (https://
the presence of poly[[(S)-alanine] was developed at our institute by Julià and Colonna in
creativecommons.org/licenses/by/
1980 [21].
4.0/).

Molecules 2023, 28, 7576. https://doi.org/10.3390/molecules28227576 https://www.mdpi.com/journal/molecules

 ally NaOH in EtOH) of an arylmethylketone 2 and an aromatic aldehyde 3 (Scheme 1). In
most cases, yields are high but depending on the substituents present in each reagent the
conversions may not be so satisfactory and the reaction times can become extensive with
column chromatography or recrystallization required to afford the pure chalcone 1. In
some cases, microwave irradiation [22,23] has been used to increase the yield and reduce
Molecules 2023, 28, 7576 2 of
the reaction time, but such methodologies are not easily scalable due to the nature of 11
the
technique and often they are carried out without solvent.

Scheme 1. Synthesis of chalcones 1 from arylmethylketones 2 and aromatic aldehydes 3, with some
of their uses in organic synthesis.

Although
As a part ofseveral methodologies
our ongoing research in have been of
the field described so far for the synthesis
MAP kinase-interacting of
serine/thre-
chalcones
onine protein1 [4], the most
kinase widelyinhibitors
1 (MNK1) used method[24], is
westill the condensation
needed in basicsynthesis
a rapid and reliable medium
(usually NaOH
of chalcones in EtOH)
1, so of an arylmethylketone
we decided, on the one hand,2to and an aromatic
revise aldehyde
the possible 3 (Scheme
limitations 1).
of the
In most cases, yields are high but depending on the substituents present
Claisen condensation for the synthesis of compounds 1 depending on the nature of the in each reagent
the conversions
substituents mayinnot
present thebearylmethylketone
so satisfactory and thearomatic
2 and reaction aldehyde
times can3becomeand, onextensive
the other
with
hand,column chromatography
to determine or recrystallization
a general methodology required
not limited by to
theafford
nature the
ofpure
suchchalcone 1. In
substituents.
someForcases, microwave irradiation [22,23] has been used to increase the
this second objective, we were highly interested in the Wittig methodology pro- yield and reduce
the
posedreaction time, but such
by Dambacher et al. methodologies
[25] in which an are not easily
aromatic scalable3due
aldehyde to the nature
is reacted with a of the
stabi-
technique and often they are carried out without solvent.
lized ylide 9 in water at room temperature to afford the corresponding chalcone 1 in high
yieldsAs(Scheme
a part of2).
ourSuch
ongoing research inisthe
methodology fieldattractive
quite of MAP kinase-interacting
because organic serine/threonine
solvents are not
protein kinase 1 (MNK1) inhibitors [24], we needed
used but it has not received much attention. This is probably a rapidbecause
and reliable
in the synthesis of
reaction tri-
chalcones 1, so we decided, on the one hand, to revise the possible limitations
phenylphosphine oxide (Ph3P=O) is formed, a byproduct which is always difficult to elim- of the Claisen
condensation
inate—in fact for the aforementioned
in the synthesis of compounds
paper the 1 depending on the nature
authors describe the useofofthe substituents
flash chroma-
present in the arylmethylketone 2 and aromatic
tography employing silica gel 60 Å to purify the products. aldehyde 3 and, on the other hand, to
determine a general methodology not limited by the nature of such substituents.
For this second objective, we were highly interested in the Wittig methodology pro-
posed by Dambacher et al. [25] in which an aromatic aldehyde 3 is reacted with a stabilized
ylide 9 in water at room temperature to afford the corresponding chalcone 1 in high yields
(Scheme 2). Such methodology is quite attractive because organic solvents are not used but
it has not received much attention. This is probably because in the reaction triphenylphos-
phine oxide (Ph3 P=O) is formed, a byproduct which is always difficult to eliminate—in
fact in the aforementioned paper the authors describe the use of flash chromatography
employing silica gel 60 Å to purify the products.
Molecules 2023,
Molecules 2023, 28,
28, 7576
x FOR PEER REVIEW 33 of 11
of 11

Scheme 2. Synthesis
Scheme 2. Synthesis of
of chalcones
chalcones 11 from
from stabilized
stabilized ylides
ylides 99 and
and aromatic
aromatic aldehydes
aldehydes 33 in
in H
H22O.
O.

Consequently,
Consequently,we wedecided
decidedtoto try
try to
to improve
improve the
the protocol,
protocol, and
and the
the present
present paper
paper deals
deals
with the results obtained in the study.
with the results obtained in the study.
2. Results and Discussion
2. Results and Discussion
As mentioned the Wittig protocol described by Dambacher et al. [25] was selected
As mentioned the Wittig protocol described by Dambacher et al. [25] was selected for
for the synthesis of chalcone 1{1,1}1 (Ar12 = Ar2 = Ph) and its derivatives due to the sim-
the synthesis of chalcone 1{1,1} (Ar = Ar = Ph) and its derivatives due to the simplicity of
plicity of the procedure, the use of water as a solvent, and the potential scalability. After
the procedure, the use of water as a solvent, and the potential scalability. After performing
performing the reaction at room temp., as described in the paper, using the ylide 9{1}
the1reaction
(Ar = Ph) and at benzaldehyde
room temp., as3{1} described in the
(Ar2 = Ph) paper,2),
(Scheme using
onlythe16% ylide
yield 9{1} (Ar1 = Ph)1{1,1}
of chalcone and
benzaldehyde 3{1} (Ar 2 = Ph) (Scheme 2), only 16% yield of chalcone 1{1,1} (Ar1 = Ar2 = Ph)
(Ar1 = Ar2 = Ph) was obtained with standard magnetic stirring—the yield was determined
wasusing
by obtained with standard
1 H-NMR since the magnetic
product was stirring—the
not isolated. yieldHowever,
was determined
we noticed by using 1H-
that the
NMR
use of since the product
a magnetic stirrerwas not isolated.
produced However,
aggregation we initial
of the noticedreactants
that the impeding
use of a magnetic
proper
stirrer produced aggregation of the initial reactants impeding
homogenization. To solve this problem a Sonicator bath was used, thus improving the proper homogenization. To
solve this problem a Sonicator bath was used, thus improving
yield to 56%, also determined by NMR. The Sonicator allowed the initial reactants to be the yield to 56%, also de-
termined
better by NMR. The
homogenized Sonicator
but mainly allowed
in the solid the initial
state, reactants
therefore, to be better
increasing homogenized
the solubility of the
but mainly in
compounds andthefacilitating
solid state,the therefore,
reaction.increasing
The mixture the was
solubility
heatedofatthe compounds
reflux temperatureand
facilitating
with the reaction.
conventional stirring,The mixturecomplete
ensuring was heated at reflux
solubility, and temperature
enabling thewith yield conventional
of chalcone
stirring,
1{1,1} (Arensuring
1 = Ar2 =complete solubility,
Ph) to increase up toand100%enabling the yield ofbychalcone
(also determined NMR) in1{1,1}
only (Ar 1 = Ar2
10 min of
= Ph) to increase
reaction time. up to 100% (also determined by NMR) in only 10 min of reaction time.
The main
The main drawback
drawbackof ofthe
theWittig
Wittigreaction
reaction is is
thethe formation
formation of triphenylphosphine
of triphenylphosphine ox-
ide (Ph(Ph
oxide 3P=O), a product
3 P=O), a product thatthat
is very difficult
is very to remove
difficult to removewithout using using
without column chromatog-
column chro-
raphy whichwhich
matography normally reduces
normally the final
reduces the isolated yieldyield
final isolated of 1{1,1}. Batesky
of 1{1,1}. et al.et[26]
Batesky de-
al. [26]
scribed a method
described a method forfor
its its
removal
removal by by
using zinczinc
using chloride
chloride (Scheme
(Scheme 3). When
3). Whenwe tested this
we tested
method,
this method,unfortunately
unfortunately somesome triphenylphosphine
triphenylphosphine oxideoxide
still remained in theinisolated
still remained com-
the isolated
pound 1{1,1}.
compound 1{1,1}.

Scheme
Scheme 3.3. Conditions
Conditions described
described by
by Batesky
Batesky et
et al.
al. [26]
[26] for
for the
the removal
removal of
of triphenylphosphine
triphenylphosphine oxide
oxide
by
by reacting
reacting itit with
with zinc
zinc chloride.
chloride.

During
During these
theseexperiments,
experiments,we weobserved
observedthat triphenylphosphine
that triphenylphosphine oxide was
oxide totally
was re-
totally
tained when a TLC with CH Cl (DCM) was carried out. Consequently,
retained when a TLC with CH2Cl2 (DCM) was carried out. Consequently, we used chro-
2 2 we used chromato-
graphical filtration
matographical on a silica
filtration on a gel plug
silica gelwith
plugthe named
with solventsolvent
the named to remove this byproduct
to remove this by-
affording chalcone 1{1,1} (Ar 1 = Ar2 = Ph) of very high purity and in quantitative yield.
product affording chalcone 1{1,1} (Ar = Ar = Ph) of very high purity and in quantitative
1 2
We were
yield. Weable
were to able
modify the method
to modify to avoidtothe
the method use the
avoid of the
usechlorinated solvent by
of the chlorinated usingby
solvent a
75:25 mixture of cyclohexane:AcOEt to afford a “greener” and more industrially
using a 75:25 mixture of cyclohexane:AcOEt to afford a “greener” and more industrially friendly
protocol. Since the reaction
friendly protocol. Since theisreaction
performed in water and
is performed inthe purification
water and the method uses method
purification organic
solvents, a liquid–liquid extraction and a subsequent solvent evaporation
uses organic solvents, a liquid–liquid extraction and a subsequent solvent evaporation to to concentrate
the product are
concentrate the necessary.
product are necessary.
Although
Although the the above
aboveWittig
Wittigprotocol
protocolis is industrially
industrially friendly,
friendly, wewe decided
decided to test
to test a
a var-
variation using an organic solvent instead of water. Consequently, we tested THF and
iation using an organic solvent instead of water. Consequently, we tested THF and 1,4-
1,4-dioxane as solvents and in both cases solubility was maintained but the reaction time
dioxane as solvents and in both cases solubility was maintained but the reaction time was
was increased from 10 min to overnight with 1,4-dioxane and 56 h with THF. These results
increased from 10 min to overnight with 1,4-dioxane and 56 h with THF. These results
also proved the Dambacher et al. [25] statement on the reduction in reaction time due to the
also proved the Dambacher et al. [25] statement on the reduction in reaction time due to
nature of water as solvent. With the use of the mentioned organic solvents, no extraction
the nature of water as solvent. With the use of the mentioned organic solvents, no extrac-
was necessary, and simple concentration was enough to proceed with the elimination of
tion was necessary, and simple concentration was enough to proceed with the elimination
Molecules 2023, 28, x FOR PEER REVIEW 4 of 11
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11

of Ph3P=O upon filtration through silica. However, we decided to continue with the reac-
of Ph
Ph 3P=O
3 P=O
upon
upon filtration
filtration through
through silica.
silica. However,
However, wewe decided
decided to continue
to continue withwith
thethe reac-
reaction
tion in water.
tion in
in water.water.
Having to hand a procedure that seems to be easy and robust, we decided to test it
Having to
Having to hand
hand aa procedure
procedure that thatseems
seemstotobe beeasy
easyand
androbust,
robust,we wedecided
decided toto
test it
test
with a variety of stabilized ylides 9{x} and benzaldehydes 3{y} to synthesize a wide range
with
it witha variety
a varietyof stabilized
of stabilizedylides 9{x} 9{x}
ylides and and
benzaldehydes
benzaldehydes 3{y} to synthesize
3{y} a widea range
to synthesize wide
of chalcones 1{x,y} having different types of substituents at the ylide 9{x} and the benzal-
of chalcones
range 1{x,y} having
of chalcones different
1{x,y} having types oftypes
different substituents at the ylide
of substituents at the9{x} and9{x}
ylide the and
benzal-
the
dehyde 3{y}. For comparison purposes, we also obtained the same chalcones 1{x,y} by us-
dehyde 3{y}. For
benzaldehyde comparison
3{y}. purposes,
For comparison we alsowe
purposes, obtained the same
also obtained thechalcones 1{x,y} by
same chalcones us-
1{x,y}
ing the usual methodology for their synthesis, an aldol condensation between an aceto-
ing the usual methodology for their synthesis, an aldol condensation
by using the usual methodology for their synthesis, an aldol condensation between an between an aceto-
phenone 2{x} and a benzaldehyde 3{y} using KOH/EtOH at 40 °C in◦a Sonicator—the pro-
phenone 2{x} and
acetophenone 2{x} aand
benzaldehyde
a benzaldehyde 3{y} using KOH/EtOH
3{y} using KOH/EtOH at 40 at
°C40in aCSonicator—the pro-
in a Sonicator—the
tocol used previously in our group, adapting it from the methodologies described by Ga-
tocol used
protocol previously
used previously in our group,
in our group,adapting it from
adapting the methodologies
it from the methodologies described by Ga-
described by
nesan et al. [27] and Jin et al. [28] (Scheme 4).
nesan et al.
Ganesan [27][27]
et al. and JinJin
and et al. [28][28]
et al. (Scheme
(Scheme4). 4).

Scheme 4. Conditions for

Conditions for the
for the aldol
the aldol condensation,
aldol condensation, adapted from Ganesan
condensation, adapted Ganesan et al.
al. [27] and
and Jin et
et al. [28].
[28].
Scheme
Scheme 4.
4. Conditions adapted from
from Ganesan et
et al. [27]
[27] and Jin
Jin et al.
al. [28].

The
The two
two reactions,
reactions, aldol
aldol condensation
condensation andand Wittig,
Wittig, were
were performed
performed and and compared
compared to to
prove
prove the effectivity of the Wittig conditions as well as the purification method described
the effectivity of the Wittig conditions as well as the purification method described
above. To carry out such a comparison, the final chalcones 1{x,y} were isolated by rotary
above. To carry out such a comparison, the final chalcones 1{x,y} were isolated by rotary
evaporation of
evaporation of the
thereaction
reactionsolution
solutiontotoavoid
avoidmaterial
materialloss.
loss.InInthe
the case
case ofofthethe Wittig
Wittig proto-
protocol,
evaporation of the reaction solution to avoid material loss. In the case of the Wittig proto-
acol,
1.5:1.0 molarmolar
a 1.5:1.0 ratio ratio
of theofylide ylidewith
the 9{x} 9{x}respect to the benzaldehyde
with respect to the benzaldehyde3{y} was3{y} usedwasbecause
used
col, a 1.5:1.0 molar ratio of the ylide 9{x} with respect to the benzaldehyde 3{y} was used
such an excess was easily removed during the silica gel filtration. The
because such an excess was easily removed during the silica gel filtration. The use of an use of an excess of
because such an excess was easily removed during the silica gel filtration. The use of an
the corresponding
excess acetophenone
of the corresponding 2{x} was not
acetophenone possible
2{x} was notdue to the due
possible secondary reactions that
to the secondary re-
excess of the corresponding acetophenone 2{x} was not possible due to the secondary re-
occur
actionsduring the aldol
that occur duringcondensation and so an equimolar
the aldol condensation and so anamount
equimolarwas amount
used. was used.
actions that occur during the aldol condensation and so an equimolar amount was used.
First,
First, the
the effect
effectof ofaapara
parasubstitution
substitutionon onthe
thealdehyde
aldehyde moiety
moiety 3{y} was
3{y} was examined,
examined, using
us-
First, the effect of a para substitution on the aldehyde moiety 3{y} was examined, us-
both electron-donating
ing both electron-donating and electron-withdrawing
and electron-withdrawing groups. In thisIncase,
groups. thisno steric
case, no interference
steric inter-
ing both electron-donating and electron-withdrawing groups. In this case, no steric inter-
would
ferencebewouldexpected in any of the
be expected reactions.
in any of theAreactions.
search carried
A searchout incarried
SciFinderoutshowed more
in SciFinder
ference would be expected in any of the reactions. A search carried out in SciFinder
than 200 aldol condensations described, at mg or g scale using
showed more than 200 aldol condensations described, at mg or g scale using NaOH in NaOH in EtOH, for which
showed
the yields
moredescribed.
than 200 aldol condensations described, at mg the or gyields
scalehigher
using than
NaOH in
EtOH, for are
which the yields Onlyarein almost 39%
described. of the
Only cases were
in almost 39% of the cases were the 70%,
yields
EtOH,
and onlyfor which
in 42 the
reactionsyields are
yields described. Only in almost 39% of the cases were the yields
higher than 70%, and only in 42were they between
reactions yields were90–100%.
they between 90–100%.
higher Thethan 70%, and only in 42 reactions yields were they between 90–100%.
The results
results obtained
obtained using
using both
both protocols
protocols are
are summarized
summarized in in Table
Table 1.1.
The results obtained using both protocols are summarized in Table 1.
Table
Table 1. Comparison between
1. Comparison between aldol condensation and
aldol condensation and Wittig
Wittig protocols
protocols for
for the synthesis of
the synthesis chalcones
of chalcones
Table 1. Comparison between aldol condensation and Wittig protocols for the synthesis of chalcones
1{1,y} from para-substituted
1{1,y} from para-substituted benzaldehydes 3{2–9} and
benzaldehydes 3{2–9} and acetophenone
acetophenone2{1}2{1}or
orylide
ylide9{1}.
9{1}.
1{1,y} from para-substituted benzaldehydes 3{2–9} and acetophenone 2{1} or ylide 9{1}.

Wittig
Wittig Reaction
Reaction Aldol Condensation
Aldol
Wittig Reaction AldolCondensation
Condensation
Aldehyde
Aldehyde Chalcone Reaction Reaction
Aldehyde Chalcone
Chalcone Reaction
Reaction Yield (%)
1 Reaction Yield (%)2 22
1 Reaction
Time Yield
Time
(%) (%)
Yield 1
Time Yield
Time Yield(%)
(%)
Time Time
3{2} (G = p-NMe)2) 1{1,2} 68 h 93 2.5 h 58 3
3{2} (G==p-NMe
3{2} (G p-NMe 2 2) 1{1,2}
1{1,2} 68 h68 h 93 93 2.52.5
h h 583 3
58
3{3} (G = p-Me) 1{1,3} 19 h 91 2.5 h 743 3
3{3} (G==p-Me)
3{3} (G p-Me) 1{1,3}
1{1,3} 19 h19 h 91 91 2.52.5
h h 74
74 3
3{4} (G = p-OMe) 1{1,4} 21 h 96 96 2.52.5
h h 543 33
3{4} (G==p-OMe)
3{4} (G
p-OMe) 1{1,4}
1{1,4} 21 h
21 h 96 2.5 h 54
54
3{5} (G = p-F)
3{5} (G = p-F) 1{1,5}
1{1,5} 45 min
45 min 95 95 2.5 h
2.5 h 803,43,4
80
3{5}(G
3{6}
(G==p-Br)
p-F) 1{1,5}
1{1,6} 30
45
min
min 97
95 40
2.5 h
min
8033,4
79
3{6} (G = p-Br) 1{1,6} 30 min 97 40 min 79 3
3{6}(G(G
3{7} = p-Br)
= p-NO 2)
1{1,6}
1{1,7} 30 30
minmin 97 97 35 40
minmin 7933
100
3{7} (G = p-NO2) 1{1,7} 30 min 97 35 min 100 3
3{7}
3{8} (G == p-CN)
p-NO2) 1{1,7}
1{1,8} 45 30
minmin 90 97 20 35
minmin 1003 3
100
3{8} (G = p-CN) 1{1,8} 45 min 90 20 min 100 3
3{9}
3{8} = p-COOMe)
(G (G = p-CN) 1{1,9}
1{1,8} 145
h min 90 90 75 20
minmin 1003 3
100
3{9} (G = p-COOMe)
1 Conversions 1{1,9} 1h 90 75 min 100 3
3{9} (G = p-COOMe) 1{1,9}obtained by evaporation
are always 100%. Products 1h 90 CH2 Cl275
of the organic min 2 Products
solution. 100 3were
isolated by evaporation of the EtOH solution. 3 Purified by recrystallization from EtOH. 4 Aldol condensation
carried out at room temp.
 1Conversions are always 100%. Products obtained by evaporation of the organic CH2Cl2 solution.
Products were isolated by evaporation of the EtOH solution. 3 Purified by recrystallization from
Molecules 2023, 28, 7576 EtOH. 4 Aldol condensation carried out at room temp. 5 of 11

Comparing both procedures, when electron-withdrawing groups were present at the

paraComparing
position of both the benzaldehyde
procedures, when 3{y}electron-withdrawing
both the aldol and Wittiggroupsreactions performed
were present at sim
ilarly with very high yields and similar reaction times. Although in
the para position of the benzaldehyde 3{y} both the aldol and Wittig reactions performed all cases the conver
sion using
similarly withthevery
Wittig highprotocol was similar
yields and 100% by NMR,times.
reaction isolated yields were
Although in allslightly lower due
cases the
to the silica
conversion plug
using thefiltration.
Wittig protocol was 100% by NMR, isolated yields were slightly lower
due toWhen
the silica plug filtration.
an electron-donating group is present at the para position of the benzaldehyde
When an electron-donating
3{y} the differences in the performances group is present at the
of both para position
protocols wereofremarkable.
the benzaldehyde
Although the
3{y} the differences in the performances of both protocols were remarkable.
aldol condensation was faster in all the tested cases, the crude materials obtained needed Although
the aldol condensation was faster in all the tested cases, the crude materials obtained
purification by recrystallization and the highest isolated yield was 74%. As an example
needed purification by recrystallization and the highest isolated yield was 74%. As an
Figure 1 Figure
example, corresponds to the to
1 corresponds
1H-NMR spectrum of the crude material obtained in the aldo
the 1 H-NMR spectrum of the crude material obtained in
condensation
the of acetophenone
aldol condensation 2{1}2{1}
of acetophenone andandthethep-methoxy substitutedbenzaldehyde
p-methoxy substituted benzaldehyde 3{4}
which
3{4}, clearly
which shows
clearly shows a mixture
a mixtureofofcompounds, includingthe
compounds, including thedesired
desired chalcone
chalcone 1{1,4}, and
1{1,4},
remaining
and remaining benzaldehyde
benzaldehydetogether withresidues
together with residues ofof
thethe EtOH
EtOH usedused
in theincondensation.
the condensation.

Figure1.1. 11H-NMR
Figure H-NMRspectrum
spectrumofofthe
thecrude
crude chalcone
chalcone 1{1,4}
1{1,4} obtained
obtained in the
in the aldol
aldol condensation
condensation of of ace
tophenone 2{1}
acetophenone 2{1}and
andthe
the p-methoxy substituted
p-methoxy substituted benzaldehyde
benzaldehyde 3{4}.3{4}.

Although the Wittig protocol needs longer reaction times, the products obtained
Although the Wittig protocol needs longer reaction times, the products obtained have
have a higher purity—in fact in the spectra only the corresponding chalcone and residual
a higher purity—in fact in the spectra only the corresponding chalcone and residual di
dichloromethane are present—and isolated yields increased up to 91–96% (conversion was
chloromethane
also 100% by 1 H-NMR).are present—and isolated
The Wittig protocol is, yields
therefore,increased up toapproach
a much better 91–96% (conversion
when an wa
also 100% by H-NMR).
electron-donating
1 The Wittig
group is present at theprotocol is, therefore,
para position a much better
of the benzaldehyde approach
3{y} since the when
an electron-donating group is present at the para position of
final products are obtained with higher purity and better yields. Figure 2 shows the H- the benzaldehyde 1 3{y} since
the final
NMR products
spectrum are obtained
of chalcone with higher
1{1,4}, obtained purity through
upon filtration and better yields.
the silica Figure
plug 2 shows the
to remove
the triphenylphosphine
1H-NMR oxide (Ph P=O), showing the high purity of this
spectrum of chalcone3 1{1,4}, obtained upon filtration through the silica plug tocompound.
The differences
remove can be explained
the triphenylphosphine by the
oxide (Phnature of the groups present at the para
3P=O), showing the high purity of this com
position
pound. of benzaldehydes 3{y}. The presence of an electron-donating group increases the
electron density in the aldehyde group of 3{y} (the electrophile) making the attack of the
The differences can be explained by the nature of the groups present at the para po
nucleophile (the enolate of acetophenone 2{1} or ylide 9{1}) less favorable. It is important
sition
to of benzaldehydes
consider that, contrary to3{y}. The presence
the Wittig of an
reaction, the aldolelectron-donating group increases
condensation is reversible and the
electron density in the aldehyde group of 3{y} (the electrophile)
prone to give secondary reactions. Making the electrophile less reactive increases not only making the attack of the
nucleophile
the (the
reaction time enolate
but also theofimpurities
acetophenone
present.2{1} or case
In the ylideof9{1}) less favorable.
the Wittig It is importan
reaction, although
to consider
also sufferingthat, contraryeffect,
an electronic to thetheWittig
majorreaction,
impact is theon thealdol condensation
reaction time but notis reversible
on the and
yield or the purity of the final compound, thus making it a better and easier
prone to give secondary reactions. Making the electrophile less reactive increases not only option for the
synthesis of chalcones,
the reaction time butespecially
also thewith donor groups
impurities present.at theIn benzaldehyde
the case of the moiety.
Wittig reaction, alt
hough also suffering an electronic effect, the major impact is on the reaction time but no
Molecules 2023, 28, x FOR PEER REVIEW 6 of 11

Molecules 2023, 28, 7576 6 of 11

on the yield or the purity of the final compound, thus making it a better and easier option
for the synthesis of chalcones, especially with donor groups at the benzaldehyde moiety.

Figure2.
Figure 2. 11H-NMR spectrum of the crude chalcone
chalcone 1{1,4}
1{1,4} obtained
obtained by
by using
using the
the Wittig
Wittig protocol
protocol after
after
Ph P=O was eliminated by filtration through the silica plug.
Ph3 P=O was eliminated by filtration through the silica plug.
3

The case
The case of
of p-fluorobenzaldehyde
p-fluorobenzaldehyde 3{5} 3{5} deserves
deserves special
special mention.
mention. WhileWhile the
the Wittig
Wittig
protocol
protocolperforms
performsquite quitewell
wellandandthethe
corresponding
corresponding chalcone
chalcone1{1,5} is obtained
1{1,5} in high
is obtained inyield
high
and ◦ C in the presence
yieldpurity, we observed
and purity, that the
we observed thataldol condensation
the aldol carried
condensation out atout
carried 40 at 40 °C in the pres-
of KOH/EtOH
ence of KOH/EtOH affords a complex
affords a complexmixture in which
mixture two two
in which CHOCHO protons are detected
protons are detectedin thein
1 H-NMR spectrum together with a triplet and a quadruplet
the 1H-NMR spectrum together with a triplet and a quadrupletcorresponding
correspondingtotoan anextra
extra
ethoxy
ethoxy group.
group. A detailed analysis of the spectrum led us us to
to conclude
conclude that that the
the fluorine
fluorine
atom
atom was partially substituted by an ethoxy group, either on the final chalcone or on
was partially substituted by an ethoxy group, either on the final chalcone or on the
the
starting
starting aldehyde 3{5} as the presence of two different benzaldehydes suggests. This type
aldehyde 3{5} as the presence of two different benzaldehydes suggests. This type
of
of substitution
substitution hashas not
not been
been previously
previously described
described forfor such
such aa benzaldehyde
benzaldehyde as as part
part of of an
an
aldol
aldolcondensation,
condensation,but buta similar
a similar reaction can can
reaction be found in theinliterature
be found when 3{5}
the literature whenis treated
3{5} is
with Triton-B
treated (benzyltrimethylammonium
with Triton-B (benzyltrimethylammonium hydroxide) in methanol
hydroxide) at room temp.
in methanol at room [29].
temp.
[29]. Consequently, in this case, it was necessary to change the reaction conditions and carry
out the reaction at room temperature, using reaction conditions similar
Consequently, in this case, it was necessary to change the reaction conditions and to those described
in the out
carry literature [30], toatobtain
the reaction a reasonable yield.
room temperature, In any case,
using reaction the corresponding
conditions similar to those Wittig
de-
reaction between 3{5} and the corresponding ylide 9{1} afforded the chalcone
scribed in the literature [30], to obtain a reasonable yield. In any case, the corresponding 1{1,5} in 95%
yield
Wittigand high purity,
reaction between once
3{5}more
and showing the better ylide
the corresponding performance of thisthe
9{1} afforded protocol.
chalcone 1{1,5}
in 95% yield and high purity, once more showing the better performance ofby
To continue to compare both reactions, steric effects were considered using
this ben-
protocol.
zaldehydes 3{y} with substituents at the ortho position. In this case,
To continue to compare both reactions, steric effects were considered by using ben- a search in SciFinder
showed
zaldehydes a total
3{y}ofwith
112 aldol condensations
substituents (practically
at the ortho position.half the case,
In this casesaofsearch
those in
with a ben-
SciFinder
zaldehyde with a substituent at the para position) carried out at mg or g scale using NaOH
showed a total of 112 aldol condensations (practically half the cases of those with a ben-
in EtOH for which the yields are described. Only in 13 of the reactions (around 12%)
zaldehyde with a substituent at the para position) carried out at mg or g scale using NaOH
were yields in the range of 90–100% showing the effect of steric hindrance on the aldol
in EtOH for which the yields are described. Only in 13 of the reactions (around 12%) were
condensation. We selected three ortho-substituted benzaldehydes 3{10–12} to test the differ-
yields in the range of 90–100% showing the effect of steric hindrance on the aldol conden-
ences between the aldol condensation and Wittig protocols. The results are summarized in
sation. We selected three ortho-substituted benzaldehydes 3{10–12} to test the differences
Table 2.
between the aldol condensation and Wittig protocols. The results are summarized in Table
In this case, the electronic effects of the substituents seem not to be so important
2.
as in the case of the para-substituted benzaldehydes, as electron-donating and electron-
In this case, the electronic effects of the substituents seem not to be so important as
withdrawing groups performed similarly. However, the bigger the substituent at the
in the case of the para-substituted benzaldehydes, as electron-donating and electron-with-
ortho position, the longer the reaction time both for the Wittig and aldol condensation.
drawing groups performed similarly. However, the bigger the substituent at the ortho po-
Furthermore, while the isolated yields of the Wittig protocol are in the upper range with
sition, the longer
conversions aroundthe 100%reaction
and verytimehigh
both for thedetermined
purities Wittig andby aldol condensation.
1 H-NMR, the aldol Further-
conden-
more, while
sations the isolated
gave highly coloredyields
crude ofmaterials
the Wittigstill
protocol are in5–10%
containing the upper
of therange with
starting conver-
materials
sions around 100% and very high purities determined by
and requiring careful purifications either by crystallization or column chromatography to
1H-NMR, the aldol

afford yields in the medium range.

Molecules 2023, 28, x FOR PEER REVIEW 7 of 11

condensations gave highly colored crude materials still containing 5–10% of the starting
Molecules 2023, 28, 7576 7 of 11
materials and requiring careful purifications either by crystallization or column chroma-
tography to afford yields in the medium range.

Table
Table 2. Comparison between
2. Comparison between aldol condensation and
aldol condensation and Wittig
Wittig protocols
protocols for
for the synthesis of
the synthesis chalcones
of chalcones
1{1,y} from ortho-substituted
1{1,y} from ortho-substituted benzaldehydes
benzaldehydes 3{10–12}.
3{10–12}.

WittigReaction
Wittig Reaction Aldol
Aldol Condensation
Condensation
Aldehyde
Aldehyde Chalcone
Chalcone Reaction Reaction
Reaction Yield(%)
(%)
1
1 Reaction Yield (%)2 2
Time Yield Time Yield (%)
Time Time
3{10} (G = o-Me) 1{1,10} 45 min 81 1h 62 3
3{10} (G = o-Me) 1{1,10} 45 min 81 1h 62 3
3{11}(G(G= =o-F)
3{11} o-F) 1{1,11}
1{1,11} 3030 min
min 8383 30 min
30 min 72 33
72
3{12}(G
3{12} (G= =o-Br)
o-Br) 1{1,12}
1{1,12} 3030 min
min 8383 12 hh
12 65 44
65
Conversionsare
11 Conversions are always 100%. Products obtained by evaporation of the organic
always 100%. Products obtained by evaporation of the organic CH2Cl2 solution.
CH2 Cl2 solution. 2 Products2
3 Purified by recrystallization EtOH. 4 Purified
Products
were were
isolated by isolated by of
evaporation evaporation of the EtOH
the EtOH solution. solution. 3 Purified byfrom
recrystallization from
by
column
EtOH. 4 chromatography.
Purified by column chromatography.

It is true, that for for some

some of of these
these cases,
cases, very
very high yields have been described in the
literature for the the aldol
aldol condensation
condensation(as (asininthe
thecase
caseofofthe
the o-bromo
o-bromo benzaldehyde
benzaldehyde 3{12},
3{12}, G
G = o-Br),
= o-Br), butbut
it isitalso
is also
true true that specific
that very very specific
reactionreaction conditions
conditions have tohave to be
be used (forused (for
instance
instance
very longvery long reaction
reaction times,
times, high high concentration
concentration of base, of base,temp.,
room room etc.)
temp., etc.) iswhich
which is fara
far from
from
general a general procedure.
procedure. Once more,
Once more, the Wittig
the Wittig protocol
protocol was shown
was shown to be to be a more
a more general
general and
and reliable
reliable procedure
procedure thatthat affords
affords higher
higher yields
yields withwith purities
purities not not being
being influenced
influenced by the
by the in-
initial reagents.
itial reagents.
Our
Our last
last comparison
comparison was carried out
was carried out with
with benzaldehyde
benzaldehyde 3{1} and acetophenones
3{1} and acetophenones 2{x} 2{x}
or 9{x} bearing a substituent at the para
or ylides 9{x} bearing a substituent at the para position of the ring. A search carried out in
ylides position of the ring. A search carried out in
SciFinder
SciFinder gavegave aa total
total of
of 159
159 aldol
aldol condensations
condensations of of that
that kind
kind (at
(at mg
mg oror g scale using
g scale using NaOH
NaOH
in
in EtOH
EtOH and and for
for which
which yields
yields are
are described)
described) andand only
only 5454 with
with acetophenones
acetophenones bearingbearing aa
substituent the ortho
substituent at the ortho position. In those cases, yields in the range of 90–100% were only
at position. In those cases, yields in the range of 90–100% were only
achieved
achieved in in 18
18 (11%)
(11%) andand 1010 (19%)
(19%) ofof the
the condensations
condensations with with substituents
substituents at the para
at the para and
and
ortho
ortho positions
positions of of the
the acetophenone
acetophenone 2, 2, respectively.
respectively.
However,
However, in in this
this case,
case, the
the use
use of
of the
the corresponding
corresponding ylides ylides 99 faces
faces aa major
major problem.
problem.
Although
Although in SciFinder there are 23 ylides 9{x} commercially available with a wide range
in SciFinder there are 23 ylides 9{x} commercially available with a wide range
of possible substituents at the para
of possible substituents at the para position, in practice, only the ylide corresponding to
position, in practice, only the ylide corresponding to
acetophenone
acetophenone 9{1} 9{1}isiscommercially
commerciallyavailable
availablefrom
fromconventional
conventional vendors
vendors andand
the the
others are
others
marketed in mg quantities by companies that obtain them specifically for the customer
are marketed in mg quantities by companies that obtain them specifically for the customer
who requests them. Consequently, to use the Wittig protocol, it is necessary to obtain the
who requests them. Consequently, to use the Wittig protocol, it is necessary to obtain the
required ylide 9{x}.
required ylide 9{x}.
Such ylides 9{x} can be obtained in two steps starting from the corresponding substituted
Such ylides 9{x} can be obtained in two steps starting from the corresponding substi-
2-bromoacetophenone 10{x} treated with an equimolar amount of PPh3 in anhydrous THF un-
tuted 2-bromoacetophenone 10{x} treated with an equimolar amount of PPh3 in anhy-
der argon to afford the corresponding substituted (2-oxo-2-phenylethyl)triphenylphosphonium
drous THF under argon to afford the corresponding substituted (2-oxo-2-phenylethyl)tri-
bromide 11{x} in almost quantitative yield. The subsequent treatment of 11{x} with aqueous
phenylphosphonium bromide 11{x} in almost quantitative yield. The subsequent8treat-
Molecules 2023, 28, x FOR PEER REVIEW of 11
2M NaOH in MeOH affords the final ylide 9{x} in a very high yield (Scheme 5). We used
ment of 11{x} with aqueous 2M NaOH in MeOH affords the final ylide 9{x} in a very high
this protocol to obtain the ylides 9{2} (R = p-Me) [31] and 9{3} (R = p-NO2 ) [32].
yield (Scheme 5). We used this protocol to obtain the ylides 9{2} (R = p-Me) [31] and 9{3}
(R = p-NO2) [32].

Scheme 5. Synthesis of ylides 9{x} from 2-bromoacetophenones 11{x}.

The results
The results obtained in the
obtained in the synthesis of the
synthesis of the corresponding chalcones are
corresponding chalcones are included
included in
in
Table
Table 3.
3.

Table 3. Comparison between aldol condensation and Wittig protocols for the synthesis of chalcones
1{x,y} from substituted acetophenones 2{2–3} or the corresponding ylides 9{2–3}.
 Scheme 5. Synthesis of ylides 9{x} from 2-bromoacetophenones 11{x}.

Molecules 2023, 28, 7576 8 of 11

The results obtained in the synthesis of the corresponding chalcones are included in
Table 3.

Comparison between aldol condensation and Wittig protocols for the synthesis of chalcones
Table 3. Comparison chalcones
1{x,y} from substituted acetophenones 2{2–3} or
acetophenones 2{2–3} or the
the corresponding
corresponding ylides
ylides 9{2–3}.
9{2–3}.

WittigReaction
Wittig Reaction Aldol
AldolCondensation
Condensation
Acetophenone orYlide
Acetophenone or Ylide Chalcone
Chalcone Reaction Reaction
Reaction Yield(%)
(%)1 1 Reaction Yield (%)22
Time Yield Time Yield (%)
Time Time
2{2} or 9{2} (R = p-Me)
2{2} or 9{2} (R = p-Me)
1{2,1}
1{2,1} 3.5 h
3.5 h 90
90 22 h
h
70
70 3
3

2{3}
2{3} or 9{3}(G
or 9{3} (G==p-NO
p-NO2)
2) 1{3,1}
1{3,1} 3.53.5
h h 7373 22 h
h 50
50 3
3

1 Conversions are always 100%. Products obtained by evaporation of the organic CH2Cl2 solution.
1 2
Conversions are always 100%. Products obtained by evaporation of the organic CH2 Cl2 solution. 2 Products
Products
were were
isolated isolated byofevaporation
by evaporation of the3 EtOH
the EtOH solution. Purifiedsolution.
3 Purifiedfrom
by recrystallization by recrystallization
EtOH. from
EtOH.
As can be seen, the performance of the Wittig protocol is once again superior to the
As can
classical be condensation.
aldol seen, the performance
Althoughof the
we Wittig protocol
tested this is once
protocol andagain superior of
the filtration to the
the
classical
crude reaction product as a means to eliminate the Ph3 P=O byproduct (and the excessthe
aldol condensation. Although we tested this protocol and the filtration of of
crude reaction
9{x} used), in a product
reduced asbuta significant
means to eliminate
number of thecases,
Ph3P=O byproduct
which include (and the excess of
electron-donating
9{x} used), in a reduced but
or electron-withdrawing significant
groups both atnumber of cases, which
the benzaldehyde include
3{y} and electron-donating
acetophenone 2{x} (or
or electron-withdrawing groups both at the benzaldehyde 3{y} and acetophenone
ylide 9{x}) moieties, the results clearly show that the Wittig protocol is more robust 2{x}than
(or
ylide 9{x}) moieties, the results clearly show that the Wittig protocol is more
the classical aldol condensation and almost independent of the nature and position of the robust than
the classical aldol
substituents condensation
present and almost
at both reagents independent
participating of the nature and position of the
in the reaction.
substituents present at both reagents participating in the reaction.
3. Conclusions
3. Conclusions
In this work, we compared two different protocols for the synthesis of chalcones
In the
1{x,y}: thisaldol
work,condensation
we compared two different
between protocols2{x}
acetophenones for and
the synthesis
benzaldehydes of chalcones
3{y} in
1{x,y}:
KOH/EtOH the aldol ◦
at 40condensation between
C in a Sonicator, andacetophenones 2{x} between
the Wittig reaction and benzaldehydes
ylides 9{x} and 3{y}the
in
same benzaldehydes
KOH/EtOH at 40 °C in boiling water.and the Wittig reaction between ylides 9{x} and the
a Sonicator,
sameThe results obtained
benzaldehydes for the
in boiling aldol condensations clearly showed that this reaction
water.
only The
affords excellent
results obtainedresults
for when an electron-withdrawing
the aldol condensations clearlygroup showed is present
that thisat reaction
the ben-
zaldehyde ring 3{y}. In the rest of the cases, dark-colored crude materials
only affords excellent results when an electron-withdrawing group is present at the showing several
ben-
compounds or even unreacted benzaldehyde are obtained. In these cases,
zaldehyde ring 3{y}. In the rest of the cases, dark-colored crude materials showing several recrystalliza-
tion from EtOH
compounds or purification
or even by column chromatography
unreacted benzaldehyde are obtained. Inisthese
required
cases,torecrystallization
obtain the pure
chalcone
from EtOH while paying theby
or purification price
columnof a chromatography
significantly reduced yield. to
is required For somethe
obtain of pure
the tested
chal-
chalcones
cone whilewe foundthe
paying in the literature
price reactions in
of a significantly which the
reduced isolated
yield. yieldof
For some is the
higher
testedthan the
chal-
ones obtained in this work but a careful examination of the reaction
cones we found in the literature reactions in which the isolated yield is higher than the conditions showed
that they
ones cannot
obtained in be
thisconsidered
work but as a standard
a careful protocol but
examination require
of the fine-tuning
reaction conditions for showed
specific
compound 1{x,y}.
that they cannot be considered as a standard protocol but require fine-tuning for specific
On the1{x,y}.
compound contrary, the Wittig protocol tested based on the work of Dambacher et al. [25]
afforded, in our hands,
On the contrary, thetotal
Wittig conversions for all
protocol tested tested
based benzaldehydes
on the work of Dambacher3{y} andetslightly
al. [25]
colored chalcones 1{x,y}. The filtration of the crude reaction product
afforded, in our hands, total conversions for all tested benzaldehydes 3{y} and slightly through a silica gel
plug, introduced in this work, allowed the complete removal of the
colored chalcones 1{x,y}. The filtration of the crude reaction product through a silica gelPh 3 P=O affording
highly pure chalcones with isolated yields in the range of 80–100%, better in general than
those obtained using the aldol condensation. Furthermore, the Wittig reaction allows
the use of an excess of the ylide 9{x} because it is retained in the silica gel plug together
with the Ph3 P=O. The use in the aldol condensation of an excess of the corresponding
acetophenone 2{x} is not adequate because in many cases such excess co-eludes with the
final chalcone 1{x,y} in the column chromatography required. A recrystallization from
EtOH is an improvement but often causes a considerable reduction in yield.
The only drawback of the Wittig protocol is the lack of a broad commercial offering of
ylides 9{x} with a variety of ring substituents. However, these ylides can be obtained in
two steps from 2-bromoacetophenones 10{x}.
Molecules 2023, 28, 7576 9 of 11

Consequently, we recommend the use of the Wittig protocol, including the silica gel
plug filtration, as a general method for the synthesis of chalcones 1{x,y} in high yield and
excellent purity. Even though we have not tested the aforementioned Wittig protocol with
heterocyclic ylides or heterocyclic aldehydes, there is no indication that this protocol would
not be better than the corresponding aldol condensation.

4. Materials and Methods

All solvents and chemicals were reagent grade. Unless otherwise mentioned, all sol-
vents and chemicals were purchased from commercial vendors (Sigma Aldrich (Burlington,
MA, USA), ABCR (Karlsruhe, Germany), Fluorochem (Hadfield, UK), Apollo Scientific
(Stockport, UK), Activate Scientific (Prien, Germany), Alfa Aesar (Ward Hill, MA, USA),
and ACROS Organics (Antwerp, Belgium)) and used without further purification.
1 H- and 13 C-NMR spectra were recorded on a Varian 400-MR spectrometer (1 H NMR

at 400 MHz, and 13 C NMR at 100.5 MHz). Chemical shifts were reported in parts per
million (δ) and are referenced to the residual signal of the solvent DMSO-d6 2.50 ppm or
tetramethylsilane (TMS) 0 ppm in 1 H NMR spectra and the residual signal of the solvent
DMSO-d6 39.5 ppm in 13 C NMR.
General protocol for the Wittig synthesis of chalcones 1{x,y}:
An amount of 1.5 mmol of the corresponding ylide 9{x} is suspended in 5 mL of
distilled water and 1.0 mmol of the corresponding benzaldehyde 3{y} is then added. The
solution is stirred at reflux temperature until complete (monitored by TLC using 100%
DCM as eluent and 1 H-NMR). The resulting solution is then cooled down and extracted
with 3 × 10 mL of DCM. The combined extracts are dried with anhydrous MgSO4 and
concentrated in vacuo to around 2–5 mL The resulting solution is filtered through a silica
gel plug (silica gel 60, 0.063–0.200 mm, Millipore 1.07734, 1.5–2 cm of height on a 2 cm
diameter filtering plate) and washed with DCM until it comes out uncoloured (100–200 mL
depending on the case, a TLC in DCM can be used to establish the final point of the elution).
Finally, the solvent is concentrated in vacuo to afford the corresponding chalcone 1{x,y}
that is analysed using 1 H- and 13 C-NMR.
General Aldol protocol for the synthesis of chalcones 1{x,y}:
An amount of 3.23 mmol of the corresponding benzaldehyde 3{y} is dissolved in 7 mL
of EtOH followed by 3.26 mmol of the corresponding acetophenone 2{x} and 0.391 mmol
of KOH. The mixture is heated at 40 ◦ C in an ultrasound bath until reaction completion
(monitored by 1 H-NMR). The solvent is then removed under reduced pressure and the
resulting solid (in some cases an oil) is analysed 1 H- and 13 C-NMR. The crude resulting
chalcone 1{x,y} is recrystallized from EtOH or purified by column chromatography.
The chalcones 1{x,y} obtained in this work were previously described in the literature
and the spectra obtained for them are in agreement with the literature data reported
respectively in SDBSWeb (https://sdbs.db.aist.go.jp, accessed on 10 October 2023, National
Institute of Advanced Industrial Science and Technology) or in a publication as follows:
1{1,1} (G = H, SDBS-No: 5818), 1{1,2} (G = p-NMe2 , SDBS-No: 11614), 1{1,3} (G = p-Me) [33],
1{1,4} (G = p-Ome, SDBS-No: 11610), 1{1,5} (G = p-F) [34], 1{1,6} (G = p-Br, SDBS-No:
11601), 1{1,7} (G = p-NO2 , SDBS-No: 5679), 1{1,8} (G = p-CN, SDBS-No: 11654), 1{1,9}
(G = p-COOMe) [35], 1{1,10} (G = o-Me) [36], 1{1,11} (G = o-F) [34], 1{1,12} (G = o-Br) [37],
1{2,1} (R = p-Me) [38], 1{3,1} (R = p-NO2 , SDBS-No: 6385).

Author Contributions: Conceptualization, J.I.B. and R.E.-T.; methodology, A.M.M.; writing—original

draft preparation, J.I.B.; writing—review and editing, A.D.-A.; experimentation, A.D.-A., M.L.P. and
J.R.-C. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Molecules 2023, 28, 7576 10 of 11

Data Availability Statement: Data are contained within the article.

Conflicts of Interest: The authors declare no conflict of interest.

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