Lewis acid catalyst system for Claisen-Schmidt reaction under solvent free condition

Article abstract of DOI:10.1016/j.tetlet.2020.152175

Ca(OTf)₂ in combination with NBu₄.BF₄ was established to function as an efficient catalyst system for one-pot Claisen-Schmidt condensation under neat conditions. Substituted acetophenones and benzaldehydes were coupled in situ to afford their corresponding chalcones in excellent yields. The method, with a broad range of substrate tolerance and mild operational conditions can produce assorted chalcone derivatives in moderate to high yields from easily accessible starting materials.

Full text of DOI:10.1016/j.tetlet.2020.152175

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Lewis Acid Catalyst System for Claisen-Schmidt Reaction under Solvent Free
Condition
Chandni G Halpani, Satyendra Mishra
PII:
S0040-4039(20)30635-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152175
TETL 152175
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Tetrahedron Letters
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Revised Date:
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26 April 2020
18 June 2020
22 June 2020
Please cite this article as: Halpani, C.G., Mishra, S., Lewis Acid Catalyst System for Claisen-Schmidt Reaction
under Solvent Free Condition, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152175
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Tetrahedron Letters
journal homepage: www.elsevier.com
Lewis Acid Catalyst System for Claisen-Schmidt Reaction under Solvent Free
Condition
Chandni G Halpani1 and Satyendra Mishra1*
1
Department of Engineering and Physical Sciences
Institute of Advanced Research, Gandhinagar, Gujarat, 382426 India
*E-mail: satyendramishra1@gmail.com; satyendra.mishra@iar.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ca(OTf)2 in combination with NBu4.BF4 was established to function as an efficient catalyst
system for one-pot Claisen-Schmidt condensation under neat conditions. Substituted
acetophenones and benzaldehydes were coupled in situ to afford their corresponding chalcones
in excellent yields. The method, with a broad range of substrate tolerance and mild operational
conditions can produce assorted chalcone derivatives in moderate to high yields from easily
accessible starting materials.
Available online
Keywords:
Chalcones
2009 Elsevier Ltd. All rights reserved.
Claisen-Schmidt condensation
Acetophenone
Benzaldehyde
Calcium trifluoromethanesulfonate
Bu4NPF6
1. Introduction
condensations have been also reported using Ca(OH)2 catalyst
Chalcones which (1, 3- diphenyl-2-propene-1-one) are biphenyl
compound have two aryl moieties connected through -, β-
unsaturated ketones. The -α, β-unsaturated carbonyl group is a
good Michael acceptor and undergoes nucleophilic addition.
They acquire multi-prolonged activities due to methylene and
carbonyl moieties in their structures. Chalcones which is one of
secondary metabolite compounds have gained the attention of
researchers due to their therapeutic potential activities as
in aqueous ethanol.7
Recently, alkaline earth metal catalysts due to their broad natural
abundance, low-cost and safe natures have been established as
alternatives to transition metals and lanthanide based catalysts8-9.
Among them, calcium salts holding a hard conjugate base such as
triflate ions, was highly stable to moisture and air and
demonstrated as an alternative to transition metals and lanthanide
based catalysts. However, very few reports have been available
antimicrobial1a,
antifungal1b,
antioxidant1c,
antitumor1d,
about the applications of Ca(OTf)2 in organic synthesis10-11
.
antimalarial1g, anticancer1f, anti-inflammatory1e, antidepressant1h,
antituberculosis1i. Chalcones are also an imperative precursor for
biosynthesis of flavonoids2a and isoflavonoids2b and numerous
heterocyclic compounds such as benzodiazepine2c, pirazoline2d,
flavones2e and aurone2f. Chalcones have two aromatic rings and
are connected by three carbon ,  unsaturated in carbonyl
compounds system3.
Claisen-Schmidt condensation methodology is widely used in
organic synthesis ranging from the preparation of biologically
active small molecules to the total synthesis of more complex
natural products and there are a plethora of examples regarding
synthesis in the literature12. Remarkably, the substituted chalcone
structural moiety get applications in several biologically active
compounds along with marketed and investigational drugs.13 To
the best of our knowledge, there are no reports describing
chalcone synthesis in presence of Ca(OTf)2-NBu4.BF4 catalyst
system. Herein, we are reporting synthesis of a number of
aromatic chalcones using Lewis acid based calcium catalyzed
system under solvent free, base free, mild operational and wide
substrate tolerance conditions to furnish corresponding products
in moderate to good yields.
The carbon-carbon double bonds formation is essential reaction
in organic chemistry. Numerous advances have been made for
the synthesis of olefins while attempting to deal with the
demands of chalcones from time to time.4 Usually, chalcone and
their derivatives were prepared by performing the reaction
between an aromatic ketones and aldehydes under normal acidic
or alkaline conditions. This method is most often known as
Claisen-Schmidt condensation 5. Plethora of efforts have,
previously, been made for the synthetic strategies of chalcones
and their derivatives in the past decades.6 However, in the
majority cases of these transformations, strong base, noble metal
catalysts, ligands and harsh operations are always required. The
catalysts frequently used for the synthesis of chalcones were
HCl61, SOCl26b, NaOH6c, KOH6d, Fly-ash: sulphuric acid6e,
At the beginning of our strategy, a model reaction was performed
using 4-methyl acetophenone and 4-nitrobenzaldehyde as a
substrate, and 10 mol% of Ca(OTf)2 as a catalyst in water at 110
C (Table 1). Most pleasantly, the desired product 3c was
obtained in modest yield (Table 1, entry 6) after 6h. Different Ca
(II) sources such as CaCl2, CaCO3, CaSO4, Ca(OH)2 and CaNTf2
were then examined, and we observed that Ca (OTf) 2 was found
to be the most effective catalyst. We examined a number of
anhydrous zinc chloride6f, barium hydroxide6g,
anhydrous
sodium bicarbonate6-h-i, Fly-ash:water6j, triphenylphosphite6k,
6l
KF/Al2O3 ,
silica–sulphuric
acid6m-n
.
Claisen-Schmidt

2
Tetrahedron
variables including reaction time, reaction solvent, mol % of
indicates that in order to establish the real effectiveness of the
catalyst and mol % additive (Table 1).
catalyst Ca(OTf)2, addition of the additive (Bu4NPF6) is
imperative in reaction (Table 1, entry 14). It is well observed
that Bu4NPF6 helps in solubilizing the Ca(II) salts for the
enhanced reactivity.14
Table 1: Optimizations of the conditions
O
O
O
Ca(OTf)2
Table 2: Substrate scope in the Ca(II) catalyzed Claisen Schmidt
reaction of 4-Methyl acetophenone with substituted aromatic
aldehyde
H
°
120
Additive,
NO2
C
NO2
Yielda
°
Entry
[Ca(OTf)2]
(mol%)
Additive
(mol%)
Solvents
Time (h) Temp
( C)
1
10
10
10
10
10
10
15
5
0
0
0
0
0
0
0
0
0
0
H2O
6
8
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
25
O
O
O
Ca(OTf)2 5mol%
Bu4NPF6 5mol%
2
CH3CN
Toluene
EtOH
CHCl3
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
15
H
R1
R1
3
8
NR
NR
NR
56
°
120 C, 0.5 h
2
3a-k
1
4
8
Entry
1
4
R1
Product
O
Yielda
5
8
O
6
6
80
H
7
6
55
3a
8
6
55
O
O
O
9
4
6
52
94
98
2
3
4-Cl
3b
3c
10
11
12
12
13
14b
15
16
17
18
19
6
6
55
Cl
O
5
NaPF6 (5%)
6
52
4-NO2
5
NaOTs (5%)
6
55
NO2
5
Py.OTs (5%)
6
50
O
O
O
O
5
Proline (5%)
6
45
88
92
4-CH3
4
5
3d
3e
5
Bu4NPF6 (5%)
Bu4NPF6 (10%)
Bu4NPF6 (15%)
Bu4NPF6 (5%)
Bu4NPF6 (10%)
Bu4NPF6 (15%)
0.5
0.5
0.5
8
96
5
90
4-OCH3
5
90
OCH3
0
trace
trace
trace
O
O
0
8
OCH3
OCH3
96
94
6
7
3, 4, 5-OCH3
0
8
3f
OCH3
O
O
O
O
O
O
Cl
b
3-Cl
a. Isolated Yields after crystallization; . Optimum conditions; NR: no
reaction
3g
3h
85
93
95
8
3-Me
Initially the influence of solvent system was evaluated. To
optimize the reaction conditions and find the right solvent, few
experiments were carried out using 4-methyl acetophenone and
4-nitrobenzaldehyde as a model substrate with different solvents
and 10 mol % of catalyst Ca(OTf)2. Among the tested solvents
CH3CN, methanol, toluene, chloroform, water and neat system,
the reaction proceeded most efficiently in neat system at 120 C
and afforded the desired product in good yield (Table 1, entry 6).
Indeed, we used an extremely fundamental procedure and
examined various solvent/base systems for the synthesis of
representative compound 3c (Table 1).
OCH3
3-OCH3
3,4-OCH3
4-OH
3i
3j
9
O
O
O
O
OCH3
OCH3
10
11
3k
92
OH
a. Isolated Yields after crystallization
Considering the importance of the additive Bu4NPF6 we also
carried out the reaction with 5 mol% of Bu4NPF6 (without
Ca(OTf)2) and no product formation of chalcone product was
observed after 8 h (Table 1, entry 17). Increase in the additive
(Bu4NPF6) loading from 5 to 15 mol% has also not showed any
remarkable effect on the reaction time and yield (Table 1, entries
17-19). These studies confirm that the additive (Bu4NPF6) alone
does have even minor effect on the reactions. Interestingly, no
product formation was detected in the absence of catalyst
Ca(OTf)2 (Table1, entries17-19). In order to establish the real
effectiveness of the catalyst Ca(OTf)2 and addition of the
additive (Bu4NPF6) is imperative in reaction (Table 1, entry 14).
Further, in order to evaluate the correct catalyst Ca(OTf)2
loading, a model reaction using 4-nitrobenzaldehyde and 4-
methyl acetophenone was carried out using 4 mol%, 5 mol %, 10
mol % and 15 mol % of catalyst under neat system (Table 1,
entries 6–10). It was found that 5 mol % of catalyst showed
maximum yield in minimum time. Higher percentage of loading
of the catalyst (10 to 15 mol %) neither increased the yield nor
decreased the conversion time. The effective amount of the
catalyst required for optimal yield was 5 mol % because on
decreasing the amount of the catalyst from 5 mol% to 4 mol%,
the yield was reduced (Table 1, entry 8 versus 9) while it did not
change on using 6 mol% of the catalyst (Table 1, entry 8 versus
10). So, 5 mol % of catalyst was found to be the optimal quantity
and sufficient to drive the reaction forward.
The reaction of the 4-Nitrobenzaldehyde with 4-methyl
acetophenone gave excellent yields of the desired adduct in
presence of 5 mol% of catalyst Ca(OTf)2 and 5 mol % of
additives Bu4NPF6 under neat condition at 120 C (Table 1, entry
14).. Originally, we allowed the reaction to proceed for 4 h but
later found the reaction to be complete within 30 min of at 120
C. With this optimal reaction condition in hands the scope of
this greener catalytic system was then studied, we extended our
study with various substituted acetophenones and substituted
benzaldehyde as reaction patterns (Table 2 and 3).15
In order to scrutinize role of additive on reaction, initially, we
examined the reaction with seven different additives NaPF6,
NaBF4, Bu4NPF6, NaOTs, NaNO3, CF3SO2Na, proline along with
catalyst Ca(OTf)2. Among these additives, the reaction with
Bu4NPF6 gave the best results (Table 1, entry 14). The other six
additives screened did not provide satisfactory yields of the
desired product. When the same reaction was carried out in the
absence of the additive Bu4NPF6 and the presence of catalyst 5
mol% of Ca (OTf)2, 55% of chalcone (3c) was isolated. This

Table 3: Substrate scope in the Ca(II) catalyzed Claisen Schmidt
reaction of 4-Bromo acetophenone with substituted aromatic
aldehyde
To investigate the generality of the reaction, we extended our
study using Ca(OTf)2/Bu4NPF6 (5 mol %) as catalyst system
under solvent-free condition at 120 C with different aromatic
aldehydes to prepare a series of chalcones. Under the established
optimized reaction conditions a series of aldehydes were reacted
with acetophenones (1 and 4) respectively. The corresponding
(3a-f and 5a-f) were obtained in good to excellent yields. The
results are summarized in Table 2 and 3.
O
O
O
Ca(OTf)2 5mol%
Bu4NPF6 5mol%
H
R1
R1
Br
Br
5a-i
4
2
120°C, 0.5
h
Entry
1
R1
H
Product
Yielda
85
O
O
O
Subsequently, the reaction scope was evaluated by varying the
aldehydes and the groups, attached to acetophenone ring (Table
2). When the reaction was performed using substituted aldehydes
with the electron-withdrawing groups high to excellent results
were achieved (88–99%) with full utilization of the starting
materials within eight hours. The presence of the electron-
donating groups on the substituted aldehydes slightly decreased
the reactivity (Table 2 and 3, entries 1, 4). Subsequent to the
completion of the reactions, the reaction mixtures were filtered to
collect the precipitates and it was further purification by
recrystallization to afford the pure chalcones 3a–k and 5a-i in 80–
99% yield.
1
5a
Br
Br
Br
Br
O
O
O
95
99
80
4-Cl
2
3
4
5
6
5b
5c
5d
Cl
O
O
4-NO2
4-CH3
4-CH3
Br
Br
Br
Br
NO2
O
O
88
96
5e
5f
Br
Br
OMe
O
O
OMe
OMe
3, 4,5 -OCH3
Here, we would like to conclude that we have presented a broad-
spectrum and efficient method for the synthesis of Claisen
Schmidt adducts (chalcones) of acetophenones and aromatic
aldehydes in the presence Ca(OTf)2/Bu4NPF6.The mild reaction
conditions, no workup, easy purification, higher yield, and
economic availability of the catalyst make this procedure an eco-
friendly attractive alternative to the existing methods for the
synthesis of chalcones. This catalyst may find application in
organic synthesis.
a. Isolated Yields after crystallization
Br
Br
Br
OMe
O
O
Cl
97
7
8
9
3-Cl
5g
5h
Br
O
O
O
OMe
NO2
3-OMe
3-NO2
85
98
Br
Br
Br
Br
O
5i
b. Isolated Yields after crystallization
Acknowledgments
We have performed reactions with Ca(OH)2 and TfOH on a
number of aromatic aldehydes, under the reaction conditions
which were used in the case of Ca(OTf)2/ NBu4.BF4 system but
this did not work well . Neither the Ca(OH)2 nor the TfOH could
furnish the significant yield of chalcones even after 8 hrs at 120
C.
This work is generously supported by the Department of Science
and Technology, India (DST- SERB/ ECR/2015/000363) to SM.
SM is also Indian Institute of Science, Bangalore for the spectral
analysis.
References and notes
A
plausible mechanism for the chalcone adducts of
acetophenones and aldehydes in the presence of catalyst
Ca(OTf)2/Bu4NPF6 is depicted in Figure 1. In essence, the Ca(II)
ions act in conjugation with the non-coordinating PF6¯ in order
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Supplementary Material
Supplementary data associated with this article are attached with this
article
Conflicts of interest: The authors declare no
conflict of interest.
Highlights
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 Aryl-aryl chalcones were synthesized using
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 Better yields of the chalcones obtained
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Leave this area blank for abstract info.
Lewis Acid Catalyst System for
Claisen-Schmidt Reaction under Solvent Free Condition
Chandni G Halpani1 and Satyendra Mishra1*
O
O
O
Ca(OTf)2 (5mol%)
BuNPF6 (5 mol%)
H
°
R1
R1
R2
120 C, 30 min
R2
Solvent Free
No workup
Purification via crystalization
Excellent Yield
20 examples
Chem., 2012, 14, 2129; (c) M. Niggemann and M. J. Meel,
Angew.Chem. Int. Ed., 2010, 49, 3684 –3687; (d) V. Nina, D. A. Forkel,
M. J. Fuchter, Tetrahedron Lett, 2014, 55, 5511-5514.
 Easy-workup procedure, environmentally
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2014, 55, 4657-4660; (b) S. Yaragorla, A. Sudhakar, N. Kiranmai, Ind.
J. Chem., B, 2014, 53, 1471-1475; (c) R. Kalepu and S. Mishra, J.
Chem. Sci., 132, 48 (2020). https://doi.org/10.1007/s12039-020-1749-8
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Chem. Rev. 2017, 117, 7762; (b). Z. Rozmer, P. Perjési Phytochem Rev.
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13. According to www.drugbank.ca (accessed in September 2017) there are
13 marketed and over 20 investigational drugs bearing the chalcone
substructure
solvent free synthetic method was adopted
 Purification
through
crystallization
techniques
14. S Haubenreisser, M. Niggemann Adv Synth Catal. 2011, 353, 469.
15. General experimental procedure for the Ca(OTf)2/Bu4NPF6 catalyzed
Chalcone synthesis: Suitable acetophenones (1mmol) and substituted
benzaldehydes (1.1 mmol) were heated under solvent free condition at
120 °C for 0.5 h in the presence of Ca(OTf)2 (5 mol%) and nBu4NPF6 (5
mol%). Progress of reactions was monitored by TLC. After completion,
reaction mixtures were brought to room temperature and diluted with
Graphical Abstract