Activated charcoal-mediated synthesis of chalcones catalyzed by NaOH in water

Article abstract of DOI:10.1016/j.tetlet.2021.152918

A variety of chalcones were synthesized in good yields by the activated charcoal-mediated aldol reactions between benzaldehydes and acetophenones catalyzed by NaOH in water. 2,6-Bis((E)-benzylidene)cyclohexan-1-ones were prepared by the aldol reactions between benzaldehydes and cyclohexanone. Activated charcoal could be recycled five times without the significant decrease of yields.

Full text of DOI:10.1016/j.tetlet.2021.152918

Tetrahedron Letters 71 (2021) 152918
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Activated charcoal-mediated synthesis of chalcones catalyzed by NaOH
in water
b
Kiyoshi Tanemura a, , Taoufik Rohand
⇑
a Chemical Laboratory, School of Life Dentistry at Niigata, Nippon Dental University, Hamaura-cho, Niigata 951-8580, Japan
b Laboratory of Analytical and Molecular Chemistry, Department of Chemistry, University Cadi Ayyad, Faculty Polydisciplinaire of Safi, Sidi Bouzid, 46000 Safi, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of chalcones were synthesized in good yields by the activated charcoal-mediated aldol reactions
between benzaldehydes and acetophenones catalyzed by NaOH in water. 2,6-Bis((E)-benzylidene)cyclo-
hexan-1-ones were prepared by the aldol reactions between benzaldehydes and cyclohexanone.
Activated charcoal could be recycled five times without the significant decrease of yields.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 22 January 2021
Revised 5 February 2021
Accepted 9 February 2021
Available online 12 February 2021
Keywords:
Activated charcoal
Aldol reaction
Chalcones
Water
Introduction
coal (AC) largely accelerated the alkaline and acidic hydrolysis of
esters in water [27]. In this paper, we wish to report the AC-medi-
Organic reactions have been traditionally carried out in organic
solvents. One of the valuable challenging studies in synthetic
organic chemistry is to perform reactions in water. For this pur-
pose, surfactants are often utilized in organic synthesis in order
to dissolve organic substrates in water [1-3]. However, work-up
is often problematic because of foaming. In addition, surfactants
are toxic and are not environmentally friendly. On the other hand,
water is safe, cheap, and an environmentally benign solvent.
Chalcones are useful intermediates for the synthesis of numer-
ous compounds such as heterocyclic compounds. Chalcones are
also quite important substrates which possess a variety of biolog-
ical activities such as anticancer, antimicrobial, analgesic, antiviral,
anti-inflammatory, and antidiabetic [4-6]. Furthermore, it was
recently reported that chalcones inhibited SARS-CoV-2 (COVID-
19) [7,8]. Chalcones are prepared by the base-catalyzed or acid-cat-
alyzed aldol reactions between aromatic aldehydes and aromatic
ketones [9-18]. The aldol reaction is one of the significant reactions
ated synthesis of chalcones (4) and 2,6-bis((E)-benzylidene)cyclo-
hexan-1-ones (7) catalyzed by NaOH in water.
Result and discussions
First, we tested the aldol reactions between p-chlorobenzalde-
hyde (1d) and p-methoxyacetophenone (2a) in water as a model
reaction (Fig. 1). Aldehyde 1d (2.2 mmol) and ketone 2a (2.0 mmol)
were treated with NaOH (2.0 mmol) in water (2.0 mL) in the pres-
ence of AC at room temperature for 3 h at 400 rpm. The results are
summarized in Table 1. When 600 mg of AC was added, the corre-
sponding aldol 3 k was obtained in 77% yield (entry 2) [15,28].
Although dehydration occurred partially when 800 mg of AC was
added, mixing was somewhat difficult (entry 1). In the absence
of AC, 3 k was obtained in the lower yield (33%) (entry 5). Heating
at 50 °C in the presence of AC (600 mg) yielded the corresponding
chalcone 4 k in the good yield (81%) (entry 7). A large decrease in
the yield of 4 k was observed in the absence of AC (28%) (entry 9).
Without NaOH, the reactions did not occur at all at room temper-
ature and 50 °C (entries 6 and 10).
which gives b-hydroxyketones and
a,b-unsaturated ketones. Fur-
thermore, these compounds were led to valuable synthetic inter-
mediates and natural products. Surfactants have been used for
the synthesis of chalcones in water [19-21].
During the course of our investigation of solid-mediated organic
transformations [22-26], we recently reported that activated char-
Next, the synthesis of a variety of chalcones 4 was examined.
The results are listed in Table 2. Benzaldehydes 1a-d and acetophe-
none (2c) were treated with NaOH in water for 6 h in the presence
of AC to give the corresponding chalcones 4a-d in good yields (en-
tries 1–4). Good results were obtained by the reactions between
benzaldehyde (1c) and ketones 2a, 2b, and 2d (entries 6–8). The
⇑
Corresponding author.
E-mail address: tanemura@ngt.ndu.ac.jp (K. Tanemura).
https://doi.org/10.1016/j.tetlet.2021.152918
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

K. Tanemura and T. Rohand
Tetrahedron Letters 71 (2021) 152918
alyzed by NaOH in water at 70 °C using AC. When 600 mg of AC
was added, (E)-2-benzylidenecyclohexan-1-one (6c) and bis(ben-
zylidene)cyclohexanone 7c were obtained in 65 and 34% yields,
respectively (entry 1). When 1.5 times amounts of AC, NaOH, and
H2O were employed, the reaction was accelerated (entry 2). The
prolonged reaction resulted in the higher yield of 7c (72%) (entry
4). In the absence of AC, the reaction proceeded slower and a
remarkable amount of 6c remained (entry 5). When 1.1
Fig. 1. Structure of compounds 1–4.
other sets of aldehydes 1 and ketones 2 led to the corresponding
chalcones 4j-m in good yields (entries 10–13). Preparation of
chalcone 4n which is the precursor for the synthesis of flavanone
[29–32] was successful (81%) (entry 14). Cinnamaldehyde (1 g)
reacted with 2c to give 4o in 81% yield (entry 15). The aldol reac-
tion using p-nitrobenzaldehyde (1e) or p-nitroacetophenone (2e)
resulted in the low yield (24%) or no reaction because of the forma-
tion of complex mixture, respectively (entries 5 and 9).
We further examined the synthesis of structurally related chal-
cone hybrids 7 (Fig 2). We optimized reaction conditions for the
synthesis of 2,6-bis((E)-benzylidene)cyclohexan-1-one (7c) as a
model compound. Table 3 shows the results for the treatment of
cyclohexanone (5) with 2.2 equivalents of benzaldehyde 1c cat-
Fig. 2. Structure of compounds 5–11.
Table 1
Reactions of aldehyde 1d with ketone 2a using AC in water.a.
Entry
AC (mg)
1d (%)b
2a (%)b
3k (%)b
4k (%)b
1
2
3
4
800
600
400
200
0
600
600
400
0
16
12
37
56
65
96
0
2
29
93
17
13
37
54
66
98
0
4
32
96
60
77
54
41
33
0
13
0
0
0
0
5
6c
7d
8d
9d
10c,d
0
0
81
71
28
0
15
39
0
600
a
b
c
Aldehyde 1d (2.2 mmol), ketone 2a (2.0 mmol), NaOH (2.0 mmol), H2O (2.0 mL), room temp, 3 h, 400 rpm.
Isolated yields.
Without NaOH.
50 °C, 6 h.
d
Table 2
Synthesis of chalcones 4 using AC in water.a.
Entry
Aldehyde 1 Ar1
Ketone 2 Ar2
Temp (°C)
Yield (%)b
1c
2
3
4
5
6
7
8
9
1a p-MeOC6H4
1b p-MeC6H4
1c Ph
1d p-ClC6H4
1e p-O2NC6H4
1c Ph
1c Ph
1c Ph
1c Ph
1a p-MeOC6H4
1d p-ClC6H4
1d p-ClC6H4
1f o-ClC6H4
1c Ph
2c Ph
2c Ph
2c Ph
2c Ph
70
70
70
50
25
70
70
70
70
70
50
50
70
70
70
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
80
89
89
81
24f
80
85
81
0f
82
81
80
82
81
81
2c Ph
2a p-MeOC6H4
2b p-MeC6H4
2d p-ClC6H4
2e p-O2NC6H4
2d p-ClC6H4
2a p-MeOC6H4
2d p-ClC6H4
2d p-ClC6H4
2f o-HOC6H4
2c Ph
10d
11
12
13
14e
15
1g PhCH = CH
a
b
c
d
e
f
Aldehyde 1 (2.2 mmol), ketone 2 (2.0 mmol), NaOH (2.0 mmol), H2O (2.0 mL), AC (600 mg), 6 h, 400 rpm.
Isolated yields.
24 h.
30 h.
NaOH (4.0 mmol) was used.
Complex mixture was obtained.
2

K. Tanemura and T. Rohand
Tetrahedron Letters 71 (2021) 152918
Table 3
Reactions of cyclohexanone 5 with aldehyde 1c using AC in water.a
Entry
AC (mg)
NaOH (mmol)
H2O (mL)
Time (h)
Yield (%)b
6c
7c
1
600
900
900
900
0
2.0
3.0
2.0
3.0
3.0
2.0
2.0
3.0
2.0
3.0
3.0
2.0
6
6
24
12
12
6
65
46
0
0
56
73
34
50
57
72
42
8
2
3c
4
5
6d
600
a
b
c
Aldehyde 1c (4.4 mmol), ketone 5 (2.0 mmol), 70 °C, 400 rpm.
Isolated yields.
Polymeric material was obtained.
Aldehyde 1c (2.2 mmol) was used.
d
Table 4
Synthesis of compounds 7 using AC in water.a
Entry
Aldehyde 1 Ar1
Temp (°C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
1a p-MeOC6H4
1b p-MeC6H4
1c Ph
1d p-ClC6H4
1f o-ClC6H4
1h p-FC6H4
1i p-F3CC6H4
1e p-O2NC6H4
70
70
70
70
70
70
70
50
96
48
12
12
24
12
12
12
7a
7b
7c
7d
7f
7h
7i
7e
50c
54c
72
76
62c
70
89
0e
a
b
c
Aldehyde 1 (4.4 mmol), ketone 5 (2.0 mmol), NaOH (3.0 mmol), H2O (3.0 mL), AC (900 mg), 400 rpm.
Isolated yields.
Polymeric material was obtained.
Table 5
Recycle experiments mediated by AC.
Entry
Yield (%)a
3rd
1st
2nd
4th
5th
1b
2c
89
72
95
72
92
67
94
70
93
68
a
Isolated yields.
b
Aldehyde 1b (2.2 mmol), ketone 2c (2.0 mmol), NaOH (2.0 mmol), H2O (2.0 mL), AC (600 mg), 70 °C, 6 h, 400 rpm.
Aldehyde 1c (4.4 mmol), ketone 5 (2.0 mmol), NaOH (3.0 mmol), H2O (3.0 mL), AC (900 mg), 70 °C, 12 h, 400 rpm.
c
equivalents of benzaldehyde 1c were employed, compound 6c was
obtained as the main product (entry 6).
Based on the above results, the synthesis of various bis(benzyli-
dene)cyclohexanones 7 was investigated. The treatment of cyclo-
hexanone 5 with examined aldehydes 1 except 1e (R1 = NO2)
gave the corresponding 7 in 50–89% yields (Table 4). The reactions
of cyclohexanone 5 were slower than those of acetophenones 2.
Among them, the reactions of 5 with aldehydes 1a and 1b which
possess electron-donating groups such as methoxy and methyl
groups required longer time (entries 1 and 2). Compounds 7 have
been attracting attention owing to biological activities [33]. Espe-
cially, it has been reported that compound 7 h showed good anti-
cancer activity against different cell lines and as antileishmanial,
while compound 7i has been known to show strong inhibition to
Fig. 3. Reaction mixture consisting of organic and aqueous phases.
a-glycosidase enzyme more than acarbose [34]. Cyclopentanone
(8) was also converted into 2,6-bis((E)-benzylidene)cyclopen-
tane-1-one (9) in 76% yield by the treatment with 2.2 equivalents
of 1c at 70 °C for 12 h.
We further examined regioselectivity for the aldol reaction of 2-
hexanone (10). The reaction of 10 with benzaldehyde 1c at 70 °C
for 6 h gave only (E)-1-phenyl-1-hepten-3-one (11) in 88% yield
[35]. The selectivity was the same as that of base-catalyzed type
[33,36,37].
Fig. 4. Plausible mechanism for the aldol reaction mediated by AC.
3

K. Tanemura and T. Rohand
Tetrahedron Letters 71 (2021) 152918
The 20-fold scaled-up experiments for the synthesis of com-
pounds 4c and 7c were performed in order to extend the scope
of the present system. The reactions progressed successfully, yield-
ing 4c and 7c in 87 and 73% yields, respectively.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.152918.
We conducted the recycle experiments for the synthesis of
compounds 4b and 7c. AC could be reused five times without the
decrease of yields (Table 5).
The reaction mixture consisted of the organic phase involving
aldehyde, ketone, and AC and the aqueous phase involving NaOH
as shown in Fig. 3.
Although the detailed mechanism is not clear at the present
moment, a possible mechanism is depicted in Fig. 4. AC adsorbs
aldehyde and ketone on the surface by dispersion forces, which
may increase ketone molecules exposed to where the hydrogen
abstraction by NaOH molecules in the aqueous phase can
occur [27].
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Declaration of Competing Interest
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Acknowledgments
We thank Center for Coordination of Research Facilities, Insti-
tute for Research Promotion, Niigata University for NMR measure-
ments. K. T. thanks the Research Promotion Grant (NDU Grants N-
20009) from Nippon Dental University. T. R. is grateful to the
University Cadi Ayyad especially the Faculty Polydisciplinaire of
Safi for the financial support given to the Laboratory of Analytical
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