Gram-scale preparation of dialkylideneacetones through Ca(OH)2-catalyzed Claisen-Schmidt condensation in dilute aqueous EtOH

Article abstract of DOI:10.1016/j.cclet.2018.01.035

A synthetic method of dialkylideneacetones has been developed. Compared with known protocols, the method employed catalytic Ca(OH)₂ as the cheap, mild base catalyst and dilute aqueous EtOH (20%, v/v) as the green and safe solvent. The procedure was easily operated: In most cases, the product could be isolated by a simple filtration, and purified by washing with water. This paper provided experimental details of the reactions, which could be applied in gram-scale synthesis and should be a very reliable and practical protocol to prepare these useful compounds in laboratory and at the industrial level.

Full text of DOI:10.1016/j.cclet.2018.01.035

G Model
CCLET 4425 No. of Pages 3
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Gram-scale preparation of dialkylideneacetones through Ca(OH)2-
catalyzed Claisen-Schmidt condensation in dilute aqueous EtOH
b,
Hao Zhanga,b, Mengting Hanb, Chenggen Yangb, Lei Yua,b, , Qing Xu
*
*
a
Guangling College, Yangzhou University, Yangzhou 225002, China
b
School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A synthetic method of dialkylideneacetones has been developed. Compared with known protocols, the
method employed catalytic Ca(OH)2 as the cheap, mild base catalyst and dilute aqueous EtOH (20%, v/v)
as the green and safe solvent. The procedure was easily operated: In most cases, the product could be
isolated by a simple filtration, and purified by washing with water. This paper provided experimental
details of the reactions, which could be applied in gram-scale synthesis and should be a very reliable and
practical protocol to prepare these useful compounds in laboratory and at the industrial level.
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 30 November 2017
Received in revised form 9 January 2018
Accepted 19 January 2018
Available online xxx
Keywords:
Claisen-Schmidt condensation
Acetone
Aldehyde
a,
b
-Unsaturated ketone
Dialkylideneacetone
Dialkylideneacetones serve as the key precursors to construct/
synthesize many useful organic skeletons or natural products, such
as pyrimidines, 2,7-disubstituted tropones, cystodytins, etc. [1–3].
They are also widely employed as bioactive components in
antiangiogenic reagent, quinine reductase inducer and arginine
methyltransferase inhibitor in biochemistry studies [4–7], as
agrochemical, pharmaceutical and perfume intermediates and
ligands in fine chemical industry [8–11], and as liquid crystalline
polymer units in materials science [12]. Like simple
Our group aims to develop the green synthetic methods with
industrial application potential [29–34]. Recently, it was found that
Ca(OH)2, the cheap, mild and common but rarely used inorganic
base, could serve as the efficient catalyst in dialkylideneacetone
synthesis. The method required very low catalyst loading (10 mol%)
and could use dilute alcohol as the green solvent (20% aqueous
solution, v/v). It could be expanded to at least 100 mmol scales to
produce the related dialkylideneacetones in gram scale. Herein, we
wish to report the details of the method.
a
,
b
-unsaturated ketones, dialkylideneacetones could be prepared
The Ca(OH)2-catalyzed reaction of (E)-4-phenylbut-3-en-2-one
(1a) with benzaldehyde (2a) were initially tested. After heating
1 mmol of 1a with equivalent 2a in 1 mL of EtOH in the presence of
0.2 mmol of Ca(OH)2 at 60 ꢀC for 48 h, the desired product 3a could
be isolated in 47% yield by preparative thin layer chromatography
(Eq. (1)). In the process, partial of the Ca(OH)2 was insoluble and
precipitated at the bottom of the reaction tube. Therefore, water
was then introduced into the solvent to enhance the Ca(OH)2
solubility. The product yield was enhanced with elevated H2O
content and 20% aqueous EtOH (volume concentration) was found
to be the most preferable solvent, affording 3a in 80% yield (Fig. 1).
No reaction occurred in the absence of EtOH, although Ca(OH)2
dissolved completely in the case. This was probably due to the low
solubility of the organic reactants in water, as after the addition of
2 mol% of sodium dodecyl sulfate or benzyldodecyldimethylam-
monium bromide as surfactant, the same reactions in water could
afford the desired product 3a in 87% and 39% yields, respectively.
Thus, EtOH, as the water-soluble organic solvent, might facilitate
the contact of the organic reactants with Ca(OH)2 to promote the
through the Claisen-Schmidt reactions of acetone with aldehydes
for the high atom utilization efficiency form the industrial
viewpoint [13,14]. However, the present methods were cata-
lyzed/promoted by strong acids or bases [15–19], Lewis acid
catalysts such as Cu(OTf)2 [20], FeCl3 [21], TiCl3(OTf) [22], SmI3
[23], Yb(OTf)3 [24],etc., noble metal catalysts such as RuCl3 [25],
TMSCl/Pd-C [26], or supported catalysts/dehydrants such as KF-
Al2O3 [27], P2O5/SiO2 [28], etc., which were corrosive, expensive, or
required tedious fabrication methods or high catalyst loadings.
Moreover, although there are many reports on symmetrically
substituted dialkylideneacetones, method for the synthesis of
dialkylideneacetones with different alkylidenes has not been well
documented yet.
* Corresponding authors at: School of Chemistry and Chemical Engineering,
Yangzhou University, Yangzhou 225002, China.
E-mail addresses: yulei@yzu.edu.cn, yzuyulei@163.com (L. Yu),
qing-xu@yzu.edu.cn, xuqing@yzu.edu.cn (Q. Xu).
https://doi.org/10.1016/j.cclet.2018.01.035
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: H. Zhang, et al., Gram-scale preparation of dialkylideneacetones through Ca(OH)2-catalyzed Claisen-Schmidt
condensation in dilute aqueous EtOH, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.035

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CCLET 4425 No. of Pages 3
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H. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
Table 2
Reactions of (E)-4-phenylbut-3-en-2-one (1a) with aldehyde (2) at magnified
reaction scale.
Entry
R (2)
Reaction scale
3: Yield (%)a,b
1
2
3
4
5
6
7
8
9
10
Ph (2a)
Ph (2a)
10 mmol
100 mmol
100 mmol
10 mmol
100 mmol
100 mmol
100 mmol
100 mmol
10 mmol
10 mmol
3a: 81 (C. C.)
3a: 80 (F.W.)
3b: 79 (F. W.)
3c: 51 (C. C.)
3d: 97 (F. W.)
3e: >99 (F. W.)
3f: >99 (F. W.)
3g: 97 (F. W.)
3h: 32 (C. C.)
3i: 55 (C. C.)
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-FC6H4 (2d)
4-CF3C6H4 (2e)
2-thienyl (2f)
2-furanyl (2g)
c-C6H11 (2h)
PhCH=CH (2i)
Fig.1. Experimental results of the reactions performed in aqueous EtOH at different
volume concentrations.
reaction, and it was better than the sodium dodecyl sulfate
surfactant for the solid waste-free process.
(1)
a
Isolated yields based on 1a.
b
Product isolation methods were given in parentheses: C. C. = column
chromatography; F. W. = Filtration and washing with water.
Additional parallel experiments were conducted to optimize
the reaction conditions. Elevated Ca(OH)2 amount could hardly
improve the reaction, while the excess catalyst precipitated due to
its low solubility (Table 1, entry 1). Considering the higher turnover
number and the acceptable product yield, Ca(OH)2/1a = 10% was
then screened out to be the better condition (Table 1, entries 3 vs.1,
2, 4). The reaction was retarded at reduced temperature (Table 1,
entry 5), and afforded 3a in the highest yield (83%) at 80 ꢀC (Table 1,
entries 7 vs. 6, 8).
Under the optimized conditions, the reaction of 1a with
benzaldehyde (2a) was magnified into 10 mmol scale and the
desired product 3a could be obtained in 81% yield through column
chromatography isolation (Table 2, entry 1). Further magnified
reaction at 100 mmol was conducted and in the process, the
product 3a precipitated and could be isolated by a simple filtration
(Fig. 2, image a). After washing with water to remove the Ca(OH)2
catalyst and drying under infrared lamp irradiation, pure 3a was
obtained as a yellow solid in 80% yield (Fig. 2, image b and Table 2,
entry 2). 4-Methylbenzaldehyde (2b), the electron-enriched
aldehyde, could also react with 1a to produce the related
dialkylideneacetone 3b in good yield at 100 mmol scale (Table 2,
entry 3), but for 4-methoxybenzaldehyde (2c), since a series of
unidentified by-product was generated, no precipitation was
Fig. 2. Photographs of the reaction flask after the reaction (image a) and the
purified product 3a (image b).
observed in the 100 mmol-scale reaction and the product was
isolated in 51% yield by column chromatography in a 10 mmol-
scale reaction (Table 2, entry 4). Notably, electron-deficient
aldehydes, such as 2d–e, were preferable for the reaction, affording
the desired products in excellent to almost quantitative yields
(Table 2, entries 5 and 6). The reactions with heterocycle-
substituted aldehydes 2f–g also led to excellent product yields
(Table 2, entries 7 and 8). Aliphatic and alkenyl aldehydes 2h–i
were also applicable to produce 3h–i in 32–55% yields (Table 2,
entries 9 and 10). Because Ca(OH)2 catalyst was used in very low
loading (10 mol%) and might be deactivated by the carboxylic acid
impurities, the aldehydes should be purified by distillation or
recrystallization before using.
As (E)-4-phenylbut-3-en-2-one (1a) was synthesized through
the Ca(OH)2-catalyzed condensation of benzaldehyde (2a) with
acetone, we then tried to combined the two reaction steps in one
pot to prepare dialkylideneacetone 3a. In the process, 2a first
reacted with acetone to produce 1a. The excess acetone and
solvent were then removed by distillation and another solution of
benzaldehyde 2a in fresh EtOH/H2O was added. After heating at
80 ꢀC for 48 h, the product 3a precipitated and could be isolated by
filtration and purified by washing with water (Table 3, entry 1).
Other dialkylideneacetones 3b–i were smoothly prepared in
similar way (Table 3, entries 2–9).
Table 1
Condition optimizations for the reaction of (E)-4-phenylbut-3-en-2-one (1a) with
benzaldehyde (2a).a
b
Entry
Ca(OH)2/1a
T (ꢀC)
3a yield (%)c
1
2
3
4
5
6
7
8
30%
20%
10%
5%
10%
10%
10%
10%
60
60
60
60
50
70
80
90
82
80
79
64
44
80
83
76
Moreover, the order of introducing functional groups was
reversible. As shown in Table 4, substituted aldehydes 2 first
reacted with acetone to generate the intermediate 1 in situ, which
could then react with another benzaldehyde (2a) to produce the
same products 3 in moderate to excellent yields (Table 4, entries
1–8). Notably, the yields of 3b–c could be enhanced by using this
protocol (Table 4, entries 1 and 2 vs. Table 3, entries 2 and 3).
a
1 mmol of 1a, 1 mmol of 2a and 1 mL of EtOH/H2O solvent were employed.
Molar ratio of Ca(OH)2 vs. 1a.
Isolated yields based on 1a.
b
c
Please cite this article in press as: H. Zhang, et al., Gram-scale preparation of dialkylideneacetones through Ca(OH)2-catalyzed Claisen-Schmidt
condensation in dilute aqueous EtOH, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.035

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H. Zhang et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
Table 3
practicability for both laboratory synthesis as well as the industrial
level production.
One-pot synthesis of dialkylideneacetone 3 from 2a.
Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 21202141, 21672163), Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions (PAPD), Top-notch
Academic Programs Project of Jiangsu Higher Education Institu-
tions (TAPP), the high level talent support project of Yangzhou
University (top-notch talent, L. Yu), Yangzhou Natural Science
Foundation (No. YZ2014040) and the Natural Science Foundation
of Guangling College (No. ZKZD17005) for financial support.
Entry
R (2)
Reaction scale
3: Yield (%)a,b
1
2
3
4
5
6
7
8
9
Ph (2a)
100 mmol
100 mmol
10 mmol
100 mmol
100 mmol
100 mmol
100 mmol
10 mmol
3a: 75 (F.W.)
3b: 76 (F. W.)
3c: 46 (C. C.)
3d: 95 (F. W.)
3e: >99 (F. W.)
3f: 84 (F. W.)
3g: 97 (F. W.)
3h: 28 (C. C.)
3i: 53 (C. C.)
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-FC6H4 (2d)
4-CF3C6H4 (2e)
2-thienyl (2f)
2-furanyl (2g)
c-C6H11 (2h)
PhCH=CH (2i)
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4-MeOC6H4 (2c)
4-FC6H4 (2d)
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3c: 52 (C. C.)
3d: 98 (F. W.)
3e: >99 (F. W.)
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In conclusion, we developed a practical method for the
synthesis of dialkylideneacetones through the Ca(OH)2-catalyzed
Claisen-Schmidt condensations in dilute ethanol. The cheap, low-
loading and mild catalyst, green solvent and the easily-operated
procedures are the advantages of the protocol over many known
methods. The reactionwas scalable to at least 100 mmol to produce
the desired dialkylideneacetones in grams, showing very good
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Please cite this article in press as: H. Zhang, et al., Gram-scale preparation of dialkylideneacetones through Ca(OH)2-catalyzed Claisen-Schmidt
condensation in dilute aqueous EtOH, Chin. Chem. Lett. (2018), https://doi.org/10.1016/j.cclet.2018.01.035