Alkylacylimidazoles in Claisen–Schmidt and Knoevenagel Condensations

Article abstract of DOI:10.1134/S1070428020080187

Abstract: Alkylacylimidazoles were shown to be good reagents for Claisen–Schmidt and Knoevenagel-like condensations. The Claisen–Schmidt condensation of N-acetylimidazole with benzaldehyde followed by acidification with HCl gave cinnamic acid. The Knoevenagel-like condensation of N-(acetoacetyl)imidazole with hydrated aldehydes resulted in a fast and efficient formation of β-hydroxyketones. The studied reactions provide a new and general synthetic approach to cinnamic acid derivatives and β-hydroxyketones, as well as a new application field of alkylacylimidazoles.

Full text of DOI:10.1134/S1070428020080187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 8, pp. 1462–1467. © Pleiades Publishing, Ltd., 2020.
Alkylacylimidazoles in Claisen–Schmidt
and Knoevenagel Condensations
a
a
a
a
a
a,
H. Quan , L. Wang , Zh. Wang , X. Mei , J. Ning , and D. She *
a
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection,
Chinese Academy of Agricultural Sciences, Beijing, 100193 China
*
e-mail: dongmeishe@163.com
Received March 06, 2020; revised March 13, 2020; accepted March 18, 2020
Abstract—Alkylacylimidazoles were shown to be good reagents for Claisen–Schmidt and Knoevenagel-like
condensations. The Claisen–Schmidt condensation of N-acetylimidazole with benzaldehyde followed by acidi-
fication with HCl gave cinnamic acid. The Knoevenagel-like condensation of N-(acetoacetyl)imidazole with hy-
drated aldehydes resulted in a fast and efficient formation of β-hydroxyketones. The studied reactions provide a
new and general synthetic approach to cinnamic acid derivatives and β-hydroxyketones, as well as a new applica-
tion field of alkylacylimidazoles.
Keywords: alkylacylimidazoles, Claisen–Schmidt condensation, Knoevenagel-like condensation, cinnamic acid,
β-hydroxyketones
DOI: 10.1134/S1070428020080187
INTRODUCTION
in the formation of β-hydroxyketones 6 [Scheme 1,
reaction (2)]. Unlike the Knoevenagel condensation,
this reaction was completed at a low temperature and
in acidic conditions. In addition, the reaction products
were not dehydrated.
The need for an efficient and selective route for the
construction of C–C bonds continues to be a challenging
area in organic synthesis. Claisen–Schmidt condensation
[
1, 2] and Knoevenagel condensation [3–5] are classical
methods for forming C–C bonds. At present, the
Claisen–Schmidt reaction mainly obtains unsaturated
compounds through condensation of aromatic aldehydes
with aldehydes [6], ketones [6, 7], esters [8], nitriles
Acylimidazoles are important intermediates in
organic synthesis, and they are widely used due to
their stability and high activity [16]. However, at
present, acylimidazoles have basically been applied as
acylating agents, and only few reports are available on
the reactivity of the α-C atom in acylimidazoles. For the
first time, we have achieved the Claisen–Schmidt and
Knoevenagel-like condensation of alkylacylimidazoles
with aldehydes under mild reaction conditions. In this
study, the Claisen–Schmidt condensation is similar to
the Perkin reaction used to synthesize cinnamic acid
analogs [17, 18], but the reaction process is milder
and shorter. Furthermore, the Knoevenagel-like
condensation provides an effective supplement to aldol
reactions, which are unsuitable for the synthesis of
β-hydroxyketones from hydrated aldehydes [19].
[9] and so on compounds. Knoevenagel condensation
reaction was implemented by malonate [10], β-ketoester
[11], β-diketone [11], cyanoacetate [6, 12], malononitrile
[6, 13], and nitroacetate [14] and with other aldehydes or
ketones undergoing aldol condensation and dehydration
to obtain α,β-unsaturated compounds. The Claisen–
Schmidt and Knoevenagel condensation reactions of
alkylacyl imidazoles have not yet been reported.
We found that the Claisen–Schmidt condensation
of N-acetylimidazole (2) and benzaldehyde (1) in
the presence of sodium imidazolide (IMNa) at 0°C
followed by acidifaction with HCl gave cinnamic acid
(
3) [Scheme 1, reaction (1)]. Further on, a Knoevenagel-
RESULTS AND DISCUSSION
like condensation was quickly achieved using the sodium
enolate of N-(acetoacetyl)imidazole (4) [15], hydrated
aldehydes 5, and acetic acid at –20°C and resulted
Due to the strong electrophilicity of the imidazole
ring, the α-H atom in acylimidazole 2 is more acidic
1
462

ALKYLACYLIMIDAZOLES IN CLAISEN–SCHMIDT AND KNOEVENAGEL CONDENSATIONS
1463
Scheme 1.
O
O
O
H O
IMNa
THF
2
+
(1)
(2)
OH
N
N
HCl
1
2
3
Na+
–
OH
O
O
O
OH
AcOH
AcOEt
+
R
OH
N
R
N
4
5a, 5b
, 6, R = CHCl (a), CCl (b).
6a, 6b
5
3
2
than the carboxylate hydrogen atom, which allows
compound 2 to form a more stable enolate anion. In
addition, the negative ion that arises is further stabilized
by forming an extended π-conjugated system with the
imidazole ring. This created prerequisites for successful
Claisen–Schmidt reaction. Searching for optimal condi-
tions for the synthesis of cinnamic acid [Scheme 1, reac-
tion (1)], we varied the 1 : 2 : IMNa molar ratio, solvent,
and reaction temperature. The results are summarized
in Table 1. Increasing the amount of compound 2
and IMNa resulted in higher yields of 3 (Table 1,
entries 1–3), and, the yield was further improved, when
IMNa was taken in excess with respect to compound 2
(Table 1x7+, entries 4 and 5). Polar epoxy solvents, such
as THF and 1,4-dioxane, were more effective for the
reaction than toluene, diethyl ether, and DMSO (Table 1,
entries 4 and 6–9). Therefore, we chose the recoverable
solvent THF. When the temperatures were higher than
0°C, the yields dropped (Table 1, entries 10–12). At
temperatures higher than 0°C we detected formation of
benzoic acid and benzyl alcohol, presumably, because
part of benzaldehyde underwent a Cannizzaro reaction.
Finally, as the best conditions, we chose the conditions
shown in entry 4 in Table 1.
Table 1. Optimization of the Claisen–Schmidt reaction conditions for the synthesis of cinnamic acida
Entry no.
1 : 2 : IMNa ratio
1 : 1 : 1
Solvent
THF
T, °C
Yield, %b
77
1
2
3
4
5
6
7
8
9
0
0
1 : 1.1 : 1.1
1 : 1.2 : 1.2
1 : 1.1 : 1.2
1 : 1.1 : 1.3
1 : 1.1 : 1.2
1 : 1.1 : 1.2
1 : 1.1 : 1.2
1 :1.1 : 1.2
1 : 1.1 : 1.2
1 : 1.1 :1.2
1 : 1.1 : 1.2
THF
82
THF
0
83
THF
0
85
THF
0
85
1,4-Dioxane
DMSO
0
83
0
67
Et O
0
44
2
Toluene
THF
0
35
1
0
1
–10
10
20
83
1
THF
76
1
2
THF
75
a
Compound 1 (10 mmol), compound 2 and IMNa in solvent (25 mL) for 6 h.
Isolated yield.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

1464
QUAN et al.
Table2. OptimizationofreactionconditionsforKnoevenagel-likecondensationconditionsforthesynthesisofβ-hydroxyketonesa
Entry no.
4 : 5 : AcOH ratio
1 : 1 : 1
Solvent
THF
T, °C
–20
–20
–20
–20
–20
–20
–20
–20
–20
–10
0
Yield, %b
71
1
2
3
4
5
6
7
8
9
1 : 1.5 : 1
1 : 2 : 1
THF
82
THF
90
1 : 2 : 2
1 : 2 : 3
THF
95
THF
95
1 : 2 : 2
Ethyl acetate
Acetone
Toluene
9
1 : 2 : 2
94
1 : 2 : 2
65
1 : 2 : 2
Et O
72
2
1
0
1
1 : 2 : 2
THF
THF
THF
THF
92
1
1 : 2 : 2
87
1
2
1 : 2 : 2
20
85
1
3c
1 : 2 : 2
–20
81
a
b
c
Compound 4 (10 mmol), compound 5a and AcOH in solvent (20 mL), reaction time 1 h at T and 1 h at rt.
Isolated yield.
Compound 4 (10 mmol), compound 5b and AcOH in solvent (20 mL), reaction time 1 h at T and 1 h at rt.
The conditions for the synthesis of β-hydroxyketo-
was shown in Scheme 2, route A. First, acetylimidazole
forms anion7 under the action of sodium imidazolide and
converts it into enolate 8. Subsequently, the condensa-
tion of enolate 8 with benzaldehyde provides interme-
diate 9, which receives proton provided by imidazole
and undergoes dehydration to form intermediate 10.
Finally, the latter is hydrolyzed in HCl solution to give
the target product.
nes 6a and 6b by a Knoevenagel-like condensation
with N-acetoacetylimidazole (5a) and trichloro-
acetaldehyde hydrate (5a) as substrates [Scheme 1,
reaction (2)] were optimized in the same way by
varying the 4 : 5 : AcOH molar ratio, solvent and
reaction temperature. The results were summarized
in Table 2. Increasing the amount of compound 5a
and AcOH resulted in higher yields of compound 6a
The reaction route for the preparation of
β-hydroxyketones is shown in Scheme 2, route B.
Sodium salt of N-acetoacetylimidazole 4 is acidified with
AcOH to give enol 11, which undergoes condensation
with hydrated aldehyde 5. The dehydration of the latter
to form intermediate 12 followed by hydration and
(
Table 2, entries 1–5). Polar epoxy solvents, such THF,
ethyl acetate, and acetone, were more effective for
the reaction than toluene and diethyl ether (Table 1,
entries 4 and 6–9). At temperatures higher than –20°C,
the yields dropped (Table 2, entries 10–12). A small
amount of 5,5-dichloropent-3-en-2-one was obtained as
a by-product. Finally, as the best conditions, we chose
the conditions shown in entry 4 in Table 2. Under the
best conditions, trichloroacetaldehyde hydrate (5b) was
reacted to obtain a good yield (Table 1, entry 13). At
the same time, attempted reaction of butyraldehyde
failed.
elimination of CO and imidazole (IMD) leads to the
2
target β-hydroxyketone.
The synthesis of cinnamic acid occurs under
mild conditions and in higher yields compared
with previously reported methods. The method of
synthesis of β-hydroxyketones by the reaction of
N-(acetoacetyl)imidazole with hydrated aldehydes
overcomes the disadvantages of the previously reported
time-consuming synthesis of β-hydroxyketones
by the β-ketoacid method [20]. 5,5-Dichloro-4-
Based on our results, we propose a tentative
mechanism for the Claisen–Schmidt and Knoevenagel-
like condensations of alkylacylimidazoles (Scheme 2).
The reaction route for the preparation of cinnamic acid
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

ALKYLACYLIMIDAZOLES IN CLAISEN–SCHMIDT AND KNOEVENAGEL CONDENSATIONS
1465
Scheme 2.
hydroxypentan-2-one was prepared for the first
time.
from 25% aqueous ethanol to give the target
product.
Synthesis of β-hydroxyketones 6a and 6b (general
EXPERIMENTAL
procedure). Compound 4 (1 equiv, 10 mmol), prepared
by the reaction of 1-acetylimidazole with IMNa in THF
Materials and methods. All starting reagents
purity > 99%) and solvents (AR grade) were obtained
from Baiyin Chuangsheng Biotechnology (Beijing). The
H NMR spectra were recorded on a Bruker 300 MHz
(
[15], was added in portions to a mixture of 2 equiv of
1
AcOH and 2 equiv of hydrated aldehyde 5a or 5b in
20 mL THF, and the mixture was stirred at –20°C for 1 h
and then at room temperature for 1 h. After completion
of the reaction (by TLC), the reaction mixture was
acidified to pH < 3 with HCl and then extracted with
dichloromethane. The extract was dried over MgSO4
and concentrated under reduced pressure to give the
target product.
spectrometer and are reported in ppm downfield from
TMS (δ 0.00 ppm) and relative to the signal of DMSO (δ
1
3
1
2
.52 ppm). The C{ H} NMR spectra were recorded on
a 75 MHz spectrometer and are reported in ppm using
the DMSO-d (δ 39.7 ppm) solvent as internal standard.
6
The IR spectra were recorded for thin films on KBr
plates on a Thermo Nicolet 6700 FTIR spectrometer and
–
1
are reported in cm . The mass spectra were measured
on a Shimadzu 6890/5973 GCMS system.
Cinnamic acid (3). Yield 85%, white solid, mp 132–
–
1
1
1
5
33°C. IR spectrum (KBr), ν, cm : 3026, 1676, 1627,
Synthesis of cinnamic acid (3). A solution of
.1 equiv of compound 2 in 10 mL of THF was
added at 0°C under nitrogen over the course of 1 h to
a stirred mixture of compound 1 (1 equiv, 10 mmol),
494, 1448, 1418, 1312, 1284, 1221, 978, 768, 710, 682,
90, 541. H NMR spectrum (300 MHz, DMSO-d ),
1
1
6
δ, ppm: 6.50 d (1H, CH=, J 16.0 Hz), 7.46–7.43 m (3H,
PhH), 7.60–7.57 m (2H, PhH), 7.84 d (1H, CH=, J
1
.2 equiv of IMNa, and 15 mL of THF, after which
1
3
1
6.0 Hz), 12.50 s (1H, COOH). C NMR spectrum
stirring 0°C was continued for 5 h. After completion
of the reaction (by TLC), the reaction mixture was
acidified to pH < 3 and stirring was continued for
an additional 20 min and extracted with chloro-
form. The extract was concentrated under reduced
pressure, and the residue was recrystallized
(
75 MHz, DMSO-d ), δ, ppm: 117.1, 128.1, 128.7,
6
1
30.5, 133.7, 146.8, 172.5. Mass spectrum, m/z (I , %):
rel
+
148 (72.88) [M] , 147 (100), 131 (20.20), 103 (48.45),
102 (21.20), 91 (21.57), 77 (39.15), 51 (28.97). The
spectra are consistent with published in [21].
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 8 2020

1466
QUAN et al.
5
,5-Dichloro-4-hydroxy-pentan-2-one (6a). Yield
no. 2016YFD0200201) and the National Natural Science
Foundation of China (grant nos. 31772175 and 31621064).
–
1
9
3
5%, yellowish liquid. IR spectrum (KBr), ν, cm :
400, 3004, 2918, 1712, 1366, 1161, 1079, 780. H
NMR spectrum (300 MHz, DMSO-d ), δ, ppm: 2.24 s
3H, CH ), 2.92 t (2H, CH , J 7.0 Hz), 4.44–4.38 m (1H,
CH), 5.82 d (1H, CH, J 3.9 Hz). C NMR spectrum
75 MHz, DMSO-d ), δ, ppm: 30.7, 45.8, 71.2, 77.2,
05.8. Mass spectrum, m/z (I , %): 174 (0.01) [M +
1
CONFLICT OF INTEREST
The authors are no conflict of interest.
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(
3 2
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https://doi.org/10.1002/slct.201600776
In this study, we developed a mild and high-yield
method of synthesis of cinnamic acid, as well as a
low-temperature, acidic, and catalyst-free method of
synthesis of β-hydroxy ketones by the reactions of
acylimidazoles with aldehydes. The developed new
and general synthetic approach can greatly enhance
the accessibility of cinnamic acid derivatives and
β-hydroxyketones. In addition, a new direction for the
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