Water assisted and choline chloride-dimethylurea deep eutectic salts as catalyst towards the attractive reaction of indole, benzaldehyde, and malononitrile

Article abstract of DOI:10.3987/COM-18-13913

The condensation of indole, benzaldehyde, and malononitrile was relatively rigorous compared with other Yonemitsu type reaction. We described a strategy using catalytic amount of choline chloride-dimethylurea deep eutectic salts as cheap and safe accelerator. We also found that introducing right amount of water in reaction system was crucial. This method tolerates variations in all three components to get desired 3-substituted indoles in satisfactory yields.

Full text of DOI:10.3987/COM-18-13913

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HETEROCYCLES, Vol. 96, No. 7, 2018
HETEROCYCLES, Vol. 96, No. 7, 2018, pp. 1266 - 1274. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 26th April, 2018, Accepted, 20th June, 2018, Published online, 28th June, 2018
DOI: 10.3987/COM-18-13913
WATER ASSISTED AND CHOLINE CHLORIDE-DIMETHYLUREA
DEEP EUTECTIC SALTS AS CATALYST TOWARDS THE
ATTRACTIVE REACTION OF INDOLE, BENZALDEHYDE, AND
MALONONITRILE
Hongli Ruan, Yue Lv, Shijun Yu, Chengwei Lv,* and Yue An*
School of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, People’s Republic of China; E-mail: chengweilv@126.com,
18018928980@163.com
Abstract – The condensation of indole, benzaldehyde, and malononitrile was
relatively rigorous compared with other Yonemitsu type reaction. We described a
strategy using catalytic amount of choline chloride-dimethylurea deep eutectic salts
as cheap and safe accelerator. We also found that introducing right amount of water
in reaction system was crucial. This method tolerates variations in all three
components to get desired 3-substituted indoles in satisfactory yields.
Yonemitsu condensation which was first reported in the early 1980s is a successful multi-component
reaction for the synthesis of various 3-substituted indoles.1 Up to now, this three-component reaction
involving indole, aldehyde, and an active methylene compound has been the subject of numerous
investigations, but most of these protocols usually employed Meldrum’s acid as the reagents due to its high
activity.2 Only few examples extended the active methylene derivatives to malonesters,3 barbituric acid,4
dimedone,5 and 4-hydroxycoumarin.6 Malononitrile is a valuable nucleophile which can then be
conveniently transformed into carboxylic acid, ester, amine, or amide groups.7 However, it exhibits lower
acidity and nucleophilicity compared with Meldrum’s acid.8 This sufficiently rationalizes why the
Yonemitsu type reaction based on indole, benzaldehyde, and malononitrile need harsh conditions such as
long reaction time and high catalyst loading. Until 2011, Zhou reported this reaction could be catalyzed by
Cu(II)/Salen complex with 1.0 equiv. KH2PO4 as additive.9 Arjan reported an extensive investigation using
Zn(II)/Salen complex as mediators in the presence of 1.0 equiv. diisopropylethylamine as base.10 After that,
a ligand-free reaction was developed which utilizes Cu(OAc)2 as catalyst and 1.0 equiv. KH2PO4 as
additive.11 Wan and co-workers found that 1.0 equiv. KH2PO4 in the mixture of H2O and PEG-200 could

HETEROCYCLES, Vol. 96, No. 7, 2018
1267
promote this reaction.12 More recently, tetrabutylammonium fluoride,13 tetrabutylammonium glycinate
ionic liquid,14 L-proline,15 glycine,16 and H3PW12O40 were employed to promote this condensation.
17
Although some improvements have been achieved, searching for more general, efficient, and high yielding
route to realize this significant transformation remains a valid exercise.13-15
Deep-eutectic solvents (DES) have drawn considerable attention in recent years due to their less toxicity,
high biodegradability, comparatively low price, and straightforward synthesis.18 These features made the
applications of DES increasingly popular and DESs have been widely utilized as efficient reaction medium
or catalyst in organic synthesis.19 Our research group has interested in developing synthetic methodologies
for useful organic compounds and a part of our efforts has been focused on improving Yonemitsu
condensation.20 Based on our empirical experience, herein, we screen an appropriate DES as catalyst with
the hope of addressing this challenging reaction of indole, benzaldehyde and malononitrile (Scheme 1).
R1
CN
CHO
CN
CN
ChCl-DMU
CN
R1
+
+
N
H
R2
N
R2
H
1
2
3
4a-4r
Scheme 1. Approach for the reaction of aldehyde, malononitrile and indole
As a starting point, benzaldehyde, malononitrile and indole were selected as model substrates to investigate
the feasibility of our methodology (Table 1). Surprisingly, this three-component reaction cannot be
efficiently achieved in anhydrous ethanol and afforded arylmethylenemalononitrile as the main product via
Knoevenagel condensation between malodinitrile and aldehyde (Table 1, entry 1). Based on our empirical
experience, adding water could assist the Yonemitsu reaction.20 Thus, this strategy was tested. Product 4a
was furnished in a satisfactory result in the presence of water as we expected. After preparation of different
DES, it was found that choline chloride and 1,3-dimethylurea (ChCl-DMU) has the highest catalytic
efficiency (Table 1, entry 2). In order to confirm the effect of DES, this reaction was tested in aqueous
ethanol without catalyst. The Knoevenagel condensation product was obtained too and almost no target
product was probed (Table 1, entry 3). Solvents including ethyl lactate and methanol mixed with water
were probed but the results were poor (Table 1, entries 6, 7). In order to further increase reaction yield, the
solvent was finely tuned by employing ethanol with water in different volumes and proportions. After some
experimentations, we were pleased to find that 0.8 mL ethanol and 0.2 mL water was the best choice in
which this conversion took place with maximum isolated yield. We also observed that increasing the
amount of indole to 0.55 mmol afford 4a in 85% yield. To achieve the most suitable conditions, model

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HETEROCYCLES, Vol. 96, No. 7, 2018
reaction was tentatively run in different temperature, catalyst loading, and time. Optimization result
indicated that reacted at 50 oC for 36 h and utilizing 10 mol% of ChCl-DMU were efficient to promote this
reaction. Target molecule could form and isolate in 95% yield after washing with 50% ethanol. Therefore,
this reaction was optimized using a cheap, safe, and environmentally benign medium and catalyst.
Table 1. Optimization of the reaction conditions for the synthesis of 4a
Entrya
1
Catalyst/mol%
ChCl-DMU 20%
ChCl-DMU 20%
--
Solvent
EtOH
Vol./mL Temp./oC
Time/h
40
Yieldb/%
trace
73
1.0
30
30
30
30
30
30
30
30
30
30
30
40
50
60
50
50
50
2
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
MeOH-H2O
ethyl lactate-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
EtOH-H2O
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
0.6/0.4
1.2/0.8
0.8/0.2
0.9/0.1
0.8/0.2
0.8/0.2
0.8/0.2
0.8/0.2
0.8/0.2
0.8/0.2
0.8/0.2
40
3
40
trace
68
4
ChCl-urea 20%
ChCl-acetic acid 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 20%
ChCl-DMU 10%
ChCl-DMU 5%
ChCl-DMU 10%
40
5
40
24
6
40
45
7
40
--
8
40
67
9
40
80
10
11c
12c
13c
14c
15c
16c
17c
40
66
40
85
40
89
40
94
40
91
40
95
40
79
36
95
a The reactions were carried out with benzaldehyde, malononitrile and indole in equimolecular amounts of
0.5 mmol. b Isolated yield. c Indole 0.55 mmol.
With the best experimental conditions in hand, we turned our attention to check the generality as well as
the effectiveness of our protocol. Initially, a broad range of aromatic aldehydes were investigated under
identical reaction conditions in Table 2 to furnish the corresponding 3-substituted indoles (4a-4r) in good
to excellent yields. Due to the disfavored influence of electronic and steric effects of some substituted
aromatic aldehyde, we increased the catalyst load to 20 mol%. The results showed that the electronic
effect played a major role in governing the reactivity of the substrates. Irrespective of presence of electron
withdrawing groups in the ortho, meta or para positions on the ring of aromatic aldehydes, reactions
o
proceeded smoothly to furnish desired products in high yields at 30 C. Introduction of strongly
electron-withdrawing group on benzene ring such as nitro not only favored to the yield of reaction, but
also accelerated the reaction rate (4l, 4m). Whereas, electron-rich substrates were transformed into the

HETEROCYCLES, Vol. 96, No. 7, 2018
1269
corresponding products in a relatively lower yield. With increasing the electron donating substituents on
aromatic ring, activity was further decreased. So, methoxy substituted aromatic aldehydes gave worse
results than methyl.
Table 2. Substrate scope for the synthesis of product 4
Me
Me
Me
CN
CN
CN
CN
CN
CN
CN
CN
N
N
N
N
H
H
H
H
4b (50 °C, 82%)c
4a (50 °C, 95%)
4c (50 °C, 97%)
4d (50 °C, 76%)
O
Me
Me
Cl
CN
O
CN
CN
CN
CN
CN
MeO
CN
CN
N
H
N
H
N
major product
H
4g (30 °C, 97%)c
4e (50 °C, 76%)c
4f (50 °C, 94%)
Br
Cl
Cl
Br
CN
CN
CN
CN
CN
CN
CN
CN
N
N
H
N
H
H
N
H
4j (30 °C, 95%)c
4h (30 °C, 97%)
4i (30 °C, 97%)
4k (30 °C, 97%)
NO2
O2N
Me
CN
CN
CN
CN
CN
CN
CN
CN
N
Me
N
H
N
H
N
Me
H
H
4n (30 °C, 97%)
4l (30 °C, 92%)c,d
4m (30 °C, 97%)d
4o (30 °C, 97%)
Cl
Br
O2N
CN
NC
CN
CN
CN
CN
CN
CN
CN
CN
O
N
Me
N
Me
N
Me
major product
H
H
H
4r (30 °C, 98%)d
major product
4p (30 °C, 98%)
4q (30 °C, 98%)
a Reaction condition: aldehyde (0.5 mmol), malononitrile (0.5 mmol), indole (0.55 mmol), 20% mmol
b
c
catalyst and 1 mL EtOH-H2O (4:1) were stirred for 36 h. Isolated yield. Separated by column
chromatography. d Reaction time: 12 h.
Unfortunately, 4-methoxybenzaldehyde and 4-bromobenzaldehyde even gave the Knoevenagel
condensation adducts as main products. However, electron releasing group at the 3-position of aromatic

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HETEROCYCLES, Vol. 96, No. 7, 2018
aldehyde gave the desired products in good yields. Based on the mechanism, we think this outcome arose
from the conjugation effect. The stronger positive p-π conjugated methoxyl substituent caused electron
density of carbonyl carbon atom in benzaldehyde and exocyclic double bond in Knoevenagel
condensation intermediate to enhance. But above result was harmful to both two steps of this reaction,
especially when Michael addition of electron-rich indole with high electron density double bond of
Knoevenagel adduct was performed. In contrast, presence of methoxy in meta-position on benzene ring
had weak electron-withdrawing inductive effect and no conjugation effect. So, it afforded a better yield.
Encouraged by these results, we replaced the substrate of indole with 2-methylindole and repeated the
o
reaction at 30 C (Table 2, 4n-4r). Compared with the initial reaction, the corresponding products
obtained in better yields. Unfortunately, when employing furfural or 1-naphthaldehyde as substrate,
Knoevenagel adduct was the major product. Mainly due to they are also the electron rich aromatic
aldehyde.
R1
O
O
O
CHO
O
O
ChCl-DMU
EtOH-H2O
O
R1
+
+
O
N
H
N
H
O
1
2'
3
5a-5i
Scheme 2. Approach for the reaction of aldehyde, Meldrum’s acid and indole
To highlight the applicability of our developed catalytic system, we further employing Meldrum’s acid as
reagent reacted with indole and various aromatic aldehydes (Scheme 2). Indeed, syntheses of
corresponding 3-substituted indoles could achieve in excellent yields. The reaction time shorten to 7
Table 3. Substrate scope for the synthesis of product 5
Entrya
R
Product
5a
Yieldb/%
94
1
2
3
4
5
6
7
8
9
C6H5
3-MeC6H4
4-MeC6H4
3-MeOC6H4
2-ClC6H4
3-ClC6H4
3-BrC6H4
3-NO2C6H4
4-NO2C6H4
95
81
92
97
97
96
94
98
5b
5c
5d
5e
5f
5g
5h
5i
a Reaction condition: aldehyde (0.5 mmol), Meldrum’s acid (0.55 mmol), indole (0.50 mmol), 20% mmol
catalyst and 2 mL EtOH-H2O (4:1) were stirred at 40 oC for 7 h. b Isolated yield.

HETEROCYCLES, Vol. 96, No. 7, 2018
1271
o
hours and reaction temperature reduced to 40 C with 20 mol% catalyst in 2 mL aqueous ethanol (Table
3). However, aliphatic aldehyde as the reactant had bad reactivity in this two reaction system.
Figure 1. Crystal structure of compound 4a (CCDC. 1543655)
With the hope of further investigating the mechanism, several control experiments were tested (Figure 2).
o
We firstly verified the reaction of benzaldehyde and malononitrile with 10 mol% ChCl-DMU at 50 C
whether working well in the presence of water. 2-Benzylidenemalononitrile was obtained in 95% yield
after about 10 min in 1 mL solvent (EtOH-H2O 4:1, v/v) and only 64% yield was obtained without water
(Figure 2, run 1). Based on the mechanism of this type reaction, Michael addition of indole and the above
o
Knoevenagel adduct were performed with 10 mol% ChCl-DMU at 50 C for 36 h. A larger gap was got
and almost no target product generated in the absence of water (Figure 2, run 3). These results in accord
O
O
CN
H
H
CN
N
N
NC
CN
H
H
Figure 2. Control experiments (run 1, benzaldehyde and malononitrile; run 2, benzaldehyde and indole;
run 3, 2-benzylidenemalononitrile and indole)

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HETEROCYCLES, Vol. 96, No. 7, 2018
with our early experiences to conduct the Yonemitsu reaction and indicated that water could greatly
accelerate the two step of Yonemitsu type reaction. Fortunately, when we treated benzaldehyde with
indole in solvent I or solvent II, almost no 3-indolylmethanol and bis(indolyl)methane generated after
o
reacted at 50 C for 36 h (run 2). Avoiding this side reaction could safeguard to obtain the desired
products with high yields.
According to the literature,18d,18e we propose the plausible mechanism of this reaction in Scheme 3. First,
both the starting malononitrile and the aldehyde was activated by the DES through hydrogen binding. The
Knoevenagel condensation was assisted and led to the formation of arylidenemalononitrile. Then the
Knoevenagel adduct undergo the Michael addition with indole to give the final desired product. In this
step, the nucleophilicity of indole could also be increased by DES through hydrogen bonding.
O
OH
H
Me
N
N
H
Me
N
Cl
Me
H
CN
CN
H
H
R
H
CN
CN
O
CN
CN
-H2O
N
+
R
H
O
Me
N
H
N
H
N
H
OH
O
CN
NC
H
Me
N
N
H
N
Cl
Me
Scheme 3. Proposed mechanism of this reaction
In summary, we have provided a practical method to achieve the attractive Yonemitsu-type reaction of
indoles, aldehydes and malononitrile. Firstly, utilizing readily available choline chloride-dimethylurea
deep eutectic salts as catalyst and water as assistor is found to be valid. Furthermore, this method has broad
substrates scope and affords target 3-substituted indoles in good to excellent yields. Last but not least,
avoided the problems associated with using expensive and complicated catalyst.
EXPERIMENTAL
Martials and methods
Commercial solvents and reagents were used as received, except for benzaldehyde, which was used as a
fresh distilled sample. High resolution mass spectra (HRMS) were obtained on an Agilent 6540 UHD
Q-TOF mass spectrometer. Melting points were measured on Beijing Tech X-5 melting point detector and
were uncorrected. FT-IR spectras were determined on Bruker Shimadzu IR-460 spectrometer. 1H and 13C

HETEROCYCLES, Vol. 96, No. 7, 2018
1273
NMR spectras were recorded on Bruker Avance 500 MHz or Bruker Avance III 400 MHz. X-Ray crystal
spectra was obtained on Bruker Smart APEX II.
General procedure for the synthesis of 4a-4r
0.50 mmol Aldehyde, 0.50 mmol malononitrile, and 0.10 mmol catalyst were taken in 1 mL solvent
(EtOH-H2O 4:1, v/v). This solution was stirred in a 10 mL pressure tube at the stipulated temperature
mentioned in Table 2 for 10 min, then 0.55 mmol indole was added and continuously reacted. After
completion, 0.6 mL water and 0.4 mL EtOH was added and vigorously stirred for 10 min to remove the
impurity and catalyst. This mixture was filtered and washed with 50% cold aqueous EtOH.
General procedure for the synthesis of 5a-5i
0.50 mmol Aldehyde, 0.55 mmol Meldrum’s acid, and 0.10 mmol catalyst were taken in 2 mL solvent
o
(EtOH-H2O 4:1, v/v). This solution was stirred in a 10 mL pressure tube at 40 C for 10 min, then 0.50
mmol indole was added and continuously reacted. After completion of the reaction, 1.0 mL 40% EtOH was
added and vigorously stirred for 10 min to remove the impurity and catalyst. The mixture was filtered after
cooling in ice bath. The precipitate was washed with 75% cold EtOH without further purification to afford
the desired products.
ACKNOWLEDGEMENTS
This work was supported by National Natural Science Foundation of China (No. 21403100), and Higher
Education Research Program of Liaoning Province (No. L2014421).
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