Greener construction of 4H-chromenes based dyes in deep eutectic solvent

Article abstract of DOI:10.1016/j.dyepig.2013.09.007

Green solvents such as deep eutectic solvents are new emerging alternatives to the conventional harmful organic solvents which may find a number of interesting applications in industrial and chemical processes. A facile, atom-economic and environmentally-

Full text of DOI:10.1016/j.dyepig.2013.09.007

Accepted Manuscript
Greener construction of 4H-chromenes based dyes in deep eutectic solvent
Najmedin Azizi, Mahboobe Mariami, Mahtab Edrisi
PII:
S0143-7208(13)00332-X
10.1016/j.dyepig.2013.09.007
DYPI 4081
DOI:
Reference:
To appear in: Dyes and Pigments
Received Date: 21 July 2013
Revised Date: 4 September 2013
Accepted Date: 9 September 2013
Please cite this article as: Azizi N, Mariami M, Edrisi M, Greener construction of 4H-chromenes based
dyes in deep eutectic solvent, Dyes and Pigments (2013), doi: 10.1016/j.dyepig.2013.09.007.
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ACCEPTED MANUSCRIPT
Greener construction of 4H-chromenes based Dyes in deep eutectic solvent
Najmedin Azizi* Mahboobe Mariami and Mahtab Edrisi

ACCEPTED MANUSCRIPT
Greener construction of 4H-chromenes based dyes in deep eutectic solvent
Najmedin Azizi* Mahboobe Mariami and Mahtab Edrisi
Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran,
IranE-mail: azizi@ccerci.ac.ir
Abstract
Green solvents such as deep eutectic solvents are new emerging alternatives to the
conventional harmful organic solvents which may find a number of interesting applications in
industrial and chemical processes. A facile, atom-economic and environmentally-benign one-pot
reaction of salicylaldehyde and malononitrile with various nucleophiles, including indoles,
thiols, secondary amines, cyanide and azide were efficiently achieved in choline chloride based
deep eutectic solvent (DES).Products distribution of the current green protocol depend on the
nature of the nucleophile used in the reaction. The one-pot reaction of salicylaldehyde
derivatives and malononitrile with thiols, indoles, and cyanide give 2-amino-3-cyano-4H-
chromene derivatives. Secondary amines result in the formation of benzopyrano[2,3-d]
pyrimidines, due to the further reaction of salicylaldehyde with 4H-chromene under the same
reaction condition. The DES was recycled without any reduction in activity or yield. Therefore,
the synthesis of chromene based dyes in green solvents at room temperature under catalyst-free
conditions is a promising alternative to previously used procedures.
Keywords: benzopyrano[2,3-d]pyrimidines; choline chloride; 4H-chromene; deep eutectic
solvent; salicylaldehyde; malononitrile
1

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1
. Introduction
In the context of green chemistry, room-temperature ionic liquids (RTILs) also called molten
salts, are green alternatives to the organic solvents, because of their unique properties such as
negligible vapor pressure, large liquid range, high thermal stability, more solvation capacity and
non-flammability. Cheap and green alternatives to RTILs are DESs. DESs are obtained by
complexion of quaternary ammonium salts with hydrogen bond donors such as urea, carboxylic
acid, and amide. DESs have many characteristics of conventional ILs (e.g. high thermal stability,
the excellent solubility of organic and inorganic substances, low toxicity and nonvolatility)
which offer certain advantages. For instance, the preparation of DES in a pure state is easy and
economically viable as it shows 100% atom economy with no need to post-synthesis purification
that were used for the ILs. Furthermore, choline chloride (ChCl) and urea are both naturally
occurring biocompatible compounds that are not hazardous if they release back into the nature.
Besides, they are cheap and the processes which use these DESs are economically viable and
green [1-10].
Over the past decades, multi-component reactions (MCRs) strives to construct complex
molecules in the most efficient possible manner, are becoming one of the major searching
2

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challenges for step-economic syntheses. They are faster and cheaper than classical reactions,
since the reaction will be completed by just mixing compounds together in one vessel without
isolating any intermediate. The additional benefits to this process are the readily available
starting materials, operationally simple, easily automatable, resource effective, atom economy
and ecologically benign, with minimization of reaction time, labor, cost, and waste productions
[
11-14]. Furthermore, MCR with environmentally benign solvents like DES is one of the most
suitable strategies for green chemical process and developing the libraries of medicinal scaffolds.
4
H-chromene and their derivatives are potentially important structural units in heterocyclic
chemistry that exhibits diverse ubiquitous pharmacological properties such as antiviral and anti-
nociceptive activities [15-18]. Additionally, due to their spectroscopic properties [19] they are
used as fluorescent compounds in laser technology and monitoring of biomolecules. Thus, the
synthesis of highly substituted 4H-chromenes and their derivatives has attracted great attention
because of their wide applications. Recently, a variety of methods have been reported employing
three-component reaction using acidic catalyst or promoter constitutes in the literature [20-34].
However, to the best of our knowledge, there has been only one report about the synthesis of 4H-
chromene derivatives in imidazolium-based ionic liquids under catalyst- free condition [17].
Therefore, development of simple and efficient procedures for the catalyst-free synthesis of 4H-
chromenes in the novel reaction media is a challenging task. Herein we report an efficient three-
component synthesis of 4H-chromenes from salicyldehyde, malononitrile, and different
nucleophiles in choline chloride based DESs.
2
. Material and methods
3

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2
.1 Materials and equipment’s:
All starting materials, reagents and solvents are commercially available and were purchased and
used without further purification. All products were confirmed by melting point, FTIR
1
1
spectroscopy, HNMR, spectroscopy and mass spectrometry. H NMR spectra were recorded on
00 MHz NMR and 80 MHz spectrometer in dimethyl sulfoxide (DMSO-d6) and chloroform
CDCl ) using a Bruker Avance 500 or Bruker AC-80 NMR spectrometer. All amines,
5
(
3
aldehydes, isocyanides and acids are commercially available. Water and ethanol were distilled
before used. All the reactions are monitored by thin layer chromatography (TLC) carried out on
0
.25 mm silica gel with UV light as detecting agents. Melting points were recorded on Buchi 535
melting point apparatus and are uncorrected. FT-IR spectra were determined on a Bruker Vector-
2 infrared spectrometer using KBr disks. Reactions were carried out in 5 mL test tube sealed
2
with a septum. Flash column chromatography was performed with silica gel eluting with ethyl
acetate-petroleum ether. Element analyses were carried out on an Elemental Analyzer vario EL
cube.
2
.2. Deep eutectic solvent preparation
Choline chloride-urea deep eutectic solvent was prepared according to the literature. [1] For DES
preparation, urea (200 mmol) and choline chloride (100 mmol) were mixed, stirred and heated
until a clear liquid was appeared. The obtained deep eutectic solvent was used without any
further purification (Fig. 1).
Fig. 1.
2
.3. General procedure for the preparation of 4H-chromene derivatives
4

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Salicylaldehyde (0.5 mmol), malononitrile (0.5 mmol), nucleophile (0.5 mmol), and DES (0.5
mL) were taken in a test tube. The reaction mixture was stirred at room temperature for 15-80
min. After completion of the reaction as indicated by TLC, (in the most cases, reaction mixture
were directionally solidified) water (5 mL) was added while stirring and the residue collected by
filtration. The resulting solids or viscous liquids were washed with water and was purified by
column chromatography or recrystallization with ethanol or diethyl ether to give pure products.
For the viscous liquids, ethyl acetate was used for extraction of products. The DES was
recovered from the filtrate by evaporating the water phase at 80 °C under vacuum.
2
.4. General procedure for the preparation of 4H-chromene [2,3-d]pyrimidine derivatives
Salicylaldehyde (1.0mmol), malononitrile (0.5 mmol), amine (0.60 mmol) were dissolved in
choline chloride –urea based deep eutectic solvent (0.5 mL), and were mixed and vigorously
stirred at room temperature or 60 °C for 60-200 minutes. After completion of reaction, water was
added. The DES being soluble in water and comes in the water layer. The resulting solids were
purified by column chromatography or recrystallization with ethanol or ethyl acetate to give pure
products. All the products are known and were fully characterized by a comparison with
authentic samples.
Selected data
1
Table 1, entry 1: H NMR (DMSO-d ); δ = 5.29 (s, 1H), 6.65 (d, 1H, J = 7.2 Hz), 7.00 (brs,
6
1
3
2
1
H), 7.10-7.35 (m, 8H); C NMR (DMSO-d ) δ =47.3, 53.2, 114.8, 119.1, 121.3, 124.8, 128.3,
6
-1
1
29.2, 130.2, 135.8, 148.1, 160; IR (KBr): 3420, 3310, 2234 cm Table 1, entry 2: H NMR
1
3
(
DMSO-d ); δ = 2.35 (s, 3H), 5.38 (s, 1H), 6.66-7.45 (m, 10 H); C NMR (DMSO-d ) δ = 25.5,
6
6
5

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4
6.4, 53.1, 114.1, 119.5, 120.9, 124.1, 128.1, 128.4, 128.9, 129.1, 131.0, 136.1, 149.3, 161.2,
1
Table 1, entry 3: H NMR (500 MHz, DMSO-d ): δ = 5.35 (s, 1H), 6.64 (d, 1H, J = 7.2 Hz),
6
1
3
7
4
.06-7.12 (m, 6H), 7.21-7.23 (m, 1H), 7.38-7.39 (m, 2H); C NMR (125 MHz, DMSO-d ): δ =
6
6.5, 54.6, 115.1, 118.1, 119.9, 124.6, 126.1, 128.9, 133.1, 134.2, 138.6, 139.8, 146.6, 160.4;
1
Table 1, entry 4: H NMR (500 MHz, DMSO-d ): δ = 5.38 (s, 1H), 6.62 (d, 1H, J = 7.8 Hz),
6
1
3
7
1
.01-7.04 (m, 7H), 7.25-7.36 (m, 2H); C NMR (125 MHz, DMSO-d ): δ = 46.1, 53.2, 114.8,
6
1
19.2, 119.9, 124.1, 125.8, 128.1, 133.9, 134.8, 138.1, 140.4, 147.1, 161.3; Table 1, entry 5: H
NMR (500 MHz, DMSO-d ): δ = 3.67 (s, 3H), 5.35 (s, 1H), 6.62-7.08 (m, 8H), 7.21-7.39 (m,
6
1
3
2
1
H); C NMR (125 MHz, DMSO-d ): δ = 45.4, 53.1, 54.7, 115.1, 118.1, 118.9, 125.1, 125.9,
6
1
28.1, 133.1, 134.5, 137.9, 140.7, 147.7, 160.6; Table 1, entry 6: H NMR (80 MHz, DMSO-
1
d ): 5.56 (s, 1 H), 7.44-8.12 (m, 13H): Table 1, entry 7: H NMR (80 MHz, DMSO-d ): 2.35 (s,
6
6
1
3
H), 5.48 (s, 1 H), 7.01-7.88 (m, 10 H): Table 1, entry 10: H NMR (500 MHz, DMSO-d ): 5.42
6
1
3
(
s, 1H), 6.62 (d, 1H, J = 7.2 Hz), 7.06-7.42 (m, 8H); C NMR (125 MHz, DMSO-d ): δ 45.9,
6
5
3.8, 116.2, 118.1, 119.1, 124.8, 128.1, 129.9, 132.1, 132.9, 136.8, 139.1, 147.9, 160.9; Table 1,
1
13
entry 11: H NMR (500 MHz, DMSO-d ): δ = 2.24 (s, 3H), 5.38 (s, 1H), 6.68-7.42 (m, 9H); C
6
NMR (125 MHz, DMSO-d ): δ = 26.2, 46.4, 54.6, 115.6, 119.1, 119.9, 123.7, 129.6, 130.2,
6
1
1
5
1
31.9, 132.5 137.1, 138.6, 148.5, 161.0; Table 1, entry 12: H NMR (500 MHz, DMSO-d ): δ =
6
1
3
.38 (s, 1H), 6.92-7.98 (m, 8H); C NMR (125 MHz, DMSO-d ): δ = 45.1, 54.7, 116.1, 117.2,
6
1
19.1, 122.9, 129.1, 130.5, 132.9, 132.5 137.9, 138.9, 146.9, 160.8; Table 1, entry 13: H NMR
1
(
80 MHz, DMSO-d ): δ = 5.45 (s, 1H), 7.02-8.12 (m, 9H); Table 1, entry 14: H NMR (80
6
1
MHz, DMSO-d ): δ = 3.68 (s, 3H), 5.42 (s, 1H), 6.54-7.75 (m, 9H); Table 1, entry 15: H NMR
6
6

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(
80 MHz, DMSO-d ): δ = 2.35 (s, 3H), 3.68 (s, 3H), 5.52 (s, 1H), 6.54-8.00 (m, 8H); Table 1,
6
1
entry 16: H NMR (80 MHz, DMSO-d ): δ = 5.57 (s, 1H), 3.66 (s, 3H), 6.40-7.90 (m, 8H);
6
1
Table 2, entry 1: H NMR (500 MHz, CDCl ): δ = 5.36 (s, 1H), 7.12 (d, 1H, J= 8.4 Hz), 7.28
3
1
3
(
t, 1H, J =7.5 Hz), 7.42-7.46 (m, 2H), 7.52 (brs, 2H); C NMR (125 MHz, DMSO-d ): δ = 26.1,
6
4
1
1
1
2
6.9, 116.1, 117.8, 119.9, 121.6, 125.1, 130.3, 131.2, 148.9, 161.2. IR (KBr): 3388, 3322, 2195,
-1
1
658 cm ; Table 2, entry 3: H NMR (500 MHz, DMSO-d ): δ = 5.02 (s, 1H), 6.82-7.20 (m,
6
1
3
1H), 10.75 (brs, 1H); C NMR (125 MHz, DMSO-d ): δ = 33.4, 56.2, 112.1, 116.9, 119.5,
6
19.9, 120.1, 120.8, 121.9, 123.8, 124.1, 124.8, 125.4, 127.9, 130.1, 137.6, 148.6, 160.8; Table
1
, entry 4: H NMR (500 MHz, DMSO-d ): δ =4.68 (d, 1H, J = 3.8 Hz), 5.10 (d, 1H, J = 3.8
6
13
Hz), 7.14 (d, 1H, J = 8.0 Hz), 7.27 (dd, 1H, J = 7.2 Hz, 1.4 Hz,), 7.39-7.41 (m, 4H); C NMR
(
125 MHz, DMSO-d ): δ = 31.4, 38.2, 50.1, 112,3, 113.8, 116.8, 120.1, 125.9, 129.4, 131.2,
6
1
1
5
1
48.9, 162.8; Table 2, entry 5: H NMR (80 MHz, DMSO-d ): δ = 5.49 (s, 1H), 7.28-7.80 (m,
6
1
H); Table 2, entry 8: H NMR (500 MHz, DMSO-d ): δ = 4.88 (d, 1H, J = 3.7 Hz), 5.26 (d,
6
1
3
H, J = 3.8 Hz), 7.20 (d, J = 8.1 Hz, 1H), 7.45-7.72 (m, 4H), C NMR (125 MHz, DMSO-d ) δ
6
=
33.1, 37.8, 49.2, 113.1, 113.8, 116.7, 119.4, 119.9, 121.0, 132.1, 132.7, 149.3, 162.8; Table 2,
1
entry 9: H NMR (500 MHz, DMSO-d ): δ = 3.75 (s, 3H), 5.34 (s, 1H), 6.79 (m, 5H); Table 2,
6
1
entry 11: H NMR (500 MHz, DMSO-d ): δ = 3.68 (s, 3H), 4.54 (d, 1H, J = 3.7 Hz), 5.12 (d,
6
1
H, J = 3.8 Hz), 6.98 (dd, 1H, J = 7.2 Hz, 1.2 Hz), 7.18 (dd, 1H, J = 7.1 Hz, 1.2 Hz), 7.20-7.52
1
(
m 3H). Table 3, entry 1: H NMR (500 MHz, DMSO-d ): δ = 1.54-1.60 (m, 6H), 3.42-3.48
6
1
3
(
m, 4H), 4.01 (s, 2H), 6.84–7.40 (m, 7H), 8.30 (d, 1H, J = 5.8.0 Hz), 12.85 (brs, 1H, OH). C
NMR (125 MHz, DMSO-d ): δ = 25.1, 25.8, 26.9, 50.2, 98.4, 115.9, 118.6, 118.9, 119.8, 121.2,
6
7

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1
1
26.1, 128.4, 129.8, 130.2, 134.1, 151.2, 160.8, 161.4, 164.2, Table 3, entry 2: H NMR (500
MHz, DMSO-d ): δ = 3.42 (s, 4H), 3.74 (s, 4H), 3.86 (s, 2H), 6.80−8.18 (m, 8H), 11.85 (brs, 1H,
6
1
3
OH). C NMR (125 MHz, DMSO-d ): δ = 25.8, 49.2, 67.1, 98.4, 117.1, 118.2, 118.9, 119.8,
6
1
1
20.6, 125.4, 129.1, 129.8, 130.1, 134.1, 150.6, 161.0, 161.5, 163.7, 164.9. Table 3, entry 3: H
NMR (500 MHz, DMSO-d ): δ = 3.20 (s, 6H), 4.08 (s, 2H), 7.03-7.38 (m, 7H), 8.44-8.46 (m,
6
1
3
1
1
H), 13.25 (brs, 1H, OH); C NMR (125 MHz, DMSO-d ): δ = 26.3, 41.5, 95.2, 117.8, 118.4,
6
19.8, 120.1, 120.8, 124.8, 128.7, 128.9, 129.9, 134.1, 151.2, 160.9, 161.9, 164.2; Table 3,
1
entry 5: H NMR (500 MHz, DMSO-d ): δ = 1.64-1.66 (m, 6H, 3.40-3.41 (m, 4H), 3.86 (s, 2H),
6
6
.80−7.62 (m, 5H), 8.18-8.20
(m, 1H), 13.40 (1H, brs, OH)
3
. Results and discussion
As a consequence of our interest in the organic synthesis in green solvent as an environmentally
attractive media [35-38] and our continual work on the synthesis of heterocyclic chemistry
guided by the observation that the presence of salicylaldehyde as simple starting material in
biologically heterocyclic moieties. Herein, we describe a mild convenient and simple procedure
for the direct synthesis of 4H-chromenes derivatives with one-pot reaction of salicyldehyde (1),
malononitrile (3), different nucleophiles (thiols, amines, nitrile, and indoles) without using any
catalyst at room temperature with good yields. The experimental procedure is very simple and
easy. The biodegradable DES was prepared with simple mixing of choline chloride (100 mmol)
۫
and urea (200 mmol) and heated to 80C in air with stirring till a clear solution was obtained,
which was used without any purification. Since this method forms eutectic mixture with no
8

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byproduct formation, it provides 100% atom economy. After preparation of DES, it was found
that upon simple mixing of salicyldehyde, (0.5 mmol), thiophenol, (0.5 mmol), and malononitrile
(0.5 mmol), in choline chloride-urea based DES (0.5 mL), the corresponding product 4 was
formed as the only detectable product and isolated in 97 % yield after washing with water and
ethanol (Scheme 1). The DES was recovered easily from filtrate by evaporating the water under
vacuum and reused for three successions of the reaction without much loss of product yields.
Furthermore, it was possible to monitor the reaction visually. A white suspension solution was
obtained after addition of the all components to the DES, and the reaction mixture became
orange viscose liquid or solids after the reaction is complete. However, the same reaction without
DES under solvent-free condition gave only starting materials after 60 minutes.
Scheme 1
On the basis of the interesting results, and in order to establish the generality and scope of these
catalyst-free multicomponent reactions, additional reactions of various substituted salicyldehydes
with thiols, and malononitrile were carried out under above condition. The results are
summarized in Table 1. Not only electron-rich salicyldehyde such as 3-methoxysalicyldehyde
but also electron deficient salicyldehyde, 5-bromosalicyldehyde, in the reactions afforded 4H-
chromene derivatives in 65–98% yields. Aromatic thiols such as 2-naphthyl thiol and a variety of
substituted
thiophenols
(thiophenol,
4-chloro-thiophenol,
4-bromo-thiophenol,
4-
methylthiophene, 4-methoxylthiophenol, 2-methylthiophene) furnished excellent yield of
chromene under mild reaction conditions. Electron withdrawing as well as electron-donating
substituent on the thiophenol did not make any difference to the reactivity and selectivity of the
reaction. Similarly, the corresponding products from the reaction of aliphatic thiols were
9

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obtained albeit in moderate yield and selectivity. The generality of this green protocol was
further demonstrated in the reaction between salicyldehydes, and malononitrile with other
nucleophiles (5) such as cyanide, indoles and secondary aliphatic amines under similar reaction
condition. The reaction of salicyldehyde, 5-bromosalicyldehyde and 3-methoxysalicyldehyde,
with malononitrile and trimethylsilyl cyanide were performed and the desired products were
obtained in short reaction time in 95%, 95% and 92% yields, respectively (Table 2). The reaction
of salicyldehyde derivatives with malononitrile and sodium cyanide, indole and malononitrile
was also performed under similar reaction conditions and the desired products were isolated in
lower yield.
To further highlight the potential of this green methodology a three-component coupling of
salicyldehyde , malononitrile , and secondary amines under same reaction condition was
developed to provide rapid access to benzopyrano[2,3-d]pyrimidine (Table 3). Furthermore,
secondary aliphatic amines such as piperidine, morpholine and dimethyl amine underwent a
three-component reaction and leading to the desired product in good yields. However, the
reaction fails with primary amine like benzyl amine under this reaction condition. Investigation
of the aldehyde scope demonstrated that, 5-bromosalicyldehyde with electron-withdrawing
groups performed in a slightly superior manner, and 3-methoxysalicyldehyde were also
compatible with the reaction. The reaction setup is quite simple and practical, as it requires only
stirring the three components in DES at room temperature. The component of DES is
1
0

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biodegradable and can be easily accessed from commercially available materials. Moreover, it
can easily be prepared and recovered with high efficiency after the reaction.
In order to test the robustness of the procedure that would be an interesting application in
industrial and chemical process, a relatively large-scale reaction of salicylaldehyde (10.0 mmol),
malononitrile (10.0 mmol), thiophenol (10.0 mmol) in DES (2 mL) in 15 minutes under the
optimal conditions were performed. In gram scale, the corresponding product 4 was isolated in
9
0% yields with simple and clean purification (filtration followed by washing) without any
organic solvent (Fig. 2).
Fig. 2
Based On the above observations and the literature survey, the plausible mechanism for the
green one-pot reaction in DES is illustrated in Fig.3. The urea components of DES facilitate the
Knoevenagel -type condensation through hydrogen bonding between urea and the oxygen of
carbonyl groups of salicyldehyde. On the other hand, urea can activate malononitrile so that
deprotonation of the C−H bond occurs in the presence of Lewis basic sites of urea and form
intermediate (I). Then the higher reactivity of the of salicyldehyde and malononitrile is utilized
to facilitate the Knoevenagel condensation to produce intermediate (II), and subsequently
1
1

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nucleophilic attack of thiophenol to the electron-poor C=C double bond (III) affords 2-amino-2-
chromene derivatives 4a (Fig. 3)
Fig. 3
Finally, the recycling of DES was examined using the three component reaction of
salicyldehyde, thiophenol and malononitrile in DES (0.5 mL), under optimized conditions. The
recovered DES was then reused for three runs without obvious loss of activity (95%, 95%, 90%
yields respectively). After completion, water (3 mL) was added to the reaction mixture, shacked
vigorously and solid or viscous liquid was separated by filtration. The deep eutectic solvent was
◦
recovered from filtrate by evaporating the water phase at 80 C under vacuum and reused for the
next batch and recycled again.
4
. Conclusion
In summary, we have demonstrated a green, general; three component reaction can take place
between salicylaldehyde, malononitrile and different nucleophiles in DES. The novelty of this
work is the catalyst free synthesis of chromene and benzopyrano(2,3-d)pyrimidines, using non-
toxic, low cost and environmentally benign solvents. This procedure offers additional advantages
such as simple workup, general applicability, high isolated product yields which makes it highly
suitable for industrial synthesis of biologically active chromene derivatives. Furthermore, it is
easy to separate the solvent and product after completion of the reaction with simple workup.
1
2

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Table 1 catalyst-free multicomponent synthesis of various substituted 4H-chromene in DES
a
Entry
Salicyldehyde (1)
Thiol (2)
Yields (%)
1
8

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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2a
2b
2c
2d
2e
2f
2g
2h
2i
2a
2b
2c
2d
2a
2b
2c
2f
98
98
92
95
92
88
90
45
28
95
92
90
86
95
92
88
80
O
OH
0
1
2
3
4
5
6
7
Br
O
OH
MeO
1
OH
O
a
Isolated yields
Table 2 DES promoted themulti-component reactions of salicyldehydes and malononitrile with various nucleophiles
Nu
R
CN
O
CN
CN
DES (1mL)
+
+
Nu
OH
R
O
NH2
r.t. 20-200 min
1
3
5
6
6
0-95 %
DES: choline cholide -urea (1:2)
R = H, Br, OMe
Nu: TMS-CN (5a)
NaCN (5b)
indole (5c)
malononitrile CH (CN) (5d)
2 2
1
9

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a
Entry
Salicyldehyde (1)
Nu (5)
Yields (%)
1
2
3
4
5a
5b
5c
5d
95
68
80
82
O
OH
5
6
7
8
Br
5a
5b
5c
5d
90
62
75
72
O
OH
9
1
1
5a
5c
5d
82
68
60
0
1
MeO
OH
O
a
NMR yields
Table 3 Green synthesis of benzopyrano[2,3-d]pyrimidine via a three-component coupling of salicyldehyde, secondary amines,
and malononitrile
2
0

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N
N
R
O
CN
CN
DES (0.5 mL)
N
OH
+
+
OH
N
O
R
rt, 60-200 min
H
1
3
8
7
00-78 %
R = H, OMe, Br
DES: choline cholide -urea (1:2)
NH2
:
NH
NH
O
NH
NH
7
a
7b
7c
7d
a
Entry
Salicyldehyde (1)
amine (7)
Yields (%)
1
2
3
4
7a
7b
7c
7d
78
75
70
00
O
OH
5
6
7
Br
7a
7b
7c
72
75
72
O
OH
8
9
1
7a
7b
7c
68
65
60
0
MeO
OH
O
a
NMR yields
2
1

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Fig. 1 Deep eutectic solvent preparation
Fig. 2 The gram scale synthesis of 4a in DES
Fig. 3 Plausible mechanistic pathway for the domino synthesis of 4H-chromene derivatives
2
2

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Ph
S
O
SH
DES (1mL)
r.t. 15 min
CN
CN
CN
+
+
OH
O
NH2
1
2a
3
4
Scheme 1. Model reaction in DES (choline chloride-urea)
2
3

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Table 1 catalyst-free multicomponent synthesis of various substituted 4H-chromene in DES
Table 2 DES promoted themulti-component reactions of salicyldehydes and malononitrile with various
nucleophiles
Table 3 Green synthesis of benzopyrano[2,3-d]pyrimidine via a three-component coupling of
salicyldehyde, secondary amines, and malononitrile
Fig. 1 Deep eutectic solvent preparation
Fig. 2 The gram scale synthesis of 4a in DES
Fig. 3 Plausible mechanistic pathway for the domino synthesis of 4H-chromene derivatives
Scheme 1. Model reaction in DES (choline chloride-urea)

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►
►
►
►
Deep eutectic solvents (DES) are green solvents and catalyst for dye synthesis
Natural products were used as a source for deep eutectic solvents in multicomponent reaction
This approach eliminates the use of hazardous organic solvents and toxic catalysts.
Lost cost, wide scope and highly efficient substituted 4H-chromenes were prepared in a single
pot using DES