Choline chloride/pentaerythritol: a deep eutectic solvent for the synthesis of pyran and chromene derivatives

Article abstract of DOI:10.1007/s13738-020-02108-5

Abstract: A novel deep eutectic solvent system was prepared by mixing choline chloride as a hydrogen-bond acceptor with 2,2-bis(hydroxymethyl)propane-1,3-diol (pentaerythritol) as a hydrogen-bond donor. This green solvent was used for the one-pot synthesi

Full text of DOI:10.1007/s13738-020-02108-5

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-02108-5
ORIGINAL PAPER
Choline chloride/pentaerythritol: a deep eutectic solvent
for the synthesis of pyran and chromene derivatives
Setareh Azimzadeh‑Sadeghi1 · Issa Yavari2
Received: 11 July 2020 / Accepted: 19 October 2020
© Iranian Chemical Society 2020
Abstract
A novel deep eutectic solvent system was prepared by mixing choline chloride as a hydrogen-bond acceptor with
2,2-bis(hydroxymethyl)propane-1,3-diol (pentaerythritol) as a hydrogen-bond donor. This green solvent was used for the
one-pot synthesis of pyran and chromene derivatives from aromatic aldehydes, 1,3-dicarbonyl compounds, and malononitrile.
The solvent was readily recycled and can be reused three times without signifcant loss of activity or mass. This procedure
ofers advantages such as environmental friendliness, shorter reaction times, and higher yields.
Graphical abstract
Keywords Deep eutectic solvent · Choline chloride · Pentaerythritol · Pyran · Chromene · Green chemistry
Introduction
been investigated in academic and applied research for more
than a decade. In general, a DES is defned as simple mixture
of two or three components forming a eutectic with lower
melting point than each of the pure components. This liquid
system, composed of a network of hydrogen-bond accep-
tor and hydrogen-bond donor molecules, provides suitable
polarity owing to the abundance of hydrogen bond [5–9].
These solvents are less toxic, biodegradable, cheap, easy to
prepare, with low vapor pressure and melting points, and
often good thermal stability [10, 11].
The design of innovative organic and green solvents plays a
signifcant role in synthetic organic chemistry [1–3]. Deep
eutectic solvents (DESs) are a new class of green organic
solvents introduced by Abbott [4] and continuously have
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-020-02108-5) contains
supplementary material, which is available to authorized users.
The combination of choline chloride (ChCl) and urea
as a deep eutectic solvent has been applied to the syn-
thesis of benzo-fused seven-membered heterocycles via
a one-pot, three-component reaction [12]. Recently, sus-
tainable synthesis and application of natural DES systems
based on malic acid, citric acid, xylitol, and water were
* Issa Yavari
yavarisa@modares.ac.ir
1
Department of Chemistry, Science and Research Branch,
Islamic Azad University, Tehran, Iran
2
Department of Chemistry, Tarbiat Modares University,
Tehran, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
reported [13]. The efect of water on the physicochemical
properties and on the structural features of three DESs
formed by ChCl and glycols with a diferent number of
oxyethylene units has been evaluated [14]. A series of ter-
nary DES systems have been prepared using a mixture of
microorganism-derived (R)-3-hydroxynonanoic and (R)-
3-hydroxyheptanoic acids as hydrogen-bond donors and
selected quaternary ammonium salts as hydrogen-bond
acceptors [15].
chromene derivatives from aromatic aldehydes, malononi-
trile, and 1,3-dicarbonyl compounds.
Experimental
Materials and methods
All starting materials and DES components were purchased
from Merck and were used without further purifcation.
Melting points were measured on an Electrothermal 9100
apparatus. FT-IR spectra were recorded on a Shimadzu
IR-460 instrument using the KBr self-supported pellet tech-
nique. 1H and 13C NMR spectra: Bruker DRX-300 Avance
instrument at 300 and 75 MHz, resp.; δ in ppm, J in Hz
(Scheme 1).
Pyrans are attractive heterocyclic compounds with
various biological and pharmacological activities such
as antimicrobial [16], antioxidant [17], antibacterial [18],
anticancer [19], and antiproliferative [20] properties.
Various approaches have been employed for the synthe-
sis of pyrans, some of them sufered from disadvantages
including the use of toxic and volatile organic solvents
and expensive catalysts, high temperatures, laborious
and complex procedures. Following the increasing envi-
ronmental and economic considerations, the search for
enviro-economic synthetic methods for organic reactions
has received overwhelming attention. In this regard, eforts
are being made to replace the expensive and hazardous
solvents and catalysts with environmentally benign bio-
degradable materials. Herein, we describe the preparation
and characterization of choline chloride/pentaerythritol
(ChCl/PE) DES system and its application as dual solvent
and organocatalyst in the one-pot synthesis of pyran and
Preparation and characterization of ChCl/PE DES
system
ChCl/PE DES was prepared by mixing choline chloride
(ChCl) and pentaerythritol (PE) with 1:1 molar ratio and
heating the mixture at 75–80 °C for a period of 1 h until
a clear solution was obtained (see Scheme 2). The reac-
tion mixture was dissolved in water, and the insoluble
crude ChCl/PE DES was fltered of. Colorless solid; M.p.:
75–80 °C. IR (KBr): (νmax, cm−1) = 3327 (O–H), 2954
(C–H), 2886 (C–H), 1481, 1409, 1276, 1129, 1016, 955; 1H
Scheme 1. Preparation of
ChCl/PE DES from choline
chloride and pentaerythritol
Scheme 2. Proposed mechanism of the reaction in ChCl/PE DES system
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Journal of the Iranian Chemical Society
NMR (300 MHz, DMSO-d6): 3.12 (9 H, s, Me3N), 3.26 (8 H,
d, 3 J=5.7 Hz, 4 CH2O), 3.41 (2 H, t, 3 J=5.0 Hz, CH2N),
3.77–3.79 (2 H, m, CH2O), 4.34 (2 H, t, 3 J =5.7 Hz, 4 OH),
L viscometer, ftted with a thermostatic jacket and a tem-
perature probe. The viscometer jacket was connected to an
external thermostated bath. The viscosity measurements
were carried out using a spindle attachment. The profles of
viscosity versus T (in °C) are shown in Fig. 1. The viscosity
of ChCl/PE DES follows an Arrhenius-like behavior as it
decreases with increase in temperature.
3
5.40 (1 H, t, J = 5.0 Hz, OH) ppm; 13C NMR (75 MHz,
DMSO-d6): 46.0 (Me3N), 53.3 (CH2O), 55.3 (CH2N), 60.6
(4 CH2O), 67.1 (C) ppm.
The viscosity of the ChCl/PE DES was measured in a
temperature range of 99–119 °C, using a Fungilab Expert
General procedure for the synthesis of pyran
derivatives 4 and 6
A mixture of aldehyde 1 (1 mmol), nitrile 2 (1 mmol),
1,3-dicarbonyl compound 3 or hydroxyl compounds 5
(1 mmol), and ChCl/PE DES (2 mL) was heated at 75–80 °C
for 1 h. After reaction completion (monitored by TLC),
about 5 mL water was added to the mixture. In cases of
precipitate formation, the solid was fltered. When a viscose
liquid was separated after water addition, EtOAc was added
to extract the product from the organic layer. The products 4
or 6 were purifed by recrystallization from EtOH. All prod-
ucts were known and were characterized by comparison of
their melting points (see Tables 2, 3) and spectroscopic data
with those described in the literature [16, 21–24, 26–30].
Results and discussion
To examine the viability of this protocol, the three-com-
ponent reaction of benzaldehyde (1a), malononitrile (2a),
and dimedone (3a) was selected as a model reaction. As
shown in Table 1, the reaction proceeds in common sol-
vents such as H2O, EtOH, and DMF at 80 °C and afords
Fig. 1 Viscosity (η) profles of ChCl/PE DES in the temperature
range between 99 and 119 °C
Table 1 Synthesis of 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a) in various solvents
Entry
Solvent
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
H2O
EtOH
DMF
80
80
80
80
80
80
60
60
65
75
80
78
96
70
ChCl/urea (1:2)
ChCl/malonic acid (1:1)
ChCl/PE (1:1)
ChCl/PE (1:1)
aReaction condition: 1a (1 mmol), 2a (1 mmol), 3a (1 mmol), in solvent (2 mL) for 1 h
bIsolated yield
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Journal of the Iranian Chemical Society
Table 2 Three-component synthesis of tetrahydro-4H-chromene derivatives 4
3
Entry
1
Ar
Ph
E
3
Product yield (%)
M.p. (°C)
found {reported}
CN
228–230
{232 [21]}
2
3
4
5
p-Me-C6H4
p-Cl-C6H4
CN
CN
CN
CN
213–215
{212 [21]}
212–214
{213–215 [16]}
p-O2N-C6H4
p-Me2N-C6H4
173–175
{176 [21]}
209–211
{208–210 [24]}
6
2-Furyl
CN
CN
CN
CN
CN
224–224
{224 [21]}
7
Ph
189–191
{192 [21]}
8
p-Me-C6H4
p-O2N-C6H4
p-Cl-C6H4
155–157
{158 [21]}
9
180–182
{183 [21]}
10
262–263
{263–264 [21]}
11
p-Me-C6H4
CN
202–204
{203 [25]}
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Journal of the Iranian Chemical Society
Table 2 (continued)
Entry
Ar
E
3
Product yield (%)
M.p. (°C)
found {reported}
12
p-Cl-C6H4
CO2Et
257–259
{256–259 [22]}
13
14
p-O2N-C6H4
m-O2N-C6H4
CO2Et
CO2Et
180–182
{181–183 [23]}
183–185
{182–184 [23]}
15
16
p-O2N-C6H4
p-MeO-C6H4
CO2Et
CO2Et
153–155
{152–155 [28]}
166–168
{167–169 [28]}
aReaction condition: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), in ChCl/PE DES (2 mL) at 80 °C for 1 h
bIsolated yield
2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (4a) in moderate to good yields
(Table 1, entries 1–3). Using ChCl/urea and ChCl/malonic
acid DES systems, the yield of 4a was increased to 80%
and 78%, respectively. When the reaction was carried out in
ChCl/PE DES solvent, product 4a could be obtained in 96%
yield (Table 1, entry 6). Increasing the reaction temperature
to 90 °C did not improve the yield of 4a, but decreasing the
temperature to 60 °C reduced the yield to 70% (Table 1,
entry 7). Thus, the optimal reaction conditions for prepara-
tion of 4a is equimolar amounts of 1a, 2a, and 3a in ChCl/
PE DES system at 80 °C.
active methylene compound 3a to aford intermediate 8a.
Subsequently, intramolecular cyclization of 8a gives imine
9a, which is converted to product 4a by imine–enamine tau-
tomerization. ChCl/PE DES system can play a dual role in
this reaction: (a) as a solvent and (b) as an organocatalyst
which activates the carbonyl and nitrile functional groups
via extensive hydrogen bond formation.
To further explore the potential of this one-pot reac-
tion for synthesis of chromene derivatives, we investigated
the reaction of benzaldehydes 1 and malononitrile (2a) in
the presence of 1-naphthole (5a), 2-naphthole (5b), and
4-hydroxycumarin (5c) (see Table 2). As shown in Table 3,
highly functionalized chromene derivatives 6a–6 g are
obtained in good to excellent yields.
Using the optimal reaction conditions, we extended the
scope of the process using a broad range of aromatic alde-
hydes containing electron-withdrawing or electron-donating
groups 1 and cyano components 2 in the presence of cyclic
and open-chain 1,3-dicarbonyl compounds 3, which led to
the formation of products 4 in good yields (Table 2).
Hydrogen bonding and basicity of ChCl/PE DES are
important factors that infuence the reactivity and selectiv-
ity of these reactions. A proposed mechanism for the for-
mation of product 4a is outlined in Scheme 2. The reaction
proceeds by initial formation of aldehyde-malononitrile
condensation adduct 7a. This intermediate reacts with the
The stability of ChCl/PE DES was tested on the reaction
of benzaldehyde, malononitrile, and 1-naphthol. The reac-
tion mixture was dissolved in water, and the insoluble crude
product 6a was fltered of. The DES was readily recycled
from the aqueous layer resulted from work up, dried at 80 °C
for 2 h, and reused three times with 1–3% loss of activity or
mass (see Table 4).
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Journal of the Iranian Chemical Society
Table 3 Three-component reaction of benzaldehydes, malononitrile, naphthols, and 4-hydroxycoumarin in ChCl/PE DES
Entry
1
Ar
5
Product 6
M.p. (°C)
Found
Reported
C6H5
215–217
216–217 [29]
2
p-MeO-C6H4
196–197
195–196 [29]
3
4
5
p-Cl-C6H4
242–244
235–237
188–190
243–244 [26]
236 [27]
p-O2N-C6H4
p-O2N-C6H4
187 [27]
6
7
Ph
255–257
265–266
256–258 [30]
264–266 [26]
p-Cl-C6H4
aReaction condition: 1 (1 mmol), 2 (1 mmol), 5 (1 mmol), in ChCl/PE DES (2 mL) at 80 °C for 1 h
bIsolated yield
Table 4 Recycling of ChCl/PE
DES for synthesis of product
6a by condensation reaction
benzaldehyde, malononitrile,
and 1-naphthol
donor. This DES was used for the one-pot synthesis of pyran
derivatives from aromatic aldehydes, 1,3-dicarbonyl com-
pounds, and malononitrile. Highly functionalized chromene
was also prepared using benzaldehydes and malononitrile in
the presence of 1-naphthole, 2-naphthole, and 4-hydroxycu-
marin. The easy preparation, short reaction time, high yield,
and simple work-up procedures are signifcant advantages
of this method.
Cycle
Yield (%)
1
2
3
94
93
91
Conclusions
In summary, we have described the preparation of a new deep
eutectic solvent system by mixing choline chloride (ChCl)
as a hydrogen bond acceptor with 2,2-bis(hydroxymethyl)
propane-1,3-diol (pentaerythritol, PE) as a hydrogen bond
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