Facile Protocol for the Synthesis of 2-Amino-4H-Chromene Derivatives using Choline Chloride/Urea

Full text of DOI:10.1080/00304948.2020.1833623

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Facile Protocol for the Synthesis of 2-Amino-4H-
Chromene Derivatives using Choline Chloride/Urea
Behrooz Maleki , Reza Tayebee , Ali Khoshsima & Farshid Ahmadpoor
To cite this article: Behrooz Maleki , Reza Tayebee , Ali Khoshsima & Farshid Ahmadpoor
(2021) Facile Protocol for the Synthesis of 2-Amino-4H-Chromene Derivatives using Choline
Chloride/Urea, Organic Preparations and Procedures International, 53:1, 34-41, DOI:
10.1080/00304948.2020.1833623
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 1, 34–41
https://doi.org/10.1080/00304948.2020.1833623
EXPERIMENTAL PAPER
Facile Protocol for the Synthesis of 2-Amino-4H-Chromene
Derivatives using Choline Chloride/Urea
Behrooz Malekia, Reza Tayebeea , Ali Khoshsimab , and Farshid Ahmadpoora
b
aDepartment of Chemistry, Hakim Sabzevari University, Sabzevar, Iran; School of Petroleum and
Chemical Engineering, Hakim Sabzevari University, Sabzevar, Iran
ARTICLE HISTORY Received 25 May 2020; Accepted 3 July 2020
Deep eutectic solvents (DESs) have recently obtained attention as environmentally
friendly alternative solvents to replace volatile organic compounds (VOCs). Most DESs
are biodegradable, biocompatible and non-toxic.1 Therefore, compared to the traditional
solvents, DESs are considered both promising and versatile.2–3 Low vapor pressure
(nonvolatility), a wide range for the liquid state, thermal and chemical stability, low
flammability, high solvation capability, and inertness towards reactions with water qual-
ify them as a good extractants. Due to self-association through intermolecular hydrogen
bond interactions, DESs have lower lattice energies and therefore lower melting points
than those of their single components. Compared to ionic liquids (ILs), DESs are easier
to prepare, cheaper in cost, and more environmentally friendly, while maintaining their
task-specific character.4 In comparison to ILs, which consist of a cation and a complex
anion, DESs comprise a cation, an anion and a complexing agent. DESs are obtained by
the simple mixing and heating of one or more hydrogen bond donors (HBDs) with one
or more hydrogen bond acceptors (HBAs) to form a eutectic mixture.5 The purity of
the prepared mixture is only dependent on the purity of the individual components.
Multicomponent reactions (MCRs) comprise an attractive strategy within synthetic
organic chemistry due to their minimal workup requirements, suitability for one-pot
synthesis, molecular economy, and ease of processing.6–9
The chromene ring system is a widely-used scaffold for pharmaceutical applications,
and chromenes have a variety of divergent biological activities, acting as anti-inflamma-
tories,10 antitubercular agents,11 antitumor agents,12 enzyme inhibitors,13 and potassium
channel activators.14 Generally, 2-amino-4H-chromenes and their derivatives have been
synthesized using MCR with malononitrile, aldehydes, and phenols. Catalytic procedures
have been reported using methanesulfonic acid (CH3SO3H),15 silica tungstic acid
(STA),16 potassium phthalimide (POPI),17 CuSO4Á5H2O,18 disodium hydrogen phos-
phate (Na2HPO4),19 Fe(HSO4)3,20 tetrabutylammonium chloride (TBAC),21 lipase AS
(that is, lipase from Aspergillus niger),22 Fe3O4/SiO2/Propyl-Pip,23 potassium fluoride,24
triethanolamine,25 ilmenite (FeTiO3),26 banana peel ash,27 lemon fruit shell ash
(WELFSA),28 aspartic acid,29 molecular sieves under microwave-irradiation,30 and
K2CO3/cyanuric acid.31 Despite their usefulness in many applications, some of the latter
CONTACT Behrooz Maleki
b.maleki@hsu.ac.ir; malekibehrooz@gmail.com
Department of Chemistry, Hakim
Sabzevari University, Sabzevar, Iran
ß 2020 Taylor & Francis Group, LLC

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
35
Scheme 1. Synthesis of 2-amino-4H-chromenes using choline chloride/urea.
approaches call for the use of drastic conditions (acidic or basic), multiple steps, com-
plicated synthetic operations or lengthy work-up procedures.
Choline chloride/urea (ChCl/urea) is one of the most commonly used DESs in
organic synthesis. The most commonly employed is the 1:2 molar mixture of choline
chloride and urea which affords a viscous liquid at room temperature. Advantages of
this solvent are several-fold: it is relatively inexpensive (being comparable in price to
conventional organic solvents such as acetonitrile and DMF), it is non-toxic, exhibits no
detectable vapor pressure under ambient conditions, and is based on biorenewable
materials.32–34 Further to our own interest in green chemistry,35–50 we considered ChCl/
urea as a catalyst for three-component coupling of 2-naphthol or phenol, aromatic alde-
hydes, and malononitrile in water/ethanol at 80 ꢀC to obtain 2-amino-4H-chromene
derivatives (Scheme 1).
To optimize the reaction conditions, the one-pot reaction of 2-naphthol and benzal-
dehyde with malononitrile was examined in ChCl/urea as a model reaction. Among the
various tested conditions, the best results were given with ChCl/urea in water/ethanol
(2:1, v/v)/80 ꢀC (92% within 15 min (Table 1, entry 3).
In order to explore the versatility of the synergistic effect of ChCl/urea, we examined
different substrates. As shown in Table 2, all of them gave the desired products in very
good to excellent yields (89-93%). Electron-withdrawing and electron-donating substitu-
ents were generally well tolerated, affording the desired products 5a-k. To further
extend the reaction scope, we then studied the reaction of phenol with various alde-
hydes and malononitrile under the optimal conditions (Table 2, entries 6a-d).
Finally, to access the efficiency and generality of this methodology, we compared this
method with previously reported catalysts in the synthesis of representative 2-amino-
4H-chromene derivatives 5a and 5h (Table 3). The data show that ChCl/urea is the
most efficient catalyst with respect to reaction times, temperature and the avoidance of
drastic conditions (acidic or basic).
In summary, a very simple approach towards the one-pot multi-component synthesis
of 2-amino-4H-chromene derivatives was developed using biocompatible ChCl/urea.

36
B. MALEKI ET AL.
Table 1. Optimization of reaction conditions for 5a.a
Entry
Catalyst (ml or g)
Conditions
Time (min)
15
Yield (%)
58
1
2
3
4
5
6
7
8
ChCl/urea (0.1 ml)
ChCl/urea (0.1 ml)
ChCl/urea (0.1 ml)
ChCl/urea (0.1 ml)
ChCl/urea (0.1 ml)
ChCl/urea (0.1 ml)
ChCl/urea (0.2 ml)
ChCl/urea (0.05 ml)
ChCl (0.04 g)
Water/80 ꢀC
Ethanol/80 ꢀC
15
15
15
15
15
15
15
15
15
30
76
92
60
82
45
84
80
20
32
Water/Ethanol (2:1, v/v)/80 ꢀC
Solvent-free/80 ꢀC
Water/Ethanol (2:1, v/v)/70 ꢀC
Water/Ethanol (2:1, v/v)/rt
Water/Ethanol (2:1, v/v)/80 ꢀC
Water/Ethanol (2:1, v/v)/80 ꢀC
Water/Ethanol (2:1, v/v)/80 ꢀC
Water/Ethanol (2:1, v/v)/80 ꢀC
Water/Ethanol (2:1, v/v)/80 ꢀC
9
10
11
Urea (0.01 g)
b
c
–
–
aReaction conditions: benzaldehyde (1 mmol), malononitrile (1.2 mmol) and 2-naphthol (1 mmol) in 0.1 ml water/ethanol
(2:1, v/v).
bThis reaction was carried out in the absence of ChCl/urea.
cNo product 5a observed.
Advantages of this procedure include all of the merits of using a DES: short reaction
times, simple operation, easy handling, low cost, and high yields. The procedure com-
pletely avoids strongly basic or acidic conditions and toxic solvents.
Experimental section
All starting materials and DES components were commercially available and purchased
from Merck. Melting points were determined on Electrothermal 9200 apparatus and are
uncorrected. IR spectra were recorded as KBr pellets on a Shimadzu 435-U-04 spectro-
1
photometer. H and 13C NMR spectra were determined on a Bruker DRX-300 Avance
spectrometer using CDCl3 or DMSO-d6, and shifts are given in ppm downfield from
tetramethylsilane (TMS) as an internal standard. All the reactions were monitored with
thin layer chromatography (silica gel, eluting solvent: n-hexane/ethyl acetate (4/1)) and
UV light as detecting agent.
Preparation of ChCl/urea
The ChCl/urea was prepared according to the procedures reported in literature32 simply
by heating a mixture of choline chloride and urea with a molar ratio of 1:2 at 80 ꢀC
until a homogeneous liquid was formed.
General procedure for the synthesis of 2-amino-4H-chromene derivatives (5a-k or
6a-d)
A mixture of aldehyde (1 mmol), malononitrile (1.2 mmol) and 2-naphthol or phenol
(1 mmol) in the presence of 0.1 ml of ChCl/urea in water/ethanol (2:1, v/v, 0.1 ml) was

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Table 2. One-pot synthesis of 2-Amino-4H-chromene derivatives using ChCl/urea.
mp (0C)
Entry
Products
Yield (%)
92
Time (min)
15
Found
Lit.ref
278-27918
5a
278-280
5b
91
20
205-207
205-20616
5c
89
90
25
25
254-256
218-220
256-25817
5d
220-22226
5e
90
25
184-186
182-18315
5f
90
25
252-254
248-25021
(continued)
placed in a round-bottomed flask (10 ml) fitted with a condenser. The flask was placed
in an oil bath and heated to 80 ꢀC. The reaction process was monitored by TLC (silica
gel, n-hexane/ethyl acetate (4/1)). After completion of the reaction, 5 mL water was

38
B. MALEKI ET AL.
Table 2. Continued.
mp (0C)
Entry
Products
Yield (%)
93
Time (min)
20
Found
Lit.ref
242-24427
5g
242-244
5h
93
92
20
20
188-190
286-288
188-18915
5i
284-28619
5j
89
90
25
25
180-182
280-282
181-18316
5k
280-28218
6a
6b
92
90
15
20
163-165
193-195
162-16431
192-19431
(continued)

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Table 2. Continued.
mp (0C)
Entry
Products
Yield (%)
90
Time (min)
15
Found
Lit.ref
162-16431
6c
166-168
6d
94
15
198-200
200-20231
Table 3. Comparison of methods for the synthesis of 2-amino-4h-chromene derivatives.
Compounds
Conditionsref
Time (min)
Yield (%)
ChCl/urea/H2O/EtOH/(2:1, v/v)/80 ꢀC (present work)
15
180
180
60
92
91
90
95
89
86
80
36
CH3SO3H/CH3CN/reflux15
Silica tungstic acid (STA)/solvent-free/120ꢀC16
CuSO4Á5H2O/H2O/reflux18
Na2HPO4/solvent-free/120ꢀC19
60
Fe(HSO4)3/CH3CN/reflux20
2700
120
5760
Tetrabutylammonium chloride (TBAC)/water/100ꢀC21
Lipase AS (Aspergillus niger)/CH3CN/100ꢀC22
Fe3O4/SiO2/Propyl-Pip/solvent-free/120ꢀC23
Aspartic acid/solvent-free/100ꢀC29
40
30
20
240
120
60
5760
50
95
92
93
91
80
93
84
83
94
ChCl/urea/H2O/EtOH/(2:1, v/v)/80 ꢀC (present work)
CH3SO3H/CH3CN/reflux15
Silica tungstic acid (STA)/solvent-free/120ꢀC16
Tetrabutylammonium chloride (TBAC)/water/100ꢀC21
Lipase AS(Aspergillus niger)/CH3CN/100ꢀC22
Fe3O4/SiO2/Propyl-Pip/solvent-free/120ꢀC23
FeTiO3/H2O/reflux26
50
added to the reaction mixture and the solid was filtered. The products were recrystal-
lized from ethanol (96%) to give pure compounds 5a-l or 6a-e. The known compounds
were identified by matching their melting points with those reported in the literature
cited in Table 2. For the sake of completeness, characterization data for the representa-
tive compound 5h are provided below.
2-Amino-4-(3-nitrophenyl)-4H-benzo[f]chromene-3-carbonitrile (5h)
1HNMR (300 MHz, DMSO-d6); 5.81 (s, 1H), 7.27 (s, 2H, exchangeable with D2O),
7.32–7.40 (m, 4H), 7.79–8.16 (m, 6H); 13CNMR (75 MHz, DMSO-d6); 39.38, 57.14,

40
B. MALEKI ET AL.
115.53, 118.01, 118.54, 122.86, 123.93, 124.92, 125.67, 128.08, 128.96, 129.44, 129.56,
130.35, 131.06, 131.97, 132.62, 144.16, 148.21, 166.24; IR (KBr, cmÀ1): 3468, 3350, 3224,
3070, 2890, 2201, 1658, 1580, 1530, 1418, 1370, 1224, 1157, 1092, 1030, 810.
ORCID
Reza Tayebee
Ali Khoshsima
http://orcid.org/0000-0003-1211-1472
http://orcid.org/0000-0002-3210-7203
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