New magnetic-responsive deep eutectic catalyst based on Co2+/choline chloride for the synthesis of tetrahydro-pyrazolopyridines and pyrroles in water

Article abstract of DOI:10.1016/j.molliq.2020.112722

A new magnetic-responsive deep-eutectic (MDE) was detected by screening the components at different mole ratios in the solid-liquid equilibrated mixtures of CoCl₂·6H₂O and choline chloride (ChCl) followed by vacuum evaporation. Among

Full text of DOI:10.1016/j.molliq.2020.112722

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New magnetic-responsive deep eutectic catalyst based on
Co2+/choline chloride for the synthesis of tetrahydro-
pyrazolopyridines and pyrroles in water
Fatemeh Tamaddon, Ali Khorram
PII:
S0167-7322(19)36657-7
DOI:
https://doi.org/10.1016/j.molliq.2020.112722
MOLLIQ 112722
Reference:
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
3 December 2019
12 February 2020
14 February 2020
Please cite this article as: F. Tamaddon and A. Khorram, New magnetic-responsive deep
eutectic catalyst based on Co2+/choline chloride for the synthesis of tetrahydro-
pyrazolopyridines and pyrroles in water, Journal of Molecular Liquids(2020),
https://doi.org/10.1016/j.molliq.2020.112722
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New magnetic-responsive deepeutectic catalystbasedon Co /choline chloride
for the synthesis of tetrahydro-pyrazolopyridines and pyrroles in water
Corresponding Author: Fatemeh Tamaddon*, Department of Chemistry, Faculty of Science,
Yazd University, Yazd 89195-741, Iran E-mail: ftamaddon@yazd.ac.ir
Author2: Ali Khorram, Department of Chemistry, Faculty of Science, Yazd University, Iran. E-
mail: khorram@stu.yazd.ac.ir
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New magnetic-responsive deepeutectic catalystbasedon Co /choline chloride
for the synthesis of tetrahydro-pyrazolopyridines and pyrroles in water
Fatemeh Tamaddon,* Ali Khorram
Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-74, Iran
Abstract: A new magnetic-responsive deep-eutectic (MDE) was detected by screening the
components at different mole ratios in the solid-liquid equilibrated mixtures of CoCl2.6H2O and
choline chloride (ChCl) followed by vacuum evaporation. Among these complexes, the bluish
complex 2ChCl.2Ch+:CoCl42- (Co4ChDES), given at 1:4 mole ratio of CoCl2:ChCl showed a
very deep decrease in mp as well as paramagnetic properties. All complexes were compared by
mp, UV-vis, and FT-IR, while the Co4ChDES was finely analyzed by energy-dispersive X-ray
spectroscopy (EDX), vibrating sample magnetometery (VSM), and EDS mapping. The positive
magnetic response, surface elemental analysis, and characteristic UV-vis absorption wavelengths
2-
for Co4ChDES confirmed the presence of magnetic tetrahedral counter ion CoCl4 in the
2-
structure of this DES. The anionic complex CoCl4 which provides magnetically recovering of
Co4ChDES in cooperation with the four choline groups are hydrogen bond-acceptor and
hydrogen bond-donor components of this DES. The 0.75 mol% and 1.5 mol% of Co4ChDES
represented high catalytic performance in the water-based multi-component reactions (MCRs)
for the synthesis of substituted tetrahydropyrazolopyridines (THDPPs) and pyrroles under very
mild conditions. High efficiency, simple recovery, and reusability are advantages of this non-
corrosive liquefy catalyst which makes it a better alternative than that homogenous liquid acid
catalysts.
2-
Keywords: Magnetic deep eutectic; Choline chloride; Tetrahedral CoCl4 ; Pyrazolopyridines;
substituted pyrroles
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1. Introduction
Deep eutectic solvents (DESs) are highlight solvents/catalysts in different fields of science and
technology [1-8]. While DESs are composed of hydrogen bond acceptor (HBA) and hydrogen
bond donor (HBD) components, the first DESs are moister-stable Lewis acids prepared from
choline chloride (ChCl) and metal halides [9-11]. Recently, various types of DESs have been
prepared and used as catalyst or solvent in different organic transformations [12-14]. Despite the
polarity and low vapor-pressure advantages of DESs, their recovery and reusability are
problematic [15] that could be solved by magnetization either by magnetic supports [12, 14] or
entering of the magnetic counter-ions in the structural formula of DESs [16]. Among these
magnetization techniques, entering a magnetic counter ion in DES-structure is more considerable
due to the difficults associated with the linking of DESs to magnetic supports [14]. We have
recently prepared new magnetically separable DESs based on a gemini-surfactant (GS) and
2-
tetrachlorometallate anions (MCl4 ) and used them as catalysts in organic synthesis [16, 17].
Typically, we have prepared the ferromagnetic DES complex GS2+.CoCl42- and compared its
-
catalytic activity with the other MCl4 -complexes in organic synthesis by multi-component
reactions (MCRs) [17]. Due to the no formation of magnetic CoCl42- in the originally prepared
DES of CoCl2:ChCl by Abbott [9, 15, 18], the magnetic behavior, and magnetically recovering
of Co2+/choline chloride-based DESs has not been evaluated. Besides, because of growing need
to DESs as solvents/catalysts, their recovery issues, biocompatibility of ChCl, and Lewis acidity
of CoCl2.6H2O, the preparation, characterization, and catalytic application of the low-cost,
simple, and magnetically separable DESs complexs with tetrahedral counter ion CoCl42- from
CoCl2.6H2O and ChCl is highly desirable.
Tetrahydro-di-pyrazolopyridines (THDPPs) are fused heterocycles, bearing important
pharmacophores of 1,4-dihydropyridine (1,4-DHP) [19-21] and pyrazol rings [22]. THDPPs
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have been prepared by a modified Hantzsch MCR run with the two in situ formed pyrazolon
rings instead of 1,3-dicarbonyls, an aldehyde, and ammonium acetate [23-26]. As a result, a
variety of catalytic MCRs as modified pseudo-six-component reactions have been developed for
the synthesis of THDPPs using L-proline [27], carbonaceous acid [28], sulfonic resins [29],
nano-CdZr4(PO4)6 [30], or nano CeO2 as catalyst [31]. Design of a more efficient and reusable
homogeneous DES catalyst for this MCR synthesis is anticipated.
Poly-substituted pyrroles are another biologically active nitrogenous heterocycles prepared by
different tunable MCRs [32-34]. The four-component condensation of aldehydes, 1,3-
dicarbonyles, and amines, with nitromethane, is a typical developed [1+1+1+2] strategy for the
MCR synthesis of substituted pyrroles in the presence of homogeneous and heterogeneous
catalysts [33, 35]. The non-reusable DES of ChCl:malonic acid [36] has been recently used to
promote this reaction, while a more efficient magnetically separable DES catalyst for synthesis
of pyrroled in water is of interest.
Due to the synergistic advantages of magnetic Co2+/choline chloride-based DES with water-
based MCRs and biological activities of THDPPs and pyrroles, design of a reusable and polar
magnetically recoverable DES for the upgraded synthesis of these heterocycles has been
subjected of this project. Besides, this is the first attempt on the preparation, characterization, and
using of a simply prepared cobalt-based liquified magnetic DES in organic synthesis.
2. Experemental
2.1. Materials
All chemicals were purchased from Merck (Darmstadt, Germany), Sigma-Aldrich and used
without further purification. The FT-IR spectra of CoCl2/ChCl complexes and products as KBr
discs were recorded on a Bruker spectrophotometer. Melting points were determined by a Buchi
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B-540 apparatus. The absorbance UV-Vis spectra of CoCl2/ChCl complexes were run in
acetonitrile by Bruker spectrophotometer. The pH of samples was recorded at room temperature
by inolab pH 7110. The vibration sample-magnetometry (VSM) for Co4ChDES was monitored
by the Lake Shore Cryotronics 7404 at 298 K,whereas its energy dispers X-ray spectroscopy by
EDS mapping and EDX were performed with MIRA3TESCAN-XMU, SEM system.
2.2. Preparation of complexes from CoCl2.6H2O and ChCl
Various (CoCl2)n/(ChCl)m complexes were prepared by stirring the stoichiometric amounts of
white powder of ChCl and pink solid of CoCl2.6H2O in different 1:1, 2:1, 1:2, and 1:4 mole
ratios. Typically, the blue magnetic DES complexe CoCl2:4ChCl was prepared by stirring of a
mixture of CoCl2.6H2O (5 mmol) and ChCl (20 mmol) at 100 °C for 1h, washing and hexane,
and drying under vacuum to remove the solvent. The obtained DES of CoCl2:4ChCl was named
as Co4ChDES.
2.3. Characterization of complexes
The structure of complexes was characterized and confirmed by FT-IR, UV-Vis spectroscopy,
pH, EDS mapping, EDX, VSM, and melting point analysis.
2.4. Catalytic experiments
2.4.1. General procedure for the CoCl2:4ChCl-catalyzed synthesis of THDPPs
To a stirring mixture of aldehyde (2.0 mmol), 1,3-dicarbonyl (4.4 mmol), hydrazine (4.4 mmol),
and ammonium acetate (3.0 mmol) in water (0.5 mL) was added CoCl2:4ChCl (0.015 mmol) and
the mixture was stirred for the given short times at room temperature, until the product was
precipitated in water. The solid product was filtered, washed, dried, and isolated in excellent
yields. Then the magnetic DES catalyst was recovered from the magnetically isolated aqueous
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phase of CoCl2:4ChCl in quantitative yield by evaporation of the trace water with a vacuum
pump. The EDX and VSM analysis of the recovered catalyst was the same as original complex
DES. The purity of the precipitated THDPP product was enough to show the expected
spectroscopic data for structure confirmation.
2.4.2. Spectroscopic data for the selected THDPP products
́
2.4.2.1. 3,5-Dimethyl-4-(4-hydroxy-phenyl)-1,4,7,8-tetrahydrodipyrazolo [3,4-b, 4,3-e] pyridine
(Entry 3, Table 3): White solid, mp = 267–269 °C (Lit. 267–268 °C) [37]. FT-IR (KBr): 3234
1
(overlapped NH and OH stretching), 2935 (CH stretching), 1600 (C=N stretching), cm-1. H
NMR (400 MHz, DMSO-d6): δ = 2.05 (s, 6H, 2 CH3), 4.68 (s, 1 H, CH), 6.57 (d, J = 8 Hz, 2 H,
Harom), 6.89 (d, J = 8 Hz, 2 H, ArH), 9.15 (s, OH), 11.52 (s, 3 H, 3 NH) ppm. 13C NMR (100
MHz, DMSO-d6): δ = 10.35, 31.76, 104.51, 114.45, 128.25, 133.36, 139.75, 155.05, 161.05 ppm
́
2.4.2.2. 3,5-Dimethyl-4-(4-methyl-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b, 4,3-e] pyridine
(Entry 5, Table 3. ): White solid, mp = 244–246 °C (Lit. 244–246 °C) [37]. FT-IR (KBr): 3170
(NH stretching), 2920 (CH stretching), 1610 (C=N stretching), 1520 (C=C aromatic), 1139 (C–N
-1
1
stretching) cm . H NMR (400 MHz, DMSO-d6): δ = 2.1 (s, 6H, 2 CH3), 2.20 (s, 3 H, CH3
(para)), 4.78 (s, 1 H, CH), 6.99–7.00 (m, 4H, Harom), 11.25 (s, 3 H, 3 NH) ppm. 13C NMR (100
MHz, DMSO-d6): δ = 10.85, 20.98, 32.85, 104.85, 127.82, 128.83, 134.70, 140.20, 140.75,
161.50 ppm.
́
2.4.2.3. 3,5-Dimethyl-4-(4-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b, 4,3-e] pyridine
(Entry 11, Table 3): Cream solid, mp = 333–335 °C (Lit. >300 °C) [37]. FT-IR (KBr): 3250 (NH
stretching), 2985 (CH stretching), 1605 (C=N stretching), 1489 (overlapped asymmetrical
stretching NO2 with C=C aromatic), 1352 (NO2 symmetrical stretching), 753 (out of plane
-1
1
bending C–H, para-substituted) cm . H NMR (400 MHz, DMSO-d6): δ = 2.1 (s, 6 H, 2 CH3),
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4.95 (s, 1H, CH), 7.35 (d, J = 8 Hz, 2 H, Harom), 8.1 (d, J = 8 Hz, 2 H, Harom), 11.20 (s, 3H, 3 NH)
ppm. 13C NMR (100 MHz, DMSO-d6): δ = 10.70, 33.40, 103.60, 123.40, 129.20, 140.20, 146.1,
152.25, 161.35 ppm.
2.4.3. General procedure for the Co4ChDES -catalyzed synthesis of substituted pyrroles
The CoCl2:4ChCl (0.03 mmol) was added to the mixture of aldehyde (2.0 mmol),
ethylacetoacetate (2.0 mmol), aniline derivative (2.0 mmol), and nitromethane (1.0 mL) in
distilled water (0.5 mL) and the mixture was stirred at room temperature. After the reaction
completion (TLC monitoring), the aqueous phase of the catalyst was isolated by an external
magnet and the oily product was extracted with ethyl acetate. The vacuum evaporation of water
from the aqueous phase of the magnetic catalyst gave the recovered DES complex and the pure
pyrrole product was obtained by removing ethylacetate under reduced pressure.
2.4.4. Spectroscopic data for selected pyrrole products
2.4.4.1. Ethyl 1‐(4‐chlorophenyl)‐2‐methyl‐4‐(p‐tolyl)‐1H‐pyrrole‐3‐carboxylate (Entry 3, Table
5): White solid, mp = 130‐132 °C (Lit. 130‐132 °C) [38]. FT-IR (KBr): 2983 (CH stretching),
-1
1
1667 (C=O stretching) 1434-1554 (C=C aromatic), 1172 (C–N stretching) cm . H NMR (400
MHz, DMSO‐d6): δ = 7.92 (d, J = 8.0 Hz, 2 H, Harom), 7.65 (d, J = 8.0 Hz, 1 H, Harom), 7.76 (s, 1
H, Harom), 7.70 (d, J = 8.0 Hz, 1 H, Harom), 7.50 (d, J = 8.0 Hz, 4 H, Harom), 3.85(q, J = 8.0 Hz, 2
H, CH2), 2.20 (s, 3 H, CH3), 1.70 (s, 3 H, CH3), 1.25 (t, J = 8.0 Hz, 3 H, -CH3). 13C NMR (101
,
MHz, DMSO‐d6): δ = 180.0, 170.0, 168.0, 164.5, 161.0, 157.5, 152 148.4, 140.0, 137.2, 133.0,
131.5, 128.3, 124.0, 123.0, 120.0, 115.2, 45.5, 36.0, 31.5, 28.0.
2.4.4.2. Ethyl 4‐(4‐methoxyphenyl)‐2methyl‐1‐phenyl‐1H‐pyrrole‐3‐carboxylate (Entry 4, Table
5): White solid, mp = 108‐110 °C (Lit. 108‐110 °C) [39]. FT-IR (KBr): 2980 (CH stretching),
-1
1
1695 (C=O stretching) 1449-1500 (C=C aromatic), 1171 (C–N stretching) cm , H NMR (400
MHz, DMSO‐d6): δ = 8.10 (s, 1 H, Harom), 7.9 (d, J = 8.0 Hz, 2 H, Harom), 7.62 (t, J = 8.0 Hz, 1
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H, Harom), 7.32 (d, J = 8.0 Hz, 2 H, Harom), 7.30 (d, J = 8.0 Hz, 2 H, Harom), 7.20 (d, J = 8.0 Hz, 2
H, Harom), 3.72 (s, 3 H, -CH3), 3.35 (q, J = 8.0 Hz, 2 H, -CH2), 1.90 (s, 3 H, -CH3), 1.25 (t, J =
8.0 Hz, 3 H, -CH3). 13C NMR (101 MHz, DMSO‐d6): δ = 179.0, 167.2, 164.0, 160.0, 155.5,
152.0, 149.5, 145.6, 146.0, 141.0, 131.0, 129.5, 128.53, 128.0, 124.5, 123.0, 120.0, 115.7, 44.2,
35.4, 31.0, 27.0.
2.4.4.3. Ethyl 1‐(4‐chlorophenyl)‐2‐methyl‐4‐phenyl‐1H‐pyrrole‐3‐carboxylate (Entry 9, Table
5): Yellow solid, mp = 126‐128 °C (Lit. 127‐129 °C) [39]. FT-IR (KBr): 2916 (CH stretching),
-1
1
1709 (C=O stretching) 1440-1530 (C=C aromatic), 1139 (C–N stretching) cm . H NMR(400
MHz, DMSO‐d6): δ = 8.30 (s, 1 H, Harom), 7.85 (d, J = 8.0 Hz, 2 H, Harom), 7.6 (t, J = 8.0 Hz, 1
H, Harom), 7.45 (d, J = 8.0 Hz, 2 H, Harom), 7.35 (d, J = 8.0 Hz, 4 H, Harom), 3.74 (q, J = 8.0 Hz, 2
H, -CH2), 2.20 (s, 3 H, -CH3), 1.15 (t, J = 8.0 Hz, 3H, CH3,): 13C NMR (101 MHz, DMSO‐d6) δ
= 180.0, 168.5, 166.0, 162.0, 158.0, 153.5, 148.0, 144.4, 136.5, 133.0, 131.0, 127.0, 124.0,
123.0, 120.0, 116.5, 115.6, 46.5, 32.0, 25.0.
3. Results and discussions
Firstly, various (CoCl2)n(ChCl)m complexes were prepared by stirring of a vacuumed
mixture of the pink solid CoCl2.6H2O and white powder ChCl at controlled stoichiometric ratios
of components and 100 °C under solid-liquid equilibrium. Then, the melting points and magnetic
responses of these complexes to the NdFeB magnet with magnetic power 3.2 T were evaluated.
The physiochemical properties of the as-prepared complexes including formula, color, melting
points, and magnetic response to external magnet are summarized in Table 1.
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Table 1. Physiochemical properties of the as-prepared (CoCl2)n/(ChCl)m complexes
Entry ChCl:CoCl2.6H2O Mp
Chemical composition Color/physical state/magnetic response
(Proposed)
(mol ratio)
1:0
(°C)
1
2
3
4
5
300-302 ChCl
Colorless/solid/negative
Pink/solid/negative
Blue/solid/negative -
Blue/solid/negative
Blue/liquida/positive
0:1
1:1
1:2
4:1
724-726 CoCl2.6H2O
108-110 ChCl:CoCl2
148-150 ChCl:2CoCl2
72-74
4ChCl:CoCl2
(2ChCl.2Ch+:CoCl42-
)
6
2:1
350-352 2ChCl:CoCl2
Blue/solid/positive
2
(2Ch+:CoCl4 )-
a at>40 °C this amorphos solid was softed and melted at 72-74 °C.
As results show, a deep decrease in the melting point is evident for some complexes
formed (entries 3-5) that supports formation of three DES kinds from the same components. The
extreme deep decrease is due to the complex formed from ChCl and CoCl2.6H2O in a 4:1 molar
ratio which cotributes in an exceptional deep eutectic phenomenon (entry 5). Experimenting the
complexes by NdFeB magnet with magnetic power 3.2 T resulted magnetic responsivity of the
CoCl2:2ChCl and CoCl2:4ChCl complexes (entries 5 and 6), although magnetic properties of the
liquify CoCl2:4ChCl was superior than the solid high-melting point complex CoCl2:2ChCl (Fig
1).
Fig 1. Magnetic response of Co4ChDES to NdFeB
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Owing to no magnetic properties of ChCl and our previous experiences on the magneticity
of GS+.CoCl42--complex [12], the positive responses of the complexes formed at entries 5 and 6
to NdFeB magnet are attributed to the presence of the magnetic tetrahedral counter ion
2-
tetrachlorocobaltate (CoCl4 ) in their structure. The magneticity of Co4ChDES was also
evaluated by room temperature VSM analysis at field range -1.5-1.5 T (Fig 2).
250
200
150
100
50
0
-15000
-10000
-5000
0
5000
10000
15000
-50
-100
-150
-200
-250
-300
Applied Field (Oe)
Fig 2. The VSM curve analysis of Co4ChDES
As VSM-curve shows, the complex Co4ChDES is magnetic responsive with paramagnetic
properties and magnetic saturation (Ms) = 224 memu/g. This MS-value is higher than gemini
sutfactant-cobalt complex GS2+.CoCl42- that we prepared previously [16]. The Ms value, positive
response to magnetic field, and blue color of Co4ChDES are logical reasons for the presence of
the tetrahedral magnetic anionic complex CoCl42- in the structure of DES formed at CoCl2.4ChCl
2-
(entry 5, Table 1). The literature data for the magnetic properties of CoCl4 in other ionic liquids
[40-42] supports our suggestion. Considering the CoCl42- as a component of this DES, the
2-
following formula for the intermolecular hydrogen bonding interactions of CoCl4 as HBA with
choline groups as HBD is proposed (Scheme 1).
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2-
Scheme 1. The proposed formula for CoCl4 .2Ch+.2ChCl abbreviated as Co4ChDES
To determine the element distribution in Co4ChDES complex, the EDS mapping was
recorded (Fig. 3).
Fig 3. The EDS mapping analysis of Co4ChDES
According to EDS results, the C, N, Cl, and Co have a homogeneous distribution in the
surface of Co4ChDES indicating the high uniformity in structure of this complex. Alternatively,
chemical composition of Co4ChDES was checked by the EDX analysis and the results show
55.14% C, 13.40% N, 11.44% O, 15.14% Cl, and 4.85% Co, which are compatible with the
proposed structural formula of 2ChCl.2Ch+:CoCl42 (Fig 4).
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Fig 4. The EDS analysis of Co4ChDES
Based on the overlaid FT-IR spectra of the as-prepared Co2+ complexes, the characteristic
-1
-1
-1
-1
-1
absorption bands at 3433 cm , 2926 cm , 1605 cm , 1478 cm , and 1100-1300 cm are related
to the OH stretching, aliphatic CH stretching, CH2 bending, adsorbed surface water, and C-N/C-
O stretchings, respectively. With the similar vibrational modes to other complexes, a large shift
-1
-1
for OH stretching from ~3400 cm to 3259 cm in the spectrum of Co4ChDES is due to the
HBD role of cholines OHs in the DES formed that causes shift to the lower adsorption
wavenumbers. It is notable that, the broad peaks at 3200 to 3500 and 1632 cm-1 in the spectrum
of CoCl2.6H2O are related to the vibrational modes of surface water [41, 42] (Fig. 5).
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Fig 5. The comparative FT-IR spectra of the CoCl2.6H2O, ChCl, and the as-prepared complexes
The UV-Vis spectra of ChCl/CoCl2 complexes in acetonitrile were compared in two
domains of absorption wavelengths for metal-ligand transitions at 200-300 nm and d-d
transitions at 500-800 nm (Fig. 6).
8
Co4ChDES
2Ch⁺:CoCl₄²⁻
ChCl:2CoCl₂
ChCl
7
6
5
4
3
2
1
0
ChCl:CoCl₂
210
240
270
300
 (nm)
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2.5
2
Co4ChDES
2Ch⁺:CoCl₄²⁻
ChCl:2CoCl₂
ChCl:CoCl₂
1.5
1
0.5
0
500
550
600
650
 (nm)
700
750
800
Fig 6. The UV-Vis spectra of ChCl and ChCl/CoCl2-complexes at 200-300 nm and 500-800 nm
Because diverse types of charge-transfer complexes between ChCl and CoCl2, the UV-
absorption for metal-ligand transitions of complexes at 200-300 nm region are different,
although the variance in absorption bands for d-d transitions of complexes at 500-800 nm are
also significant. However, absorbtion wavelengths at 210 nm, 212 nm, 215 nm, 591 nm, and 691
2-
nm confirmed the presence of the tetrahedral bluish complex CoCl4 , which have been
previously detected by UV-Vis absorption as counter ion of ionic liquids. The magnetic anion
CoCl42- was formed in Co4ChDES by the transfer of two Cl- from two ChCl molecules into the
CoCl2 to give the CoCl42-.2Ch+.2ChCl complex (Co4ChDES). The obvious hypsochromic shift
and the minimum absorbance for this DES complex are also attributed to the maximum charge
transfer interactions between choline,s OH and Co2+ in the Co4ChDES. This fact is in agreed
with the large shift of choline,s OH-stretching to the lower adsorption wavenumbers in the FT-IR
spectrum of Co4ChDES (Fig. 5). However, all specra-analytical evidences supports surrounding
of anionic complexe CoCl42- by choline-grups.
The catalytic efficiencies of the prepared Ch-based magnetized-Lewis acid complexes
were furture examined in MCR synthesis of THDPPs. So, factors affecting on the synthesis of 4-
nitrophenyl-1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4',3'-e]pyridine (THDPP1) by the
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pseudo-six-component reaction of 4-nitrobenzaldehyde, hydrazine, ammonium acetate, and
ethylacetoacetate were optimized (Table 2).
a
Table 2. Optimization of conditions for the Co2+-complexes-catalyzed synthesis of THDPP1
Entry Conditions
Time IsolatedYield
Catalyst (per 2 mmols of aldehyde)/Solvent (0.5mL) (min) (%)
1
CoCl2 (0.015 mmol)/H2O
60
60
60
60
30
45
45
15
30
40
45
45
60
18
15
17
20
76
69
45
96
85
76
58
70
35
2
ChCl (0.015 mmol)/H2O
3
ChCl:CoCl2 (0.015 mmol)/H2O
ChCl:2CoCl2 (0.015 mmol)/H2O
2Ch+:CoCl42- (0.015 mmol)/H2O
2Ch+:CoCl42- (0.015 mmol)/-
2Ch+:CoCl42- (0.015 mmol)/EtOH
Co4ChDES (0.015 mmol)/H2O
Co4ChDES (0.02 mmol)/H2O
Co4ChDES (0.025 mmol)/H2O
Co4ChDES (0.015 mmol)/EtOH
Co4ChDES (0.015 mmol)/EtOH-H2O
Co4ChDES (0.015 mmol)/-
4
5
6
7
8
9
10
11
12
13
a The reactionwas performedby 4-nitrobenzaldehyde (2.0mmol), hydrazine(4.0mmol), ammonium acetate(3.0mmol), ethylacetoacetate (4.1
mmol), and catalyst in 0.5 mL solvent at room temperature.
According to the results, the best yield of THDPP1 was obtained using 1.5 mol% of the
Co4ChDES for 2 mmol scale reaction in water at room temperature (entry 8), while the other
choline/Co2+-based complexes had no similar catalytic effect (entries 3-7). The lower yield and
longer time for the model reaction run in EtOH (entry 11) and EtOH/water (entry 12) than water
(entry 8) is attributed to the destruction of the tetrahedral complex Co4ChDES by entrance of
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EtOH instead of choline-OHs. For reaction in water, hydrogen-bonded water molecules protect
the tetrahedral complex core, increase the internal pressure, and enhance the contact area of
catalyst with the reactants. No color change of catalyst from blue to pink-purple during the
reaction in water is an extra evidence for no change of tetrahedral complex Co4ChDES to its
hydrated octahedral form. The superiority of Co4ChDES in a very low loading of 0.0075 mmol
(0.75 mol%) per 1 mmol of the limited-reactant can be related to the tolerance Lewis acidity of
CoCl42-, DES efficacy for providing the maximum contact between the starting materials, and
directing the reaction to a lower energy path. At higher DES-loading, the efficiency was
2-
dramatically reduced due to the increase in CoCl4 concentration and strong interaction of
hydrazine as another HBD with this HBA, which results in the destruction of original
Co4ChDES as well as less contribution of hydrazine in synthesis of THDPP1. To confirm this
suppose, hydrazine was added to Co4ChDES in an individual experiment, which led to
precipitate of components and destruction of DES.
Reusability of the magnetic Co4ChDES was examined in the reaction performed for the
synthesis of THDPP1 at 10 mmol scale by reusing the catalyst after each cycle. Thus, after the
magnetic separation, the recovered bluish catalyst Co4ChDES was washed with EtOAc and kept
under vacuum to remove the solvent. The recovered catalyst was reused in further reaction
cycles for the synthesis of THDPP1, while only 5% catalytic activity loss was observed in
respect to reaction yield after the sixth reaction run (Fig. 7).
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95
93
91
90
92
91
90
70
50
30
10
1
2
3
4
5
6
Number of reaction cycles
Fig 7. Reusability of Co4ChDES in the synthesis of THDPP1
In terms of pharmaceutic uses of THDPPs, the product contamination with Co2+ was
studied by ICP analysis of the THDPP1 solution. No detection of Co2+ confirmed no leaching of
this metal cation from complex Co4ChDES.
Due to the superiority of Co4ChDES in a low loading, the scope of the Co4ChDES-
catalyzed synthesis of THDPPs was then demonstrated by the reaction of various ketoesters and
aldehydes with hydrazine and NH4OAc to give the corresponding products (Table 3).
Table 3. The Co4ChDES-catalyzed synthesis of THDPPs in water
Entry Ar
R
Time Yield Mp (°C)
(min) (%) Found/reported[37, 44]
1
2
3
4
5
Ph
Et
15
94
95
92
94
88
235-237/240-242
239-241
Ph
Me 10
4-OHC6H4
4-ClC6H4
4-CH3C6H4
Et
Et
Et
20
25
18
267-269/267-268
254-256/254-256
244-246/244-246
17

6
4-CH3C6H4
2-NO2C6H4
2-NO2C6H4
4-N(CH3)2
4-N(CH3)2
4-NO2C6H4
4-NO2C6H4
2-ClC6H4
Me 15
Et 12
Me 10
Et 17
Me 18
Et 10
Me 10
92
91
93
97
97
94
95
86
82
90
78
242-245
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7
185-187/187-188
185-187
8
9
242-244/240-242
242-244
10
11
12
13
14
15
16
333-335/>300
334-335
Et
12
30
220-222/164-165
182-184/185-187
183-185
4-CH3OC H4 Et
6
4-CH3OC H4 Me 20
6
4-BrC6H4
Et
30
165-167/165-167
Based on the results, Co4ChDES is an efficient catalyst for a broad scope of substrates to
give the pure products with compatible spectroanalytical data with the literature [44], although in
all cases methyl acetoacetate reacted faster than ethylacetoacetate (entries 2, 6, 8, 10, 12, 15).
With some autority, this method is comparable with previously reported methods for
synthesis of THDPP2 in terms of reaction times, yields, catalyst loading, solvent, and
temperature (Table 4).
Table 4. The synthesis of THDPP2 in various reported conditions.
Entry Conditions
Time Isolated Yield
Catalyst (mg/1 mmol ofstartingmaterial)/Solvent/Temp. (°C) (h)
(%) [Ref]
94 (This work)
94 [30]
1
2
3
4
Co4ChDES (0.75 mol%)/H2O/r.t.
0.25
0.66
0.33
4
Nano-CdZr4(PO4)6 (0.6 mol%)/EtOH/Reflux
CuFe2O4@HNTs (5 mg)/EtOH/r.t
-/H2O:HOAc (3:1)/80 °C
96 [45]
95 [46]
18

5
-/EtOH/Reflux
5
79 [47]
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Next, the versatility of the magnetic catalyst Co4ChDES was evaluated in the more
problematic water-based synthesis of substituted pyrroles by four-component condensation of
ethylacetoacetate, nitromethane, aniline, and benzaldehyde under various conditions (Table 5).
Table 5. Optimization of conditions for pyrroles synthesis using Co4ChDESa
Entry Conditions
Time Isolatedyield
Catalyst (per 2 mmols of startingmaterials) (min) (%)
/Solvent/Temp. (°C)
1
Co4ChDES (0.04 mmol)/-/60
Co4ChDES (0.03 mmol)/-/60
Co4ChDES(0.05 mmol)/H2O/60
Co4ChDES (0.04 mmol)/H2O/65
Co4ChDES (0.015 mmol)/H2O/60
Co4ChDES (0.03 mmol)/H2O/60
-/H2O/65
60
45
30
60
30
15
60
240
70
60
52
75
28
67
78
96
21
95
73
49
2
3
4
5
6
7
8
Co4ChDES (0.03 mmol)/H2O/r.t
Co4ChDES (0.03 mmol)/EtOH/60
Co4ChDES (0.03 mmol)/EtOH-H2O/60
9
10
a The reactionwas performedby Benzaldehyde (2.0 mmol),ethylacetoacetate (2.0mmol), aniline (2.0mmol), nitromethane (1.0 mL) andcatalyst
under various conditions.
According to the results, 1.5 mol% of Co4ChDES catalyst, water, and 60 °C were
optimized conditions for the best yield of ethyl-1,4-diphenyl‐2-methyl‐1H‐pyrrole‐3‐carboxylate
(pyrrole 1) in 1 mmol scale (entry 6). The superiority of reaction run in water (entry 6) than
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EtOH (entry 9) and EtOH/water (entry 10) is maybe due to the reaction of the tetrahedral
complex Co4ChDES with EtOH and destruction of the active tetrahedral complex Co4ChDES.
Then, these conditions were extended to the other aldehydes and ß-ketoesters. Table 6
shows the generality of the Co4ChDES-catalyzed synthesis of substituted pyrroles that isolated
in high yield and purity with the same characteristic data in literature [48].
Table 6. The Co4ChDES-catalyzed synthesis of substituted pyrroles
Entry Ar1
Ar2
R
Time Yield Mp (°C)
(min) (%)
Found/reported[Ref.]
Oil/Oil [39]
1
Ph
Ph
Ph-NH2
Ph-NH2
OEt
Me
60
70
70
70
70
80
90
50
70
94
92
89
91
89
78
88
92
92
95
2
106-108/106-107[49]
130-132/130-132[38]
108-110/108-110[39]
120-122/120-122[39]
140-142/141-143[49]
136-138/136-137[49]
Oil/Oil [45]
3
4-OCH3C H4 4-ClC6H4NH2
OEt
OEt
OEt
Me
6
4
4-OCH3C H4 Ph-NH2
6
5
4-CH3C6H4
Ph
Ph-NH2
6
4-BrC6H4NH2
7
4-OCH3C H4 4-CH3OC6H4NH2 Me
6
8
4-NO2C6H4
Ph-NH2
Me
9
Ph
Ph
4-ClC6H4NH2
Ph-NH2
OEt
126-128/127-129[39]
Oil/Oil [49]
10
OMe 50
To show the performance of magnetic catalyst Co4ChDES, the synthesis of pyrrole1 in the
presence of this catalyst was compared with some previously reported methods (Table 7). This
method is superior to others with respect to the catalyst loading, reaction yield, solvent, and
reaction time.
Table 7. Performance of Co4ChDES in pyrrole synthesis.
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Entry Conditions
Time Isolated Yield
Catalyst (mg/1 mmol ofstartingmaterial)/Solvent/Temp. (°C) (h)
(%) [Ref]
96 (This work)
93 [39]
1
2
3
4
5
Co4ChDES (1.5 mol%)/H2O/60 °C
SBCu@silica‐Fe3O4 (0.23 mol%)/-/r.t
Cu2O/Ag (5 mg)/N2 atmosphere/r.t
NiO NPs (5 mol%)/N2 atmosphere/r.t
Graphite (20 mol%)/CH3NO2/Reflux
0.25
0.5
15
4
98 [33]
89 [50]
6
88 [51]
A proposed mechanism for the catalytic roles of Co4ChDES is outlined in Scheme 2. The
superior role of this magnetic DES catalyst is the carbonyl activation by complexation with the
HBA part of this DES and the help of the catalyst to removing of NO2 in the last step. Generally,
this DES catalyst leads to the reducing of the activation energy and acceleration of the reaction
2-
rate. The presence of tetrahedral counter ion CoCl4 in the Co4ChDES structure provides easy
separation of catalyst by magnet and its reusability.
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Scheme 2. The proposed mechanism for Co4ChDES-catalyzed synthesis of substituted pyrroles.
The performed leaching test [52] after 50% progress of the model reaction showed stop of
the pyrrol1 synthesis by magnetically removing of the Co4ChDES at half reaction time using an
external magnet. This means no leaching of the active species of CoCl42- and choline groups as
HBA and HBD components in to the reaction mixture.
Conclusion
The separation and reusing of deep eutectics are important challenges. Thus in this work,
by screening the mole ratios of CoCl2.6H2O and ChCl at 1:1, 2:1, 1:2, and 1:4, a series of
complex mixtures were prepared. In the latter case, the best complex deep eutectic (DE) with a
deep decrease in melting point was formed, while its paramagnetic properties was confirmed by
magnetic responsively and VSM analysis. The magnetic response of this DES is due to the
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presence of magnetic tetrahedral counter ion CoCl4 as HBA H-bonded to the choline groups as
HBD components of this catalyst. Thus, the 2ChCl.2Ch+:CoCl42- (Co4ChDES) formula is
proposed for this magnetic DE, which was also identified by FT-IR, energy-dispersive X-ray
spectroscopy, EDS mapping, and UV-vis analysis. The existence of CoCl42- was similarly
confirmed by characteristic UV-vis absorption wavelengths. A low-loading of this magnetic DES
catalyst showed a superior activity in the rapid synthesis of THDPPs and pyrroles in water,
whereas the role of this magnetic DES catalyst is activation of carbonyl groups by complexation
with the CoCl42- part of this catalyst. Co4ChDES is magnetically recoverable and no significant
activity loss and leaching was observed after six consecutive cycles reusing of it in the rapid and
efficient synthesis of pyrrole derivatives.
Acknowledgment
We gratefully thank the Yazd University Research Council for financial support.
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Declaration of competinginterests
☒ The authors declare that they have no known competing financialinterests orpersonal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
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Graphical Abstract
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Highlights
 The CoCl2.6H2O and choline chloride (ChCl) at 1:4 ratios gives Co4ChDES.
2-
 The magnetic response of Co4ChDES is due to the tetrahedral counter ion CoCl4 .
 The CoCl42- and four choline-OHs are own H-bonding acceptors and donors.
 This magnetic deep eutectic catalyst was structurally confirmed by various methods.
 Co4ChDES is a reusable catalyst for synthesis of N-heterocycles in water.
28