Nicotine-based ionic liquid supported on magnetic nanoparticles: An efficient and recyclable catalyst for selective one-pot synthesis of mono- and bis-4H-pyrimido[2,1-b]benzothiazoles

Article abstract of DOI:10.1002/aoc.5681

In this study, an acidic nicotine-based ionic liquid supported on magnetic nanoparticles ([NicTC]HSO₄@MNPs) was synthesized and characterized by different techniques. The activity of this catalyst was evaluated in a multi-component reaction of

Full text of DOI:10.1002/aoc.5681

Received: 11 January 2020
DOI: 10.1002/aoc.5681
Revised: 27 February 2020
Accepted: 4 March 2020
F U L L P A P E R
Nicotine-based ionic liquid supported on magnetic
nanoparticles: An efficient and recyclable catalyst for
selective one-pot synthesis of mono- and bis-4H-
pyrimido[2,1-b]benzothiazoles
Nasrin Alishahi | Mahboobeh Nasr-Esfahani | Iraj Mohammadpoor-Baltork
|
Shahram Tangestaninejad
| Valiollah Mirkhani | Majid Moghadam
Department of Chemistry, Catalysis
Division, University of Isfahan, Isfahan,
81746-73441, Iran
In this study, an acidic nicotine-based ionic liquid supported on magnetic
nanoparticles ([NicTC]HSO4@MNPs) was synthesized and characterized by
different techniques. The activity of this catalyst was evaluated in a multi-
component reaction of 2-aminobenzothiazole, aldehydes/dialdehydes and β-
ketoesters/1,3-diketones to afford a series of novel mono- and bis-4H-
pyrimido[2,1-b]benzothiazole derivatives. In addition, mild reaction condi-
tions, high yields, excellent selectivity as well as easy recovery and reusability
of the catalyst, make this method an economic and environmentally-benign
process.
Correspondence
Iraj Mohammadpoor-Baltork, Department
of Chemistry, Catalysis Division,
University of Isfahan, Isfahan, Iran.
Email: imbaltork@sci.ui.ac.ir
K E Y W O R D S
4H -Pyrimido[2,1-b]benzothiazoles, fused heterocyclic compounds, nicotine-based ionic liquid,
selective synthesis, solvent-free conditions
1 | INTRODUCTION
friendly protocol for the synthesis of complex deriva-
tives of pyrimido[2,1-b]benzothiazole is still required.
Pyrimido[2,1-b]benzothiazoles are an important class of
fused nitrogen heterocycles, which has been found in
the manufacture of natural molecules and drug mole-
cules with various biological activities.[1–4] Further-
more, these compounds act as chemosensitizers in
chemotherapy and neuroprotectant-cerebral anti-
ischemic agents.[5] Up to now, several methods have
been described for the synthesis of simple derivatives
of these heterocycles.[6] Although the reported methods
are more or less useful, but in some cases, high load-
ing non-reusable catalysts and high temperatures are
required for successful transformation. On the other
hand, the synthesis of bis-4H-pyrimido[2,1-b]ben-
zothiazoles has not been reported so far. Consequently,
introduction of an efficient and environmentally-
In recent years, ionic liquids (ILs) have attracted a
considerable attention in catalytic systems because they
can dissolve a wide variety of organic, organometallic,
and inorganic compounds.[7] In addition, they have
low vapor pressure, low melting point and relatively
thermal stability.[8] Despite these advantages, their
high viscosity, difficulties in recovery and reusability
limit their practical applications in chemical pro-
cesses.[9] Moreover, the toxicity of some ILs renders
their utilization in biological systems such as microor-
ganisms[10] and human cell line.[11] To overcome these
problems, they can be prepared from biocompatible
materials or immobilized on solid supports to obtain
heterogeneous catalysts. In this respect, nicotine as a
biocompatible material and as an efficient alternative
Appl Organometal Chem. 2020;e5681.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5681

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ALISHAHI ET AL.
for hazardous pyridine, has been recently applied for
production of ionic liquids.[12] Among the solid sup-
ports, magnetic nanoparticles (MNPs) are of practical
importance because of their unique features including
providing greater accessibility of active sites, easy syn-
thesis and functionalization, good stability and facile
separation by applying an external magnet.[13–15] Also,
these nanoparticles have been used in many fields
such as magnetic recording devices, targeted drug
delivery, biomedicine, biosensors, magnetic fluids, bio-
probes and catalysis.[16] According to the above men-
tioned advantages of nicotine and MNPs, the
application of nicotine-based ionic liquid supported on
magnetic nanoparticles as catalyst provides an environ-
mentally benign process.
2 | EXPERIMENTAL
2.1 | General
The chemicals were purchased from Fluka and Merck
chemical companies. 2,20-(hexane-1,6-diylbis (oxy))
dibenzaldehyde 2q and 2,20-(butane-1,4-diylbis (oxy))
dibenzaldehyde 2r were prepared according to the previ-
ously reported method.[18] Melting points were deter-
mined with a Stuart Scientific SMP2 apparatus. FT-IR
spectra were recorded on a Nicolet-Impact 400D spectro-
photometer. 1H and 13C NMR (400 and 100 MHz) spectra
were recorded on a Bruker Avance 400 MHz spectrome-
ter using DMSO-d6 solvent. Elemental analysis was per-
formed
on
a
LECO,
CHNS-932
analyzer.
In continuation of our interest relating to the intro-
duction of valuable catalytic systems,[17] we report an
acidic nicotine-based ionic liquid supported on magnetic
nanoparticles ([NicTC]HSO4@MNPs) as a reusable het-
erogeneous catalyst for the efficient synthesis of novel
mono- and bis-4H-pyrimido[2,1-b]benzothiazoles under
solvent-free conditions (Scheme 1).
Thermogravimetric and derivative thermogravimetric
analysis (TGA/DTG) were evaluated on a Perkin-Elmer
STA 6000 instrument under argon flow at a uniform
heating rate of 20 ꢀC min−1 in the range 30–600 ꢀC. Mag-
netic measurements were carried out with a vibrating
sample magnetometer (Meghnatis Daghigh Kavir Co.) at
room temperature. The scanning electron microscope
SCHEME 1 Synthesis of mono- and bis-4H-pyrimido[2,1-b]benzothiazoles catalyzed by [NicTC]HSO4@MNPs

ALISHAHI ET AL.
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(SEM) measurement was carried out on a Hitachi S-4700
field emission scanning electron microscope. The trans-
mission electron microscopy (TEM) was carried out on a
Philips CM10 instrument operating at 100 kV. X-ray dif-
fraction patterns were obtained with a Bruker XRD D8
Advance instrument with Co Kα radiation at 40 kV.
nicotine-based ionic liquid supported on magnetic
nanoparticles ([NicTC]HSO4@MNPs).
2.3 | General procedure for the synthesis
of 4H-pyrimido[2,1-b]benzothiazoles
catalyzed by [NicTC]HSO4@MNPs
2.2 | Preparation of nicotine-based ionic
liquid supported on magnetic
nanoparticles ([NicTC]HSO4@MNPs,
scheme 2)
A mixture of 2-aminobenzothiazole 1 (1 mmol), aryl alde-
hyde 2 (1 mmol), and β-ketoester/1,3-diketone 3 (1 mmol)
and [NicTC]HSO4@MNPs catalyst (25 mg, 1 mol% HSO4)
̄
was stirred at room temperature for the appropriate time
stated in Table 3. The reaction progress was monitored
by TLC (eluent: petroleum ether/EtOAc, 4:1). After com-
pletion of the reaction, hot ethanol (5 ml) was added and
the catalyst was simply separated using an external mag-
net and then washed with hot ethanol (5 ml). The
organic residue was cooled to room temperature, filtered,
washed with EtOH for several times and dried under vac-
uum to provide the pure desired products in 83–98%
yields (Table 3).
The magnetic nanoparticles (MNPs) and silica coated
magnetic nanoparticles (SiO2@MNPs) were prepared
according to the previously reported method.[19] Then, a
mixture of 3-aminopropyltriethoxysilane (APTES, 6 ml)
and dispersed SiO2@MNPs (2 g) in dry toluene (40 ml)
was refluxed under nitrogen atmosphere for 24 h. The
resulting AP@MNPs were separated by an external mag-
net, washed with diethyl ether and dried under vacuum.
Subsequently, the dispersed AP@MNPs (2 g) were
reacted with 1.85 g trichlorotriazine (TC) and 1.7 ml
diisopropylethylamine (DIPEA) in 10 ml dry THF at
0–20 ꢀC.[20] The solid material was magnetically sepa-
rated, washed with hot THF and then dried under vac-
uum to provide APTC@MNPs. After that, the dispersed
APTC@MNPs (2 g) ꢀin 20 ml DMF was reacted with nico-
tine (5.4 g) at 100 C for 24 h. The solid material was
magnetically separated, washed with DMF and ethanol
and then dried to produce [NicTC]Cl@MNPs. Finally, a
mixture of [NicTC]Cl@MNPs (1.85 g) and sodium hydro-
gen sulfate (9.25 g) was stirred in water (30 ml) at room
temperature for 12 h. The solid material was magneti-
cally separated, washed with water and ethanol and dried
in a vacuum oven at 80 ꢀC to produce the desired
2.4 | General procedure for the selective
synthesis of mono- and bis-4H-
pyrimido[2,1-b]benzothiazoles from
dialdehydes catalyzed by [NicTC]
HSO4@MNPs
For the synthesis of mono- derivatives, a mixture of
2-aminobenzothiazole (1 mmol), dialdehyde (1 mmol), β-
ketoester/1,3-diketone(1mmol)and[NicTC]HSO4@MNPs
(25 mg, 1 mol% HSO4−) was stirred at 50 ꢀC under
solvent-free conditions for the suitable time presented in
Schemes 3 and 4. After completion of the reaction as
monitored by TLC (eluent: petroleum ether/EtOAc, 4:1),
SCHEME 2 The schematic procedure for the
preparation of [NicTC]HSO4@MNPs catalyst

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ALISHAHI ET AL.
SCHEME 3 Selective synthesis of mono-
4H-pyrimido[2,1-b]benzothiazoles from β-
ketoesters catalyzed by [NicTC]HSO4@MNPs
SCHEME 4 Selective synthesis of
mono-4H-pyrimido[2,1-b]benzothiazoles
from 1,3-diketones catalyzed by [NicTC]
HSO4@MNPs
the crude product was purified according to the above
mentioned procedure to provide pure mono-4H-
pyrimido[2,1-b]benzothiazole derivatives in 68–83%
yields.
2-aminobenzothiazole (1 mmol), dialdehyde (0.5 mmol)
and β-ketoester/1,3-diketones (1 mmol) was carried out
in the presence of [NicTC]HSO4@MNPs (50 mg, 2 mol%
HSO4 ) at 50 C for 1.4–2 h. The workup was performed
according to the procedure above mentioned and purifi-
cation of the crude product by silica gel column
−
ꢀ
For the synthesis of symmetric bis-4H-pyrimido[2,1-b]
benzothiazoles,
the
reaction
between

ALISHAHI ET AL.
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chromatography (eluent: petroleum ether/EtOAc, 4:1)
provided the pure symmetric bis- derivatives in 69–81%
yields (Schemes 5, 6).
NicTC@nSiO2)
for
the
Regarding
synthesis
our
of
1,5-benzodiazepines.[12g]
previous
research, herein, the synthesis of an acidic nicotine-based
ionic liquid stabilized on magnetic nanoparticles
([NicTC]HSO4@MNPs) was investigated (Scheme 2).
In brief, magnetic nanoparticles (MNPs) were pre-
pared via the coprecipitation method and preserved with
For the synthesis of unsymmetric bis-4H-
pyrimido[2,1-b]benzothiazoles,
a
mixture
of
2-aminobenzothiazole (1 mmol), dialdehyde (0.5 mmol),
0.5 mmol of each of two different 1,3-dicarbonyl com-
pounds and [NicTC]HSO4@MNPs (50 mg, 2 mol%
a
layer of silica (SiO2@MNPs).[21] Treatment of
−
ꢀ
HSO4 ) was stirred at 50 C for 1.4–1.5 h. At the end of
the reaction which was monitored by TLC (eluent: petro-
leum ether/EtOAc, 4:1), the workup and purification of
the crude product was performed according to the above
mentioned procedure to produce the pure unsymmetric
bis-derivatives in 67–70% yields (Scheme 7).
SiO2@MNPs with 3-aminopropyltriethoxysilane (APTES)
under inert conditions produced AP@MNPs. In the fol-
lowing, the amino group of AP@MNPs was reacted with
trichlorotriazine
(TC)
in
the
presence
of
diisopropylethylamine (DIPEA) in anhydrous THF at
0–20 ꢀC to provide APTC@MNPs.[20] Then, the active
chlorine groups were substituted with nicotine in DMF at
ꢀ
100 C to produce [NicTC]Cl@MNPs. Finally, the target
3 | RESULTS AND DISCUSSION
acidic catalyst, [NicTC]HSO4@MNPs was prepared by
adding NaHSO4 to [NicTC]Cl@MNPs in water. The syn-
thesized [NicTC]HSO4@MNPs was characterized using
different techniques, including FT-IR, VSM, TEM, SEM,
EDX, TG/DTG, XRD and elemental analysis.
The FT-IR spectra of MNPs, SiO2@MNPs,
APTC@MNPs and [NicTC]HSO4@MNPs are presented
in Figure 1. The characteristic bands at 560 and
465 cm−1, attributed to the symmetric and asymmetric
3.1 | Preparation and characterization of
nicotine-based ionic liquid supported on
magnetic nanoparticles ([NicTC]
HSO4@MNPs)
Recently, we reported
a
new nicotine-based
organocatalyst supported on silica nanoparticles (Fe (III)-
SCHEME 5 Selective synthesis of symmetric bis-4H-pyrimido[2,1-b]benzothiazoles from β-ketoesters catalyzed by [NicTC]
HSO4@MNPs

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ALISHAHI ET AL.
SCHEME 6 Selective synthesis
of symmetric bis-4H-pyrimido[2,1-b]
benzothiazoles from 1,3-diketones
catalyzed by [NicTC]HSO4@MNPs
SCHEME 7 Selective synthesis of unsymmetric
bis-4H-pyrimido[2,1-b]benzothiazoles catalyzed by
[NicTC]HSO4@MNPs

ALISHAHI ET AL.
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FIGURE 2 Magnetization curves for MNPs, SiO2@MNPs and
[NicTC]HSO4@MNPs
catalyst is smaller than that of the bulk magnetic sample,
but it is enough for easy separation of the catalyst from
the reaction mixture by an external magnet.
The morphology of the surface of [NicTC]
HSO4@MNPs catalyst was investigated by SEM, SEM–
EDX and TEM spectroscopies. As shown in Figure 3, the
presence of all expected elements C, N, S, O, Si and Fe in
the EDX analysis of [NicTC]HSO4@MNPs is indicative of
successful functionalization of MNPs by covalent attach-
ment of nicotine ionic liquid. The TEM image of the cata-
lyst revealed dark spherical morphology with an average
diameter of 12–15 nm.
FIGURE 1 FT-IR spectra of: (a) MNPs, (b) SiO2@MNPs,
(c) APTC@MNPs, (d) [NicTC]HSO4@MNPs and (e) the 5-times
reused catalyst
Fe–O vibrations (Figure 1a), confirm the existence of
Fe3O4 component in all samples. Also, all these samples
show a broad band centered around 3437 cm−1 that is
assigned to the OH group. The spectrum of the
SiO2@MNPs (Figure 1b) exhibits the characteristic bands
at about 1099, 932 and 804 cm−1, which are attributed to
the stretching vibrations of Si–O–Si, Si–OH and Si–O–Fe,
respectively. In the FT-IR spectra of APTC@MNPs and
[NicTC]HSO4@MNPs (Figures 1c and 1d), the typical
bands observed at about 2940 cm−1 (C–H), 1625 cm−1
(C=N), 1561 cm−1 (C=C) and 1410 cm−1 (C–H). In addi-
tion, the bands at 1175 and 1045 cm−1 in the spectrum of
[NicTC]HSO4@MNPs (Figure 1d) correspond to the
vibrations of S=O group. These results confirm that IL
has been successfully supported on the surface of
SiO2@MNPs.
Due to importance of easy recovery of the catalyst by
an external magnet, the magnetic property of [NicTC]
HSO4@MNPs was also evaluated (Figure 2). The satura-
tion magnetization (Ms) values of MNPs, SiO2@MNPs
and [NicTC]HSO4@MNPs catalyst were obtained to be
69.40, 38.96 and 19.52 emu g−1, respectively. Although,
the superparamagnetic characteristic of the prepared
The TG/DTG analysis of the synthesized catalyst is
presented in Figure 4. As shown, [NicTC]HSO4@MNPs
ꢀ
are thermally stable up to 400–500 C, and above this
temperature the process of decomposition proceeds rela-
tively fast, in which the organic construction was omitted
from the catalyst. This high thermal stability provides the
excellent activity of the catalyst without any considerable
leak of the active species. The total weight loss was
19.60%.
The X-ray diffraction patterns of MNPs, SiO2@MNPs,
APTC@MNPs,
[NicTC]Cl@MNPs
and
[NicTC]
HSO4@MNPs show the same typical peak positions and
relative intensities (Figure 5). The peaks at 30.44ꢀ,
36.08ꢀ, 43.67ꢀ, 53.24ꢀ, 57.68ꢀ and 63.32ꢀ correspond to
the (220), (311), (400), (422), (511) and (440) reflections,
respectively, of the crystalline structure of the standard
naked MNPs sample (JCPDS 19–0629). A broad peak at
2θ = 15.16ꢀ-28.68ꢀ is attributed to the amorphous silica
shell surrounding of the MNPs core.[22] As can be seen,
the phase composition of MNPs remains intact after
coating the nanoparticles with silica.
According to the elemental analysis of the [NicTC]
HSO4@MNPs catalyst (C = 7.15, H = 1.86, N = 2.29 and

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ALISHAHI ET AL.
FIGURE 3 FE-SEM images of: (a) [NicTC]HSOa@MNPs, (b) SEM–EDX spectrum of [NicTC]HSO4@MNPs, (c) TEM image of
[SiAPTANic]HSO4@MNPs and (d) particle size distribution for [NicTC]HSO4@MNPs catalyst
FIGURE 4 TGA/DTG analysis of [NicTC]
HSO4@MNPs catalyst
S = 1.04), the amount of organic layer supported on the
magnetic nanoparticles was 0.4 mmol/g of the catalyst
(based on nitrogen content). Furthermore, the acidity of
the [NicTC]HSO4@MNPs catalyst, determined by poten-
tiometric titration (NaOH 0.01 N), showed that the acidic
sites on the magnetic nanoparticles was 0.4 mmol/g of
catalyst.
3.2 | Optimization of the reaction
conditions for the synthesis of 4H-
pyrimido[2,1-b]benzothiazole derivatives
For optimization of the reaction conditions, the present
study was initiated with 2-aminobenzothiazole 1 (1 mmol),
4-nitrobenzaldehyde 2a (1 mmol) and ethyl acetoacetate

ALISHAHI ET AL.
9 of 14
reaction was carried out in the presence of 2 mol% of dif-
ferent catalysts such as SnCl2·2H2O, FeCl3, BiCl3, Bi
(OTf)3, H3PW12O40, [Hmim]HSO4 and NaHSO4 at room
temperature under solvent-free conditions and the target
compound 4aa was obtained in 14–69% yields (Table 1,
entries 2–8). Surprisingly, application of [NicTC]
HSO4@MNPs catalyst (Table 1, entry 9), not only
enhanced the reaction rate but also provided an excellent
yield of the product 4aa (20 min, 98%). Furthermore, the
reaction was performed with 0.5 mol% and 1 mol% of the
catalyst and the yields were found to be 65% and 98%,
respectively (Table 1, entries 10, 11). In addition, the
model reaction was performed in various solvents such as
CH3CN, EtOH, CHCl3, CH2Cl2 and n-hexane instead of
solvent-free conditions (Table 1, entries 12–16). As can be
seen, the desired product was obtained in low yield
(10–68%). Accordingly, the solvent-free conditions was
regarded as the best conditions for this reaction. To com-
pare the efficiency of [NicTC]HSO4@MNPs catalyst with
those of MNPs, SiO2@MNPs, APTC@MNPs and [NicTC]
Cl@MNPs, the model reaction was also carried out in the
presence of these reagents. As shown in Table 2, MNPs
and SiO2@MNPs were not effective in this reaction but in
the presence of APTC@MNPs and [NicTC]Cl@MNPs,
the desired product was obtained in only 15% and 28%
yields, respectively. Consequently, 1 mol% [NicTC]
FIGURE 5 X-ray diffraction patterns of: (a) MNPs1,
(b) SiO2@MNPs, (c) APTC@MNPs, (d) [NicTC]Cl@MNPs and
(e) [NicTC]HSO4@MNPs
3a (1 mmol) as the model substrates at room temperature
under solvent-free conditions. The results are summa-
rized in Table 1. No reaction was observed in the absence
of the catalyst even after 7 h (Table 1, entry 1). Then, the
TABLE 1
Optimization of reaction conditions for synthesis of 4aaa
Time
(h)
Yield
(%)c
Entry
Catalyst (mol%)
-
Solvent
1
-
-
-
-
-
-
-
-
-
-
-
7
-
2
SnCl2·2H2O (2)
FeCl3 (2)
3
27
15
14
20
32
69
38
98
98
65
3
3
4
BiCl3 (2)
3
5
Bi(OTf)3 (2)
3
6
H3PW12O40 (2)
[Hmim]HSO4 (2)
NaHSO4 (2)
3
7
3
8
3
9b
10b
11b
[NicTC]HSO4@MNPs (2)
[NicTC]HSO4@MNPs (1)
20 min
20 min
3
[NicTC]HSO4@MNPs
(0.5)
12
13
14
15
16
[NicTC]HSO4@MNPs (1)
[NicTC]HSO4@MNPs (1)
[NicTC]HSO4@MNPs (1)
[NicTC]HSO4@MNPs (1)
[NicTC]HSO4@MNPs (1)
CH3CN
EtOH
3
3
3
3
3
63
68
58
30
10
CH3Cl
CH2Cl2
n-hexane
aReaction conditions: 2-aminobenzothiazole 1 (1 mmol), 4-nitrobenzaldehyde 2a (1 mmol), ethyl acetoacetate 3a (1 mmol) and catalyst at
room temperature under solvent-free conditions or in the presence of different solvents.
bAccording to CHNS analysis of [NicTC]HSO4@MNPs: 50 mg (2 mol% HSO4−), 25 mg (1 mol% HSO4−) and 12.5 mg (0.5 mol% HSO4−).
cIsolated yield.

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ALISHAHI ET AL.
(hexane-1,6-diylbis (oxy))dibenzaldehyde 2q and 2,20-
(butane-1,4-diylbis (oxy))dibenzaldehyde 2r. As revealed
in Schemes 3 and 4, when 2-aminobenzothiazole was
reacted with dialdehydes and β-ketoesters/1,3-diketones
in a 1:1:1 molar ratio under the optimized conditions,
only one formyl group participated selectively to produce
TABLE 2
Comparison of the activity of [NicTC]HSO4@MNPs
with those of other reagents in the synthesis of 4aaa
Entry Catalyst (mg)
Time (h) Yield (%)b
1
2
3
4
5
MNPs (25)
3
3
3
3
-
SiO2@MNPs (25)
APTC@MNPs (25)
[NicTC]Cl@MNPs (25)
-
15
28
98
mono-4H-pyrimido[2,1-b]benzothiazoles
in
68–83%
yields. It is worth noting that such transformation is pre-
cious since the remaining free formyl group could be
used for the production of other important organic com-
pounds. Whereas, the reaction of 2-aminobenzothiazole
with dialdehydes and β-ketoesters/1,3-diketones with a
2:1:2 molar ratio proceeded efficiently in the presence of
[NicTC]HSO4@MNPs (25) 20 min
aReaction conditions: 2-aminobenzothiazole 1 (1 mmol),
4-nitrobenzaldehyde 2a (1 mmol), ethyl acetoacetate 3a (1 mmol)
and catalyst at room temperature under solvent-free conditions.
bIsolated yield.
ꢀ
2 mol% of catalyst at 50 C under solvent-free conditions
HSO4@MNPs under solvent-free conditions at room tem-
perature was found to be optimum to give the best yield
of the desired product 4aa.
to produce the corresponding symmetric bis-4H-
pyrimido[2,1-b]benzothiazoles
in
69–81%
yields
(Schemes 5, 6).
The further superior aspect of this catalytic method
could be found in the synthesis of various unsymmetric
bis-4H-pyrimido[2,1-b]benzothiazoles (Scheme 7). In this
respect, the multi-component reaction between
2-aminobenzothiazole (1 mmol), dialdehydes (1 mmol)
and 1 mmol of each of two different 1,3-dicarbonyl com-
pounds resulted in novel unsymmetric bis-4H-
3.3 | Synthesis of 4H-pyrimido[2,1-b]
benzothiazoles
Next, we examined the scope and generality of this proce-
dure for the synthesis of different 4H-pyrimido[2,1-b]ben-
zothiazole derivatives under the optimized conditions. As
shown in Table 3, the one-pot three-component reaction
of 2-aminobenzothiazole 1 with different aryl aldehydes 2
bearing either electron-withdrawing or electron-donating
groups and β-ketoesters 3 (e.g. ethyl acetoacetate and
methyl acetoacetate) proceeded smoothly to generate the
desired 4H-pyrimido[2,1-b]benzothiazoles in excellent
yields (Table 3, entries 1–4, 10, 11). The α,β-unsaturated
aldehydes such as cinnamaldehyde, and heterocyclic alde-
pyrimido[2,1-b]benzothiazoles
in
67–70%
yields
(Scheme 7). It is important to note that the single-step
selective
zothiazoles,
synthesis
of
mono-pyrimido[2,1-b]ben-
and unsymmetric bis-
symmetric
pyrimido[2,1-b]benzothiazoles is reported for the first
time which could be considered as the most attractive
and fascinating aspect of this catalytic system
(Scheme 3–7). All products were identified by their melt-
ing points, spectral data and elemntal analysis
(Supporting Information).
hydes
such
as
6-chloro-4-oxo-4H-chromene-
3-carbaldehyde, 5-methylfurfural, and 2-thiophene-
carbaldehyde as well as polycyclic aldehydes such as
naphthalene-2-carbaldehyde also participated effectively
in this reaction to produce the respective pyrimido[2,1-b]
benzothiazoles in high yields (Table 3, entries 5–9). In
addition, when cyclic 1,3-diketones such as dimedone 3c
and 1,3-cyclohexanedione 3d were applied instead of β-
ketoesters in the aforesaid multi-component reaction,
they transformed successfully to the respective products
in high yields (Table 3, entries 12–17). In general, the reac-
tions were very fast and completed within 20–50 min and
the product yields were 83–98%.
3.5 | Reaction mechanism
Based on the experimental results, a mechanistic path-
way for synthesis of 4H-pyrimido[2,1-b]benzothiazole
4aa is described in Scheme 8. First, activation of the car-
bonyl group of aldehyde by the [NicTC]HSO4@MNPs
catalyst gives intermediate
A
which upon the
Knoevenagel condensation with enol form of ethyl
acetoacetate 3a provides B. Then, Michael type addition
of 2-aminobenzothiazole 1 to intermediate B in the pres-
ence of the catalyst results in iminium ion C which upon
proton transfer produces intermediate D. Next, the inter-
mediate D undergoes intramolecular cyclization in the
presence of the catalyst to afford E. Afterward, the inter-
mediate E is converted to the related intermediate F via
anomeric based oxidation.[23] In order to confirm this
goal, the model reaction was also performed under argon
atmosphere and the desired product was obtained in
3.4 | Selective synthesis of mono- and
bis-4H-pyrimido[2,1-b]benzothiazoles
By obtaining worthy results as above mentioned, we then
tried the synthesis of pyrimido[2,1-b]benzothiazoles by
using substrates containing two formyl groups such as
terephthaldialdehyde 2o, isophthaldialdehyde 2p, 2,20-

ALISHAHI ET AL.
11 of 14
TABLE 3
[NicTC]HSO4@MNPs-catalyzed multi-component synthesis of 4H-pyrimido[2,1-b]benzothiazolesa
Entry
R1
β-ketoester (1,3-diketone)
Product
4aa
Time (min)
Yield (%)b
Ref.
[6g]
1
4-NO2C6H4
20
30
25
40
50
50
50
40
45
50
30
98
97
92
90
88
83
85
90
86
89
95
[6g]
[6h]
2
2,4-(Cl)2C6H3
4ba
4ca
3
3-NO2C6H4
4
4-CH (CH3)2C6H4
Cinnamyl
4da
4ea
-
-
-
-
-
-
-
-
5
6
6-Chloro-4-oxo-4H-chromen-3-yl
5-Methylfuran-2-yl
Naphthalene-2-yl
Thiophen-2-yl
4fa
7
4ga
8
4 ha
4ib
9
10
11
4-PhCH2OC6H4
3-MeOC6H4
4jb
4 kb
[6e]
12
13
14
15
4-BrC6H4
4lc
35
40
40
50
96
90
88
83
3-MeOC6H4
4ic
4mc
4jc
-
-
-
4-C (CH3)3C6H4
4-PhCH2OC6H4
16
17
3-MeOC6H4
4-PhC6H4
4id
40
45
91
89
-
-
4nd
aReaction conditions: 2-aminobenzothiazole 1 (1 mmol), aldehyde 2 (1 mmol), β-ketoester/1,3-diketone 3 (1 mmol) and [NicTC]
HSO4@MNPs (1 mol%) at room temperature under solvent-free conditions.
bIsolated yield.
comparable yield. Finally, elimination of water from
F produces the desired products 4aa and releases the cat-
alyst which can be used in the next catalytic cycle.
the synthesis of 4aa by the reaction of
2-aminobenzothiazole 1, 4-nitrobenzaldehyde 2a and
ethyl acetoacetate 3a. At the end of the reaction, the mix-
ture was diluted with hot ethanol and the catalyst was
simply separated with an external magnet. The separated
catalyst was washed with hot ethanol, dried and then
reused in successive cycles. As shown in Figure 6, the cat-
alyst can be reused at least five times without any signifi-
cant loss of its efficiency and activity. On the other hand,
comparison of the FT-IR spectra of the fresh and reused
3.6 | Reusability of [NicTC]HSO4@MNPs
Due to the superparamagnetic properties and a good sat-
uration magnetization value (19.52 emu.g−1), [NicTC]
HSO4@MNPs catalyst displayed excellent reusability in

12 of 14
ALISHAHI ET AL.
SCHEME 8 Proposed mechanism for the
synthesis of 4aa
synthesis of mono-4H-pyrimido[2,1-b]benzothiazoles and
symmetric as well as unsymmetric bis-4H-pyrimido[2,1-b]
benzothiazoles from dialdehydes which is reported for
the first time, can be considered as one of the outstanding
features of this catalytic method. Furthermore, short reac-
tion times, high yields, easy work-up, prevention of poi-
sonous organic solvents as well as feasibility of recovery
and reuse of the catalyst make this method an economic
and environmentally-benign process for the formation of
such a fine heterocycles.
ACKNOWLEDGMENTS
The authors are grateful to the Research Council of
the University of Isfahan for financial support of
this work.
FIGURE 6 Recovery and reuse of the catalyst for the
synthesis of 4aa
catalyst showed no obvious change in the structure of the
catalyst and its characteristic bands, indicating that the
catalyst is stable under the reaction conditions.
(Figure 1e).
ORCID
Iraj Mohammadpoor-Baltork https://orcid.org/0000-
0001-7998-5401
Shahram Tangestaninejad https://orcid.org/0000-0001-
5263-9795
4 | CONCLUSION
Majid Moghadam https://orcid.org/0000-0001-8984-
1225
In summary, we have developed [NicTC]HSO4@MNPs as
a novel and efficient catalyst for the preparation of a
series of 4H-pyrimido[2,1-b]benzothiazole via a one-pot
multi-component reaction of 2-aminobenzothiazole, alde-
hydes and β-ketoesters/1,3-diketones at room tempera-
ture under solvent-free conditions. Also, selective
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SUPPORTING INFORMATION
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How to cite this article: Alishahi N, Nasr-
Esfahani M, Mohammadpoor-Baltork I,
Tangestaninejad S, Mirkhani V, Moghadam M.
Nicotine-based ionic liquid supported on magnetic
nanoparticles: An efficient and recyclable catalyst
for selective one-pot synthesis of mono- and bis-4H-
pyrimido[2,1-b]benzothiazoles. Appl Organometal
Chem. 2020;e5681. https://doi.org/10.1002/aoc.
5681