Application and developing of iron-doped multi-walled carbon nanotubes (Fe/MWCNTs) as an efficient and reusable heterogeneous nanocatalyst in the synthesis of heterocyclic compounds

Article abstract of DOI:10.1002/aoc.4124

Iron-doped multi-walled carbon nanotubes (Fe/MWCNTs) is an efficient, ecofriendly and reusable heterogeneous nanocatalyst for the one-pot synthesis of heterocyclic compounds including bis-spiro piperidines, piperidines, dihydro-2-oxopyrroles, pyrazoles and diazepines at room temperature with good to excellent yields. The heterogeneous nanocatalyst was fully characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), inductively coupled plasma (ICP) and FT-IR analysis. Also, the structures of all prepared compounds were characterized by ¹H NMR, ¹³C NMR, FT-IR, mass spectrometry (MS) and elemental analysis. The major advantages of these protocols are mild and green reaction conditions, short reaction times, clean reaction, operational simplicity, easy purification and good to excellent yields with the reusable heterogeneous nanocatalyst. The catalyst was ten recycled without significant loss of activity.

Full text of DOI:10.1002/aoc.4124

Received: 27 June 2017
DOI: 10.1002/aoc.4124
Revised: 29 August 2017
Accepted: 2 September 2017
F U L L P A P E R
Application and developing of iron‐doped multi‐walled
carbon nanotubes (Fe/MWCNTs) as an efficient and
reusable heterogeneous nanocatalyst in the synthesis of
heterocyclic compounds
Hashem Sharghi
| Jasem Aboonajmi | Mozhdeh Mozaffari |
Mohammad Mahdi Doroodmand | Mahdi Aberi
Department of Chemistry, College of
Iron‐doped multi‐walled carbon nanotubes (Fe/MWCNTs) is an efficient,
Sciences, Shiraz University, Shiraz 71454,
Iran
ecofriendly and reusable heterogeneous nanocatalyst for the one‐pot synthesis
of heterocyclic compounds including bis‐spiro piperidines, piperidines,
dihydro‐2‐oxopyrroles, pyrazoles and diazepines at room temperature with
good to excellent yields. The heterogeneous nanocatalyst was fully
characterized by scanning electron microscopy (SEM), X‐ray diffraction
(XRD), inductively coupled plasma (ICP) and FT‐IR analysis. Also, the struc-
Correspondence
Hashem Sharghi, Department of
Chemistry, College of Sciences, Shiraz
University, Shiraz 71454, Iran.
Email: shashem@susc.ac.ir;
hashemsharghi@gmail.com
1
tures of all prepared compounds were characterized by H NMR, 13C NMR,
FT‐IR, mass spectrometry (MS) and elemental analysis. The major advantages
of these protocols are mild and green reaction conditions, short reaction times,
clean reaction, operational simplicity, easy purification and good to excellent
yields with the reusable heterogeneous nanocatalyst. The catalyst was ten
recycled without significant loss of activity.
KEYWORDS
Fe/MWCNTs, heterocyclic compounds, heterogeneous, nanocatalyst, one‐pot
1 | INTRODUCTION
catalysts.[2] Nowadays, a great challenge for organic
chemists is the preparation of more benign and efficient
The chemistry of heterocycles has attracted considerable
interest in recent years. Heterocycles are an important
class of chemical compounds because of their widespread
appearance in chemical structure of natural products,
bio‐active molecules, pharmaceuticals such as anti‐HIV,
antidepressant, antifungal, antibiotic, antimalarial, anti-
tumor, antidiabetic, herbicidal, anti‐inflammatory agents.
Moreover these compounds are frequently applied as her-
bicide and insecticides. Structures of some biologically
important heterocyclic compounds are shown in
Figure 1.[1] It is noticeable that most of organic reactions
would be accelerated in the presence of acid or base
catalysts. In order to reach this goal, various catalytic
systems have been introduced.[3] Among them, carbon
nanotubes and their functionalized derivatives are
involved to great interest due to their unique behaviours
such as high thermal/electrical conductivity, mechanical
flexibility, medium to high specific surface areas, biode-
gradability and non‐solubility in all organic solvents.[4]
These behaviors also make carbon nanotubes (CNTs)
good candidates for the application as preparative
supports in the synthesis of supported heterogeneous
catalysts.[5] Besides, CNTs have already found practical
applications in plastic reinforcement and conductive
Appl Organometal Chem. 2017;e4124.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4124

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SHARGHI ET AL.
FIGURE 1 Pharmaceutically active heterocyclic compounds
plastics[6] as well as automotive industries. Furthermore,
there are various reports of their role in medicine,[7] elec-
tronics, energy production and storage.[8]
nanostructures with (6, 5) morphology.[11o] Trace flow of
oxygen in argon was introduced to the CVD production
line for the purification of MWCNTs from any form of
carbon‐based impurities as well as formation of –COOH
functional groups. To synthesize MWCNTs, briefly, 5%
molar percentage of ferrocene in toluene solution was
used for THE production and dope of Fe nanoparticle
(diameter 2–10 nm), followed by decomposition of acety-
lene, thermally generation of carbon vapors and finally
deposition onto the metal nanoparticles. The synthesized
Fe/MWCNTs were then directly purified by purging with
oxygen and nitric acid vapor at temperature to around
350 °C. Based on the results, trace amount of O2 (i.e.
~5%, W/W O2 in Ar) led to the selective activation of
MWCNTs. Also thermo‐oxidation of the MWCNTs during
formation of –COOH functional groups le to lave mostly
iron nanoparticles with zero oxidation number. In accor-
dance with the thermo‐gravimetric (TG) analysis and
Raman spectrometry, the purity of the MWCNTs was esti-
mated to ~99%. This result was based on the intensity as
well as bandwidth of the D‐band of the Raman spectrum,
compared to other carbon allotropes as well as observa-
tion of only one sharp reduction of the weight percentage
of the thermogram at temperature to around 550 °C dur-
ing the oxidation of MWCNTs and formation of CO2.
The synthesized nanocatalyst was further character-
ized by other analytical techniques such as patterned X‐
ray diffraction (XRD), Fourier transform‐infrared (FT‐
IR) spectrometry, as well as microscopic imaging by scan-
ning electron microscopy (SEM). Figure 2 shows the SEM
images of the CVD‐synthesized Fe/MWCNTs. The magni-
fied MWCNTs have also been exhibited according to the
inset shown in Figure 2. Multi walls of the generated
CNTs was clearly shown according to the SEM images
that clearly pointed to the generation of MWCNTs by
From the first report by Lijima et al.[9] numerous pub-
lications have been made in term of CNTs application and
their functionalized derivatives as the catalysts in organic
synthesis.[10] However, in spite of aboundance of the men-
tioned reports, most of them have been restricted to one
special reaction without sufficient generality. So there is
still a demand for the introduction of novel CNTs‐based
catalysts with higher efficiency and versatility in organic
synthesis, considering the importance of heterocyclic
compounds, bioactive molecules and CNTs based
catalysts.
In continuation of our recent research about the syn-
thesis and application of novel CNTs‐based catalytic sys-
tems,[11]
herein,
we
report
the
synthesis,
characterization, and investigation of catalytic activity of
Fe/MWCNTs as well as its application as a heteroge-
neous, efficient and reusable nanocatalyst in the synthesis
of some N‐heterocyclic compounds including bis‐spiro
piperidines, piperidines, dihydro‐2‐oxopyrroles, pyrazoles
and diazepines in good to excellent yields under mild
and more green conditions (Scheme 1).
2 | RESULTS AND DISCUSSION
Iron‐doped multi‐walled carbon nanotubes (Fe/
MWCNTs) were synthesized by the chemical vapor depo-
sition (CVD) process using acetylene as the source of car-
bon and ferrocene as the source of iron nanoparticles at
the temperature to 1300 °C in an inert atmosphere of
argon. Based on the knowledge from the previous study,
these operating conditions led to have carbon

SHARGHI ET AL.
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SCHEME 1 Synthesis of heterocyclic compounds in the presence of Fe/MWCNTs
FIGURE 3 Raman spectrum of Fe/MWCNTs
FIGURE 2 SEM image of the synthesized Fe/MWCNTs, inset
(magnified SEM image)
estimated via ratio of the intensities of G‐ and D‐ bands
(IG/ID). This value was remarkably higher than that
obtained for activated MWCNT (2.31).
According to the smoothed XRD pattern displayed in
Figure 4, the peak positioned at 2θ = ~25° was related
to the carbon matrix with (002) morphology. Also, the
peak positioned at 2θ = ~48° was correlated to the pres-
ence of Fe (111) nanoparticles in the MWCNT matrix.
Therefore, this process led to the formation of Fe
the CVD process. Based on the SEM image the diameter
of MWCNTs was estimated to 20–50 nm. Modification of
Fe on the MWCNT was clearly evaluated according to
the peak area of the D‐band (~1350 cm−1) of the Raman
spectrum (Figure 3).
Based on the Raman spectrum (Figure 3), the defect of
Fe/MWCNTs was evaluated to 3.12. This result was

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SHARGHI ET AL.
FIGURE 4 XRD pattern of Fe/MWCNTs
nanoparticles (with zero oxidation number) by the recom-
mended procedure.
The functional groups of Fe/MWCNTs were further
characterized by the FT‐IR spectrometry as shown in
Figure 5. According to Figure 5, the sharp peak at
3433 cm−1 was related to the ‐OH functional groups,
whereas the peak positioned at 1616 cm−1 pointed to the
formation of carbonyl (C = O) functional group during
the synthesis and activation of MWCNTs by the CVD
process.
To estimate the Fe content, the supported catalyst was
treated with 5.0 M HCl and HNO3 for analysis by the
inductively coupled plasma (ICP). The Fe content was
determined to be 4.83 0.02% w/w. Further characteriza-
tion of the synthesized Fe/MWCNTs was achieved using
the TG analysis.
For this purpose, ~0.1 g iron‐doped samples was intro-
duced to a homemade TG analyser and the temperature
was scanned with heat rate of 2.0 °C min−1 in an atmo-
sphere provided using 8.0% O2 in Ar. The thermogram
has been shown in Figure 6. As seen (Figure 6), significant
enhancement was observed in the weight percentage of
the sample. This result pointed out that, the Fe has been
oxidized to Fe2O3. This result also was in good agreement
with that obtained from the ICP analysis.
FIGURE 6 Thermogram of the synthesized Fe/MWCNTs
2.1 | A novel one‐pot pseudo six‐
component synthesis of bis‐spiro‐
substituted piperidines
In 1900, Bayer introduced the first spiran as a bicyclic
hydrocarbon joined by a single carbon. The spirocyclanes
term was used to describe the whole family of such as
hydrocarbons. These family of compounds have many
increasing applications for example, spiropiperidinyl are
present in many biologically active compounds, mainly
alkaloids.[12] So there is a great interest in the synthesis
of this structurally motif compounds. Multi‐component
reaction of aromatic amines, dimedone and formaldehyde
is the major procedure to synthesis of titled compounds
and there are only few reports in the literature which have
used silica supported tungstic acid (STA),[13] acetic
acid,[14] FeCl3
and [Fe(CF3CO2)3][16] to achieve bis‐
[15]
spiro‐substituted piperidines. Also this reaction has been
reported without catalyst that cause long reaction time
and limit in derivatives.[17] Regarding the advantages of
heterogeneous catalysts including the easy recovery pro-
cess by a simple filtration, operational simplicity and
short reaction time. Herein we decided to synthesize bis‐
spiro‐substituted piperidines using Fe/MWCNTs as an
efficient heterogeneous catalyst.
In this methodology, dimedone, amines and formalde-
hyde react in one step in the presence of Fe/MWCNTs in
CH2Cl2 at room temperature (Scheme 2).
To find out the suitable condition for the reaction, a
series of experiments were performed with the standard
reaction of dimedone (2.0 mmol), 4‐methyl aniline
(1.0 mmol) and formaldehyde (3.3 mmol). The results
are depicted in Table 1. A variety of solvents such as
CH2Cl2, EtOH, EtOAc, MeOH and H2O were tested to
find out the best solvent for this transformation. Among
FIGURE 5 FT‐IR spectrum of the synthesized Fe/MWCNTs

SHARGHI ET AL.
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R
O
NH2
O
N
O
Fe/MWCNTs
CH2Cl2, rt
HCHO
2
+ 3
+
O
R
O O
4a-g
SCHEME 2 Synthesis of bis‐spiro‐
substituted piperidines 4
1
3
2
TABLE 1 Optimization of the reaction conditions for the synthesis of bis‐spiro‐substituted piperidines 4aa
Entry
Catalyst/ solvent/ conditions
Time (h)/ yield/ %b
1
ZnO (20 mol%)/ CH2Cl2/ r.t
12 / 10
2
3
4
5
6
PrCl3. 6H2O (20 mol%)/ CH2Cl2/ r.t
V2O5 (20 mol%)/ CH2Cl2/ r.t
CuCl (20 mol%)/ CH2Cl2/ r.t
AgNO3 (20 mol%)/ CH2Cl2/ r.t
12 / 50
12 / trace
12 / trace
12 / trace
12 / 25
Zn(NO3)2.6H2O (20 mol%)/
CH2Cl2/ r.t
7
Fe (20 mol%)/ CH2Cl2/ r.t
12 / 47
12 / 43
4 / 95
8
MWCNTs (30 mg)/ CH2Cl2/ r.t
Fe/MWCNTs (30 mg)/ CH2Cl2/ r.t
Fe/MWCNTs (30 mg)/ EtOH/ r.t
Fe/MWCNTs (30 mg)/ EtOAc/ r.t
Fe/MWCNTs (30 mg)/ MeOH/ r.t
Fe/MWCNTs (30 mg)/ H2O/ r.t
Fe/MWCNTs (10 mg)/ CH2Cl2/ r.t
Fe/MWCNTs (20 mg)/ CH2Cl2/ r.t
Fe/MWCNTs (40 mg)/ CH2Cl2/ r.t
Fe/MWCNTs (30 mg)/ CH2Cl2/ reflux
−/ CH2Cl2/ r.t
9
10
11
12
13
14
15
16
17
18
19
20
21
7 / 75
10 / 30
8 / 62
7 / 55
7 / 70
5 / 85
4 / 95
3 / 87
24 / trace
24 / trace
24 / 55
24 / 10
−/ neat/ r.t
Fe/MWCNTs (30 mg)/ neat / 50 °C
−/ neat/ r.t/ 50 °C
aExperimental conditions: 4‐methyl aniline (1.0 mmol), dimedone (2.0 mmol), and formaldehyde (3.3 mmol), with varying amounts of catalyst Fe/MWCNTs in
solvent (4 ml).
bIsolated yield.
various solvents, CH2Cl2 was found to give the best result.
It is noteworthy that no product was obtained in the
absence of a catalyst even after 12 h (Table 1, entries
18). When the reaction was carried out under solvent‐free
conditions (Table 1, entries 19), there was no yield of
product, probably due to the absence of strong interac-
tions between the various reactants. To show the effi-
ciency of the Fe/MWCNTs in comparison with other
catalysts, ZnO, PrCl3.6H2O, V2O5, CuCl, AgNO3 and
Zn(NO3)2.6H2O were also applied and no superiority

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SHARGHI ET AL.
observed (Table 1, entries 1–6). Also, in the presence of
two other catalysts including Fe and MWCNTs, only
47% and 43% of product were detected, respectively
(Table 1, entries 7–8). These results showed that Fe/
MWCNTs catalyst is better in viewpoint of reactivity and
experimental conditions for this reaction. After this, we
studied the effect of various amounts of Fe/MWCNTs cat-
alyst for the synthesis of bis‐spiro‐substituted piperidines.
In order to evaluate the appropriate catalyst loading, a
model reaction was carried out using 10, 20 and 40 mg
of Fe/MWCNTs in CH2Cl2 at room temperature (Table 1
, entries 14, 15 and 16). The lower amounts of catalyst
gave a low yield even after a long reaction time, and a
larger loading amount of the catalyst (40 mg) neither
increases the yield nor shortens the conversion time. So,
30 mg of catalyst was found to be the optimal quantity
and sufficient to push the reaction forward.
protons of the NCH2 moiety exhibited a singlet at
δ = 3.38 ppm. The aromatic protons resonance was
observed as a mixture of doublets at δ = 7.00–7.08 ppm.
The 13C NMR spectrum of 4a showed 13 distinct reso-
nances that approve the proposed structure.
2.2 | One‐pot synthesis of highly
functionalized piperidine derivatives
Functionalized piperidines are found in various biologi-
cally active compounds.[18] For instance, the alkaloids
SS20846A and Palinavir are highly potent inhibitors in
the treatment of the immunodeficiency virus (HIV).[19]
Also, Concerta was used to treat attention deficit
hyperactivity disorder;[20] Aricept for treatment of
Alzheimer[21] and Risperdal was used for treatment of
schizophrenia.[22] Moreover, some derivatives of the
substituted piperidine L‐pipecolic acid, are a constituents
of plants, fungi and human physiological fluids.[23]
Specially, C‐2 and C‐6 substituted piperidine molecules
came from extracts of Dendrobates speciosus (Panamanian
poison frogs) have demonstrated various activities such as
After optimization of the reaction conditions, the cat-
alytic activity of Fe/MWCNTs was tested by different aro-
matic amines bearing Me, OMe, F, NO2, Cl and Br
substitutes at meta or para. In all cases, the reaction
proceeded to obtain bis‐spiro‐substituted piperidines in
good yields. The corresponding compounds (4a–g) were
synthesized by the reaction of formadehyde, aromatic
amines and dimedone using 30 mg Fe/MWCNTs in
CH2Cl2 at room temperature. The results are shown in
Table 2. It was found that this method works well with
a wide variety of substrates. The structures of compounds
cytotoxic,
antifungal,
hemolytic
and
anti‐HIV
properties.[24] Recently, the synthesis of titled compounds
were reported using a large number of catalysts, such as
bromodimethylsulfonium bromide (BDMS),[25] cerium
ammonium
nitrate
(CAN),[26]
p‐TsOH.H2O,[27]
tetrabutylammoniumtribromide (TBATB),[28] tartaric
acid,[29] Bi (NO3)3.5H2O,[30] InCl3,[31] p‐sulfonic acid
calix[n]arenes,[32] ZrOCl2.8H2O,[33] I2,[34] and sodium
dioctyl sulfosuccinate (SDOSS)[35]. Herein we report a
one‐pot three (is situ five)‐component synthesis of highly
functionalized piperidines 7 from the reaction of two
equivalents of aromatic aldehyde, two equivalents of aro-
matic amine, and β‐ketoester in the presence of Fe/
MWCNTs as an efficient, ecofriendly and reusable hetero-
geneous nanocatalyst in ethanol at ambient temperature
(Scheme 3).
1
(4a–h) were deduced from their FT‐IR, H and 13C NMR
1
spectra. For example, the H NMR spectrum of 4a exhib-
ited a sharp singlet arising from four methyl groups at
δ = 0.99 ppm and also a singlet at 2.26 ppm for methyl
on aromatic ring. The methylene protons of the C‐CH2‐
C moiety in 4a were observed as singlet at δ = 2.47. Two
doublets from four COCH2 were shown at 2.64
(J = 13.8 Hz) and 2.82 (J = 13.8 Hz). The methylene
TABLE 2 Synthesis of bis‐spiro‐substituted piperidines via six‐
Initially, in order to optimize the reaction conditions,
the synthesis of compound 7a was used as a model reac-
tion. Therefore, the reaction between a mixture of aniline
(2.0 mmol), 4‐methyl benzaldehyde (2.0 mmol) and ethyl
acetoactate (1.0 mmol) in the presence or in the absence
component reaction.
R2
CHO
NH O
2
O
O
OR3
R1
Fe/MWCNTs
EtOH, rt
R1
OR3
+
NH2
5
N
R1
6
2
R2
R2
7a-k
1
SCHEME 3 Synthesis of highly substituted piperidines 7

SHARGHI ET AL.
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of catalyst in 5 mL solvent at room temperature with
changing amounts of catalyst loading and solvents was
investigated (Table 3). The best result was obtained in
the presence of 50 mg Fe/MWCNTs in EtOH (Table 3,
entry 10). It is noteworthy that the increasing of catalyst
loading to 60 mg had no improving effect on the yield of
product (Table 3, entry 11). When the reaction proceeded
in the absence of catalyst, no product was obtained; this
observation indicated that the catalyst's presence is neces-
sary for this transformation. Under solvent‐free condi-
tions, the product was obtained in a low yield (45%) that
may be due to lack of effective interaction of reactants
with the catalyst in the absence of solvent.
After optimization of the reaction conditions, the cat-
alytic activity of Fe/MWCNTs was tested by different aro-
matic amines, a number of aromatic aldehydes and ethyl
or methyl acetoacetate. The corresponding compounds
(7a–k) were synthesized by the reaction of aldehydes,
amines, and ethyl acetoacetate using 50 mg Fe/MWCNTs
in EtOH at room temperature. The results are shown in
Table 4. It was found that this method works well in the
presence of Fe/MWCNTs with a wide variety of
substrates.
In all cases, aldehyde and amine compounds with
substituents carrying either electron‐donating or elec-
tron‐withdrawing groups reacted successfully and gave
the expected products in excellent yields. This methodol-
ogy offered several advantages, such as mild reaction
conditions, no need to column chromatography as well
as obtaining high yields. The structure of all the com-
pounds were characterized by a comparison of their
FT‐IR and 1H and 13C NMR spectra with authentic
samples.
The comparison of reported methods and the present
results are charted in Table 5. It is clear from Table 5 that
the present protocol is better than the reported protocols
with respect to solvent and yields.
2.3 | Synthesis of dihydro‐2‐oxoyrroles
under mild and green conditions
The large number of biological activities of five‐mem-
bered nitrogen heterocyclic compounds such as inhibitors
of the human immunodeficiency virus (HIV) integrase,[36]
vascular endothelial growth factor receptors (VEGFR),[37]
human mitotic kinesin Eg5,[38] CD45 protein tyrosine
TABLE 3 Optimization of the reaction conditions for the synthesis of highly substituted piperidine 7aa
Entry
Solvent/ conditions/ catalyst (mg)
Time/ h
Yield/ %b
1
CH3CN/ r.t/ 40
13
50
2
H2O/ r.t/ 40
18
24
7
38
25
80
60
55
45
59
70
92
91
‐
3
EtOAc/ r.t/ 40
EtOH/ r.t/ 40
MeOH/ r.t/ 40
EtOH/ reflux/ 40
EtOH / r.t/ 10
EtOH / r.t/ 20
EtOH / r.t/ 30
EtOH / r.t/ 50
EtOH / r.t/ 60
EeOH/ r.t/ ‐
4
5
9
6
6
7
15
11
9
8
9
10
11
12
13
5
5
48
48
Neat/ r.t/ 50
45
aExperimental conditions: 4‐methyl benzaldehyde (2.0 mmol), aniline (2.0 mmol), and ethyl acetoacetate (1.0 mmol), with varying amounts of catalyst Fe/
MWCNTs in solvent (5 ml).
bIsolated yield.

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SHARGHI ET AL.
TABLE 4 Fe/MWCNTs‐catalyzed synthesis of functionalized piperidine scaffolds.
phosphatase[39] and annexin A2‐S100A10 protein interac-
tion[40] made the synthesis of these compounds very inter-
esting. Besides, their anti‐tumor activity[41] as well as
being useful intermediates[42] increasingly need new
investigations.
These heterocycles are also important reagents in
Diels‐Alder reactions, Michael addition, intramolecular
[2 + 2]‐photocycloaddition, and useful intermediates in
organic synthesis.[43] In recent years, many research
groups have used multi‐component reactions (MCRs) of
dialkyl acetylenedicarboxylates, amines, and carbonyl
compounds for one‐pot synthesis of dihydropyrrol‐2‐
ones.[44]
However, some of the reported methods suffer from
several disadvantages such as expensive catalyst, long
reaction times, environmental pollution, utilization of
chlorinated solvent under reflux conditions, unsatisfac-
tory yields and need to column chromatography for prod-
ucts purification.
We conceived that the Fe/MWCNTs can be further
utilized for the synthesis of highly substituted dihydro‐2‐
oxypyrrole
derivatives
from
dialkyl

SHARGHI ET AL.
9 of 23
TABLE 5 Comparison of synthesis of highly functionalized piperidines with reported protocols for compound 7d
a
Catalyst
Reaction conditions (temp./solvent/time)
Yield/ %
[25]
BDMS
r.t./CH3CN/3 h
76
86
86
82
87
76
68
80
85
90
Can [26]
r.t./CH3CN/15 h
r.t./EtOH/7 h
r.t./EtOH/10 h
r.t./EtOH/7 h
r.t./EtOH/18 h
64 °c/MeOH
p‐TsOH.H2O [27]
TBATB [28]
[29]
Tartaric acid
Bi (NO3)3.5H2O [30]
[32]
p‐sulfonic acid calix[n]arenes
ZrOCl2.8H2O [33]
[34]
Reflux/EtOH/4 h
r.t./MeOH/6 h
r.t./EtOH/4 h
I2
Fe/MWCNTs
aIsolated yield
acetylenedicarboxylates, amines, and formaldehyde in
EtOH at room temperature (Scheme 4).
MeOH. In this case, we did not observe the formation of
functionalized tetrahydropyrimidines 11.
In order to optimize the reaction conditions, the reac-
tion between dimethyl acetylenedicarboxylate (DMAD)
(1.0 mmol), 4‐methoxy aniline (2.0 mmol) and formalde-
hyde (1.2 mmol) was used as a model reaction in the pres-
ence of 50 mg Fe/MWCNTs. The expected dihydro‐2‐
oxopyrroles were produced in 96% yield after 3 h in etha-
nol at room temperature. Additionally, the effect of differ-
ent solvents including H2O, MeCN, acetone, CH2Cl2 and
MeOH was also investigated on the yield and time of reac-
tion, which was found to be ineffective. It is noteworthy
that in the absence of catalyst, the reaction failed to give
the desired product, even after long reaction time.
After the standardization of the reaction condition, a
variety of amines were used (Table 6). Use of aniline,
substituted anilines, and aliphatic amines increased the
diversity of the products. Anilines containing either elec-
tron‐donating or electron‐withdrawing substituents suc-
cessfully react with dialkyl acetylenedicarboxylates and
formaldehyde, affording good yields of products.
Having established an efficient route to the dihydro‐2‐
oxypyrroles, we next turned our attention to examine the
reactions containing two different kinds of amines. At
first, one aryl amine and one aliphatic amine, such as ben-
zyl, cyclohexyl and n‐butyl amines were introduced in the
one‐pot four‐component reaction. Thus, benzyl,
cyclohexyl or n‐butyl amines firstly reacted with dimethyl
acetylenedicarboxylate
(DMAD)
or
diethyl
acetylenedicarboxylate (DEAD) to form the active inter-
mediate β‐enamino ester in ethanol at room temperature
for 20 min. Then, one aryl amine and formaldehyde as
well as Fe/MWCNTs was added. The reaction proceeded
smoothly at room temperature to give the desired
dihydro‐2‐oxypyrroles (10e, 10 k, 10 l, 10 m and 10n) in
good yields.
Three of the main advantages of this methodology are
tolerance of a wide range of functional groups in the
starting materials, no need to column chromatography
and shorter reaction time.
Abu T. Khan and coworkers[45] have synthesized func-
tionalized tetrahydropyrimidine derivatives using silica
supported perchloric acid via one‐pot reaction of DMAD,
aromatic or aliphatic amines, and formaldehyde in
The structures of compounds were confirmed by com-
1
parison of their melting points, FT‐IR, H and 13C NMR
spectra data with those of authentic samples. The struc-
tural elucidation of 10 g was discussed as an example. In
1
the H NMR spectra, showed a singlet at δ = 3.67 ppm
CO2R1
O
H
for methoxy protons of ester groups and a singlet at
δ = 3.74 ppm for 2 OCH3 of aromatic rings. The CH2 pro-
tons of dihydro‐2‐oxypyrrole ring were appeared at
δ = 4.40 ppm as singlet signal. The aromatic protons were
shown as a quartet and two doublet at δ = 6.81 (q,
J = 9 Hz, 4H), 7.04 (d, J = 8.7 Hz, 2H) and 7.60 ppm (d,
J = 8.7 Hz, 2H) respectively. A fairly broad singlet was
observed at δ = 7.95 ppm for NH proton. In the 13C
NMR spectra, showed a signal at 48.4 ppm for methylene
carbon of heterocycle ring. The signals at 51.2, 55.4 and
55.5 ppm are related to the carbon atoms for ester
N
R
N
Ar
Ar
R
NH2
+
R1O2C
CO2R1
8
Fe/MWCNTs
EtOH, rt
10a-n
9
Ar NH2
CH2O
R1O2C
R1O2C
1
N
N
3
R
11
SCHEME
4
Synthesis of highly functionalized dihydro‐2‐
oxopyrroles 10

10 of 23
SHARGHI ET AL.
TABLE 6 Library synthesis of dihydro‐2‐oxypyrrole derivatives.
functional group and methoxy group on aromatic ring
respectively. The signals at δ = 165.1 and 163.3 ppm were
assigned to ester and lactam C = O, respectively. The sig-
nals of the carbon atoms of enamine α,β‐
aminocarboxylate, linked to C = O of amide and C = O
of ester, are assigned at 100.8 and 144.0 ppm, respectively.
The comparison of reported methods and the present
results are charted in Table 7. It is clear from the table
that the present protocol is better than the reported proto-
cols with respect to solvent and yields.
2.4 | Synthesis of pyrazoles through
cyclization between 1,3‐diketones with
hydrazine/hydrazide derivatives
Pyrazoles are an important class of five‐membered hetero-
cyclic systems which are present in many medicinal
chemistry compounds.[46] Pyrazole skeletons possess a
vast spectrum of biological activities such as antibacte-
rial,[47] anticancer,[48] antidiabetic,[49] antiviral,[50] anti‐
inflammatory,[51] antiobesity,[52] and estrogen receptor
TABLE 7 Comparison of synthesis of dihydro‐2‐oxoyrroles with reported protocols for compound 10a
a
Catalyst
Reaction conditions (temp./solvent/time)
Yield/ %
[44a]
Ph3CCl
r.t./ EtOH/4 h
86
Cu(OAc)2·H2O [44c]
r.t./ MeOH/8 h
r.t./ MeOH/4 h
r.t./ MeOH/5 h
r.t./ MeOH /1 h
r.t./EtOH/4 h
90
88
81
82
91
[44d]
[n‐Bu4N][HSO4]
[44e]
Al(H2PO4)3
[44f]
I2
Fe/MWCNTs
aIsolated yield.

SHARGHI ET AL.
11 of 23
agonistic.[53] One of these examples is the blockbuster
drug Celebrex, which was used for the treatment of rheu-
matism and osteoarthritis.[54] Also, they are dye interme-
diates. N‐Phenylpyrazole is the fundamental component
of the antiflea and antitick external treatments for cats
and dogs.[55] The first method for the preparation of
celecoxib involved condensation of diketone with phenyl
hydrazine in refluxing ethanol.[56] Pyrazoles preparation
can be done by several different procedures.[57] The route
which uses 1,3‐diketones and aryl hydrazines is one of the
most famous methods for the synthesis of substituted
pyrazoles. Recently, the synthesis of pyrazoles have been
reported by using the heteropoly acids,[58] sulfamic
acid,[59] zeolite,[60] SiO2‐H2SO4,[61] Baker's yeast/phos-
phate buffer/D‐glucose,[62] and [Ce(L‐Pro)2]2 (Oxa).[63]
However, these methods suffers from one or more draw-
backs such as use of toxic, homogeneous and no recover-
able catalysts.
TABLE 8 Optimization of solvents and catalytic amount of Fe/
MWCNTs for the synthesis of pyrazolesa
Solvent/
catalyst (mg)
Time/ min:
Yield/ %b
Entry
1
EtOH / 20
MeOH / 20
CH3CN / 20
H2O / 20
8: 98
15: 92
50: 86
35: 90
60: 67
60: 60
20: 85
45: 74
20: 90
8: 98
2
3
4
5
EtOAc / 20
CHCl3 / 20
‐ / 20
6
7
8
EtOH / 5
EtOH / 10
EtOH / 30
9
Herein, we report a simple and efficient protocol for
the synthesis of pyrazoles by cyclocondensation of read-
ily available 1,3‐diketones with hydrazine/hydrazide in
the presence of Fe/MWCNTs as a reusable and heteroge-
neous nanocatalyst in EtOH at room temperature
(Scheme 5).
10
aExperimental conditions: phenyl hydrazine (1.0 mmol) and acetylacetone
(1.0 mmol) with varying amounts of catalyst Fe/MWCNTs in solvents
(3 ml) at room temperature.
bIsolated yield.
Initially, as a model study, we choose the condensa-
tion of acetylacetone (1.0 mmol) and phenyl hydrazine
(1.0 mmol) in the presence of Fe/MWCNTs, and different
solvents including EtOH, MeOH, CH3CN, H2O EtOAc
and CHCl3 were tested. Among various solvents, EtOH
was found to give the best result, as summarized in
Table 8. The reaction was carried out using different
quantities of Fe/MWCNTs. Using 20 mg of catalyst; the
maximum yield of the product was obtained.
TABLE 9 Synthesis of pyrazole derivatives.
Condensation of hydrazines/hydrazide (1.0 mmol)
and 1,3‐dicarbonyl compounds (1.0 mmol) with Fe/
MWCNTs (20 mg) in EtOH (3 ml) was then examined.
Hydrazines/hydrazide reacted efficiently with various
1,3‐diketones to afford the desired pyrazoles in good to
excellent yields (Table 9).
Ethyl
acetoacetate
reacted
readily
with
phenylhydrazine in EtOH conditions to form compound
13 k, in excellent yield. The compound 13 k exists in a
keto‐form identified by their respective 1H and 13C
NMR spectra. In addition, we also found that the
R2
N
O
O
R1
N
Fe/MWCNTs
EtOH, rt
R1-NHNH2
+
R2
R3
11
12
R2: Me, Ph
R3: Me, Ph, OEt
R3
13a-l
R1: C6H5, 4-Me-C6H4,
4-F-C6H4, 4-Br-C6H4,
4-NO2-C6H4, 2-Cl-C6H4,
2-Me-C6H4, C6F5,
reaction
of
2,4‐dinitrophenylhydrazine
with
acetylacetone afforded Schiff base compound (13 l). This
is ascribed to no reactivity of 2,4‐dinitrophenylhydrazine
for pyrazole synthesis due to electron‐withdrawing effect
of the nitro groups.
4-NO2-C6H4CO,
2,4-di-NO2-C6H3
SCHEME 5 Synthesis of pyrazoles 13

12 of 23
SHARGHI ET AL.
was easily recovered by centrifuging from the reaction
mixture and simple washing with CH2Cl2. The Fe/
MWCNTs was recovered ten times and a slight loss of cat-
alytic activity was observed for each reaction. A summary
of obtained results is provided in Figure 7.
2.5 | One‐pot synthesis of diazepines
under solvent‐free conditions
Benzodiazepine synthesis is very interesting in recent
years due to the broad and important medical properties
of these compounds.[64] Some of benzodiazepines are
widely used as anticonvulsant, antianxiety, sedative,
antidepressive, hypnotic, and neuroleptic agents,[65] also
they are peptidomimetic scaffolds and key intermediates
in the synthesis of some fused ring compounds.[66] The
major procedure for the preparation of benzodiazepines
is via the acid‐catalyzed, two‐component reactions of o‐
phenylenediamines (OPDAs) with α,β‐unsaturated car-
bonyl compounds, β‐haloketones, β‐aminoketones,
ketones, or terminal alkynes.[67] Many catalytic systems
have been reported for the two‐component synthesis of
benzodiazepines, which include organic acids,[68] silica
sulfuric acid (SSA), polymer (PVP)‐supported FeCl3,
Yb(OTf)3, ultrasound irradiation/PTSA, BF3.Et2O,
NaBH4, ceric ammonium nitrate (CAN), trichlorotriazine
(TCT), and acetic acid under microwave conditions.[69] In
this article, we report an improved catalytic and general
approach for the synthesis of diazepines by condensation
of o‐phenylenediamines with 1,3‐diketones, using Fe/
MWCNTs as a nanocatalyst under solvent‐free condition
at 60 °C (Scheme 6).
3 | CONCLUSION
In summary, Fe/MWCNTs has been successfully synthe-
sized and characterized by the several techniques such
as SEM, XRD, ICP, and FT‐IR analysis. Due to special
properties of Fe/MWCNTs in both chemical and physical
fields, it was successfully used as a heterogeneous and
reusable nanocatalyst for the one‐pot synthesis of hetero-
cyclic compounds including a noumerus derivatives of
five‐membered heterocycles (dihydro‐2‐oxopyrroles and
pyrazoles), six‐membered heterocycles (bis‐spiro piperi-
dines, piperidines) and seven‐membered ring include
diazepine compounds. The major advantages of these pro-
tocols are mild and green reaction conditions, biodegrad-
ability, short reaction times, clean reaction, good to
excellent yields, and recyclability with no loss of activity.
4 | EXPERIMENTAL SECTION
We investigated the reaction between 1,2‐
diaminobenzene (1.0 mmol) and acetylacetone (1.0 mmol)
in the presence of a catalytic amount of Fe/MWCNTs
(30 mg) and isolated the desired diazepines in a 93% yield
within 10 min at 60 °C. After this success, reactions of sev-
eral o‐phenylenediamines and 1,3‐diketones were exam-
ined in the presence of 30 mg Fe/MWCNTs under
solvent‐free conditions (Table 10).
The reaction of 1,2‐diaminobenzene with ethyl and
methyl acetoacetate, however, failed to give the desired
products.
The catalyst reusability was screened for synthesis of
products 4a, 7a, 10a and 13a. In every case, Fe/MWCNTs
4.1 | Instrumentation, analyses and
starting material
NMR spectra were recorded on a Bruker Avance DPX‐250
and DRX‐400 (1H NMR 250, 400 MHz and 13C NMR
62.9 MHz) spectrometer in pure deutrated solvents with
tetramethylsilan as an internal standard. Mass spectra were
determined on a Shimadzu GCMS‐QP 1000 EX instruments
at 70 or 20 eV. IR spectra were obtained using a Shimadzu
FT‐IR 8300 spectrophotometer. Melting point determined
in open capillary tubes in a Büchi‐535 circulating oil melt-
ing point apparatus. Scanning electron micrographs were
obtained by SEM instrumentation (SEM, XL‐30 FEG
SEM, and Philips, at 20 KV). X‐ray diffraction (XRD, D8,
Advance, Bruker, axs) were obtained for characterization
of the heterogeneous catalyst. The thermogravimetry (TG)
of the samples was analyzed using a lab‐made TGA instru-
ment. The ICP analysis data were obtained using a Varian
Vista‐pro analyzer. The purity determination of the sub-
strate and reaction monitoring was accomplished by TLC
on silica gel PolyGram SILG/UV 254 plates. Chemicals
were purchased from Merck (Darmstadt, Germany), Acros
(Geel, Belgium), Aldrich (Buchs, Switzerland) and Fluka
(Buchs, Switzerland) chemical companies and used with-
out further purification.
R2
N
NH2
O
O
R1
Fe/MWCNTs
+
NH2
R2
R3
N
Solvent-free, 60 0
C
R3
R1
15a-c
14
12
SCHEME 6 Synthesis of diazepines 15
TABLE 10 Synthesis of diazepines via two‐component reaction.
Fe/MWCNTs were synthesized by chemical vapor
deposition (CVD) method. For this purpose ferrocene

SHARGHI ET AL.
13 of 23
FIGURE 7 Reusability of Fe/MWCNTs for synthesis of products 4a, 7a, 10a and 13a
(Merck) was selected as the source of Fe, acetylene
4.2 | General procedure for the synthesis
of bis‐spiro‐substituted piperidines 4a–g
(C2H2, purity: 98%, Parsballon, Iran, Shiraz) was used
as carbon precursor. To synthesize MWCNTs were then
achieved in inside quartz tubing at 1200 °C in an inert
atmosphere of Ar/He (Volume ratio: 1:1, Purity:
99.995%, Linde, Germany). In addition highly pure H2
(purity: 99.9996, Linde, Germany) was adopted to etch
and reduce the generated MWCNTs for having carbon
nanostructures with uniform morphology. The synthesis
of MWCNTs were active via setting the flow rates of
A mixture of aromatic amine 1 (1.0 mmol), dimedone 2
(2.0 mmol), formaldehyde 3 (3.3 mmol, 37% aqueous solu-
tion), and Fe/MWCNTs (30 mg) in CH2Cl2 (4 ml) stirred
at room temperature for the stipulated 4–7 h. The prog-
ress of the reaction was monitored by TLC. After the com-
pletion of the reaction Fe/MWCNTs was removed from
the reaction mixture by centrifugation. The solvent was
removed under reduced pressure. The crude product was
then purified directly by crystallization from EtOH.
C2H2, Ar, He and H2 to 500
2, 35
1, 35
1 and
5.0 0.2 mL min−1, respectively. Also, 500 mL solution
with 14% (W/W) of ferrocene inside toluene (as solvent)
was generated. To enlarge the length of the CVD‐syn-
thesized MWCNTs, about 10.0 mL of thiophene (purity:
98%, Merck) was added to the ferrocene/toluene solu-
tion. After preheating the reagents at ~500 °C the
reagents were decomposed to and deposited to form
MWCNTs through an online process. In this experi-
ment ferrocene played role as both the Fe catalytic sup-
port during deposition of carbon vapor and also acted
as the doping nanoparticles during flowing the catalytic
effect of both Fe and MWCNTs in the organic
reactions.
4.3 | General procedure for the synthesis
of highly functionalized piperidines 7a–k
A solution of aromatic amine 1 (2.0 mmol) and β‐
ketoester 6 (1.0 mmol) in EtOH (5 ml) stirred for 20 min
in the presence of Fe/MWCNTs (50 mg) at room temper-
ature. Next, the aromatic aldehyde 5 (2.0 mmol) was
added and the reaction mixture was stirred for the time
indicated in Table 4. After the completion of the reaction,
as indicated by TLC, the Fe/MWCNTs was recovered by
centrifuging. The solvent was evaporated and the

14 of 23
SHARGHI ET AL.
resulting crude product was recrystallized from ethanol
and to give pure products in high yields.
4.7 | 3,3,11,11‐Tetramethyl‐15‐(p‐tolyl)‐15‐
azadispiro[5.1.5.3]hexadecane‐1,5,9,13‐
tetraone (4a)
Brown solid; 95% yield (0.40 mg); mp 197–199 °C (Lit.[15]
1
196–198 °C); H NMR (250 MHz, CDCl3): δ = 0.99 (s,
4.4 | General procedure for the synthesis
of functionalized dihydro‐2‐oxopyrroles
10a–n
12H, 4CH3), 2.26 (s, 3H, CH3), 2.47 (s, 2H, CH2), 2.64 (d,
J = 13.8 Hz, 4H, COCH2), 2.82 (d, J = 13.8 Hz, 4H,
COCH2), 3.38 (s, 4H, NCH2), 7.00–7.08 (m, 4H, ArH);
13C NMR (62.9 MHz, CDCl3): δ = 20.6, 28.4, 28.7, 30.8,
32.3, 51.2, 55.6, 65.8, 119.3, 129.6, 131.3, 149.6, 206.0.
A
mixture of amine 8 (1.0 mmol) and dialkyl
acetylenedicarboxylate 9 (1.0 mmol) in EtOH (3 mL)
stirred for 20 min. Next, aromatic amine 1 (1.0 mmol),
formaldehyde 3 (37% solution, 1.2 mmol), and Fe/
MWCNTs (50 mg) were added successively. The reaction
mixture was allowed to stir at room temperature for 3–
6 h. After the completion of the reaction, as indicated by
TLC, the catalyst was recovered by centrifuging. EtOH
was evaporated and the resulting crude product was
recrystallized from ethanol and to give pure products in
high yields.
4.8 | 15‐(4‐Methoxyphenyl)‐3,3,11,11‐
tetramethyl‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4b)
Brown solid; 93% yield (0.41 mg); mp 186–188 °C (Lit.[17]);
1H NMR (250 MHz, CDCl3): δ = 0.97 (s, 12H, 4CH3), 2.46
(s, 2H, CH2), 2.63 (d, J = 13.8 Hz, 4H, COCH2), 2.82 (d,
J = 13.5 Hz, 4H, COCH2), 3.32 (s, 4H, NCH2), 3.75 (s,
3H, OCH3), 6.81 (d, J = 9.0 Hz, 2H, ArH), 7.05 (d,
J = 6.5 Hz, 2H, ArH); 13C NMR (62.9 MHz, CDCl3):
δ = 28.3, 28.7, 30.8, 32.2, 51.2, 55.5, 56.4, 65.8, 114.4,
121.2, 145.8, 155.2, 206.0.
4.5 | General procedure for the synthesis
of pyrazoles 13a–l
To a mixture of a hydrazine/hydrazide 11 (1.0 mmol),
dicarbonyl compound 12 (1.0 mmol) and Fe/MWCNTs
(20 mg) in EtOH (3 ml) were added successively. The
reaction mixture stirred at room temperature for the
appropriate times. After the completion of the reaction,
as indicated by TLC, the catalyst was recovered by
centrifuging. The solvent was evaporated and the
resulting crude product was extracted with diethyl ether/
H2O. The organic extract was dried over anhydrous
sodium sulfate, and the solvent was evaporated in a vac-
uum and to give pure products in high yields.
4.9 | 15‐(4‐Chlorophenyl)‐3,3,11,11‐
tetramethyl‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4c)
White solid; 82% yield (0.36 mg); mp 216–218 °C (Lit.[14]
1
216–218 °C); H NMR (250 MHz, CDCl3): δ = 0.99 (s,
12H, 4CH3), 2.48 (s, 2H, CH2), 2.62 (d, J = 13.5 Hz, 4H,
COCH2), 2.82 (d, J = 13.6 Hz, 4H, COCH2), 3.40 (s, 4H,
NCH2), 7.02 (d, J = 8.7 Hz, 2H, ArH), 7.19 (d,
J = 8.7 Hz, 2H, ArH); 13C NMR (62.9 MHz, CDCl3):
δ = 28.3, 28.6, 30.8, 32.2, 51.2, 54.8, 65.5, 120.0, 126.4,
129.0, 150.1, 205.9.
4.6 | General procedure for the synthesis
of diazepines 15a–c
To a mixture of o‐phenylenediamine 14 (1.0 mmol),
dicarbonyl compound 12 (1.0 mmol) and Fe/MWCNTs
(30 mg) in EtOH (3 ml) were added successively. The
reaction mixture stirred at room temperature for the
appropriate times. After the completion of the reaction,
as indicated by TLC, the catalyst was recovered by
centrifuging. The solvent was evaporated and the
resulting crude product was extracted with EtOAc/H2O.
The organic extract was dried over anhydrous sodium sul-
fate, and the solvent was evaporated in a vacuum and the
product was purified by column chromatography
(EtOAc–petroleum ether, 1:10).
4.10 | 15‐(4‐Bromophenyl)‐3,3,11,11‐
tetramethyl‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4d)
Yellow solid; 94% yield (0.46 mg); mp 201–203 °C (Lit.[17]
1
202 °C); H NMR (250 MHz, CDCl3): δ = 0.99 (s, 12H,
4CH3), 2.47 (s, 2H, CH2), 2.64 (d, J = 13.8 Hz, 4H,
COCH2), 2.82 (d, J = 13.8 Hz, 4H, COCH2), 3.38 (s, 4H,
NCH2), 6.95 (d, J = 8.0 Hz, 2H, ArH), 7.30 (d,
J = 8.0 Hz, 2H, ArH); 13C NMR (62.9 MHz, CDCl3):
δ = 28.3, 28.6, 30.8, 32.1, 51.2, 54.5, 65.5, 113.8, 120.3,
131.9, 150.5, 205.9.

SHARGHI ET AL.
15 of 23
6), 6.34 (d, J = 6.0 Hz, 2H, ArH), 6.36 (s, 1H, H‐2), 6.58
(d, J = 8.4 Hz, 2H, ArH), 6.64 (t, J = 7.2 Hz, 1H, ArH),
7.09–7.29 (m, 13H, ArH), 10.35 (s, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 14.8, 21.0, 21.1, 33.7, 54.9, 57.9,
59.6, 98.4, 112.9, 116.0, 125.3, 125.5, 126.3, 126.6, 128.8,
128.9, 128.9, 129.3, 135.8, 136.6, 138.0, 139.7, 141.1,
147.1, 156.1, 168.3; MS: m/z (%): 504 (M++2, 0.5), 503
(M++1, 3.5), 502 (M+, 3.7), 411 (21.7), 306 (19.2),
234(11.6), 194 (28.1), 97 (42.7), 57 (100.0).
4.11 | 15‐(4‐Fluorophenyl)‐3,3,11,11‐
tetramethyl‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4e)
Yellow solid; 90% yield (0.38 mg); mp 143–145 °C (Lit.[14]
142–144 °C); 1H NMR (250 MHz, CDCl3): δ = 0.73 (s, 3H,
CH3), 0.84 (s, 6H, 2CH3), 1.15 (s, 3H, CH3), 1.87 (s, 2H,
CH2), 2.10 (s, 2H, CH2), 2.12 (s, 2H, CH2), 2.24 (d,
J = 14.0 Hz, 2H, CH2), 2.94 (s, 2H, CH2), 3.04 (d,
J = 13.8 Hz, 2H, CH2), 3.69 (s, 2H, CH2), 7.03–7.10 (m,
2H, ArH), 7.29–7.34 (m, 2H, ArH); 13C NMR (62.9 MHz,
CDCl3): δ = 26.5, 28.2, 29.9, 30.4, 31.1, 32.4, 41.6, 49.1,
50.7, 52.3, 61.1, 100.1, 116.9, 116.9, 129.3, 129.5, 140.2,
157.1, 159.8, 163.8, 192.7, 206.4.
4.15 | Methyl (2R,6S)‐1‐phenyl‐4‐
(phenylamino)‐2,6‐di‐p‐tolyl‐1,2,5,6‐
tetrahydropyridine‐3‐carboxylate (7b)
White solid; 94% yield (0.46 mg); mp 209–212 °C (Lit.[25]
4.12 | 3,3,11,11‐Tetramethyl‐15‐(4‐
nitrophenyl)‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4f)
212–214 °C); FT‐IR (KBr cm−1): 3232 (NH), 1658
1
(C = O); H NMR (250 MHz, CDCl3): δ = 2.36 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 2.80 (dd, J = 15.0, 2.5 Hz, 1H,
H′‐5), 2.92 (dd, J = 15.0, 5.5 Hz, 1H, H″‐5), 3.96 (s, 3H,
OCH3), 5.15 (d, J = 2.4 Hz, 1H, H‐6), 6.35 (m, 2H,
ArH), 6.45 (s, 1H, H‐2), 6.58 (d, J = 8.0 Hz, 2H, ArH),
6.63 (t, J = 7.2 Hz, 1H, ArH), 7.07–7.27 (m, 13H, ArH),
10.31 (s, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 21.0, 21.1, 33.7, 51.0, 54.9, 57.9, 98.1, 112.9, 116.0,
125.6, 125.8, 126.3, 126.6, 128.8, 128.9, 129.0, 129.3,
135.8, 136.6, 137.9, 139.70, 140.9, 147.1, 156.3, 168.6;
MS: m/z (%): 490 (M++2, 0.1), 489 (M++1, 1.3), 488 (M
+, 2.1), 413 (3.9), 196 (28.7), 145 (13.8), 99 (13.7), 83
(100.0), 57 (61.2).
Yellow solid; 89% yield (0.40 mg); mp 221–223 °C (Lit.[14]
222–224 °C); H NMR (250 MHz, CDCl3): δ = 0.95 (s,
1
12H, 4CH3), 2.52 (s, 2H, CH2), 2.60 (d, J = 14.0 Hz,
4H, COCH2), 2.80 (d, J = 13.7 Hz, 4H, COCH2), 3.67 (s,
4H, NCH2), 6.97 (d, J = 9.2, 2H, ArH), 8.06 (d,
J = 9.5 Hz, 2H, ArH); 13C NMR (62.9 MHz, CDCl3):
δ = 28.3, 28.6, 30.8, 31.9, 51.0, 51.3, 65.2, 114.3, 125.8,
139.5, 154.3, 205.6.
4.13 | 3,3,11,11‐Tetramethyl‐15‐(3‐
nitrophenyl)‐15‐azadispiro[5.1.5.3]
hexadecane‐1,5,9,13‐tetraone (4g)
Yellow solid; 85% yield (0.39 mg); mp 187–189 °C (Lit.[14]
1
4.16 | Methyl (2R,6S)‐2,6‐bis(4‐
methoxyphenyl)‐1‐phenyl‐4‐
(phenylamino)‐1,2,5,6‐tetrahydropyridine‐
3‐carboxylate (7c)
187–189 °C); H NMR (250 MHz, CDCl3): δ = 1.03 (s,
12H, 4CH3), 2.55 (s, 2H, CH2), 2.68 (d, J = 13.7 Hz, 4H,
COCH2), 2.87 (d, J = 13.7 Hz, 4H, COCH2), 3.57 (s, 4H,
NCH2), 7.26 (s, 1H, ArH), 7.41 (t, J = 8.4 Hz, 1H,
ArH),7.57–7.62 (m, 1H, ArH), 7.73–7.76 (m, 1H, ArH);
13C NMR (62.9 MHz, CDCl3): δ = 28.3, 28.6, 30.9, 32.1,
51.3, 53.5, 65.3, 110.9, 115.6, 124.9, 129.9, 205.8.
White solid; 88% yield (0.46 mg); mp 186–188 °C
(Lit.[25] 187–188 °C); 1H NMR (250 MHz, CDCl3):
δ = 2.78 (dd, J = 15.0, 2.7 Hz, 1H, H′‐5), 2.89 (dd,
J = 15.0, 5.2 Hz, 1H, H″‐5), 3.80, 3.81 (2 s, 6H,
2OCH3), 3.95 (s, 3H, OCH3), 5.12 (d, J = 2.2 Hz, 1H,
H‐6), 6.37–6.40 (m, 3H, H‐2 and ArH), 6.56 (d,
J = 8.0 Hz, 2H, ArH), 6.63 (t, J = 7.2 Hz, 1H, ArH),
6.86 (d, J = 8.5 Hz, 4H, ArH), 7.06–7.15 (m, 7H,
ArH), 7.23–7.27 (m, 2H, ArH), 10.31 (s, 1H, NH); 13C
NMR (62.9 MHz, CDCl3): δ = 33.7, 51.0, 54.5, 55.2,
55.3, 57.5, 98.1, 112.9, 113.5, 113.9, 116.0, 125.6, 125.7,
127.4, 127.6, 128.8, 134.6, 135.8, 137.9, 147.0, 156.3,
158.0, 158.6, 168.6; MS; m/z (%): 522 (M++2, 0.6), 521
(M++1, 1.8), 520 (M+, 2.1), 414 (6.3), 308 (15.4), 210
(17.9), 83 (100.0).
4.14 | Ethyl (2R,6S)‐1‐phenyl‐4‐
(phenylamino)‐2,6‐di‐p‐tolyl‐1,2,5,6‐
tetrahydropyridine‐3‐carboxylate (7a)
White solid; 92% yield (0.46 mg); mp 214–216 °C (Lit.[34]
215–217 °C); FT‐IR (KBr cm−1): 3244 (NH), 1649
1
(C = O); H NMR (400 MHz, CDCl3): δ = 1.51 (3H, t,
J = 7.0 Hz, OCH2CH3), 2.37 (s, 3H, CH3), 2.38 (s, 3H,
CH3), 2.81 (dd, J = 15.2, 2.0 Hz, 1H, H′‐5), 2.91 (dd,
J = 15.2, 5.6 Hz, 1H, H″‐5), 4.34–4.46 (m, 1H, OCHaHb),
4.48–4.52 (m, 1H, OCHaHb), 5.16 (d, J = 3.6 Hz, 1H, H‐

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SHARGHI ET AL.
127.1, 127.9, 128.1, 128.6, 130.7, 141.6, 143.3, 144.4,
150.9, 156.8, 157.8, 168.3.
4.17 | Methyl (2R,6S)‐2,6‐bis(4‐
chlorophenyl)‐1‐phenyl‐4‐(phenylamino)‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate
(7d)
4.20 | Ethyl (2R,6S)‐1‐(4‐chlorophenyl)‐4‐
((4‐chlorophenyl)amino)‐2,6‐diphenyl‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate
(7g)
White solid; 90% yield (0.48 mg); mp 188–190 °C (Lit.[25]
189–191 °C); FT‐IR (KBr cm−1): 3240 (OH, NH), 1651
1
(C = O); H NMR (250 MHz, CDCl3): δ = 2.73–2.90 (m,
2H, H′‐5 and H″‐5), 3.95 (s, 3H, OCH3), 5.16 (s, 1H, H‐
6), 6.40–6.70 (m, 6H, H‐2 and ArH), 7.07–7.27 (m, 13H,
ArH), 10.29 (s, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 33.7, 51.2, 54.7, 57.4, 97.5, 113.0, 116.8, 125.8, 126.1,
127.8, 128.1, 128.4, 128.8, 129.0, 132.2, 132.9, 137.6,
140.9, 142.4, 146.5, 156.0, 168.3; MS; m/z (%): 531 (M+
+2, 1.4), 530 (M++1, 3.8), 529 (M+, 1.9), 417 (32.6), 385
(11.9), 312 (23.9), 254 (27.9), 216 (16.6), 120 (13.1), 83
(100.0).
Pale yellow solid; 86% yield (0.47 mg); mp 201–202 °C
(Lit.[30] 200–202 °C); 1H NMR (250 MHz, CDCl3):
δ = 1.50 (t, J = 7.0 Hz, 3H, OCH2CH3), 2.72 (dd,
J = 15.2, 2.0 Hz, 1H, H′‐5), 2.84–2.94 (m, 1H, H″‐5),
4.34–4.41 (m, 1H, OCHaHb), 4.45–4.55 (m, 1H, OCHaHb),
5.13 (s, 1H, H‐6), 6.17–6.22 (m, 2H, ArH), 6.44–6.49 (m,
3H, H‐2 and ArH), 6.70–7.32 (m, 14H, ArH), 10.28 (s,
1H, NH); 13C NMR (62.9 MHz, CDCl3): δ = 14.8, 33.5,
55.3, 58.3, 60.0, 98.8, 114.1, 121.2, 126.3, 126.5, 126.6,
127.0, 127.5, 128.4, 128.7, 128.8, 129.0, 131.3, 136.4,
142.3, 143.3, 145.5, 155.4, 168.2.
4.18 | Methyl (2R,6S)‐1,2,6‐triphenyl‐4‐
(phenylamino)‐1,2,5,6‐tetrahydropyridine‐
3‐carboxylate (7e)
4.21 | Methyl (2R,6S)‐1‐(4‐bromophenyl)‐
4‐((4‐bromophenyl)amino)‐2,6‐di‐p‐tolyl‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate
(7h)
White solid; 85% yield (0.39 mg); mp 170–172 °C (Lit.[25]
169–171 °C); FT‐IR (KBr cm−1): 3240 (OH, NH), 1658
(C = O); 1H NMR (250 MHz, CDCl3): δ = 2.81 (dd,
J = 15.0, 1.8 Hz, 1H, H′‐5), 2.93 (dd, J = 15.2, 5.5 Hz,
1H, H″‐5), 3.98 (s, 3H, OCH3), 5.20 (s, J = 4.2 Hz, 1H,
H‐6), 6.31–6.34 (m, 2H, ArH), 6.51 (s, 1H, H‐2), 6.56–
6.68 (m, 3H, ArH), 7.07–7.39 (m, 15H, ArH), 10.32 (s,
1H, NH); 13C NMR (62.9 MHz, CDCl3): δ = 33.6, 51.1,
55.1, 58.2, 98.0, 112.9, 116.2, 125.8, 125.9, 126.3, 126.4,
126.7, 127.2, 128.3, 128.7, 128.8, 128.9, 137.8, 142.7,
143.9, 147.0, 156.3, 168.6; MS; m/z (%): 462 (M++2, 5.3),
461 (M++1, 12.4), 460 (M+, 12.6), 384 (100.0), 351 (23.6),
278 (34.1), 246 (25.2), 220 (21.0), 180 (21.4), 104 (15.6),
77 (29.7).
White solid; 87% yield (0.56 mg); mp 227–229 °C (Lit.[25]
1
229–230 °C); H NMR (400 MHz, CDCl3): δ = 2.35 (s,
3H, CH3), 2.37 (s, 3H, CH3), 2.72 (dd, J = 14.8, 2.0 Hz,
1H, H′‐5), 2.87 (dd, J = 15.2, 5.6 Hz, 1H, H″‐5), 3.96 (s,
3H, OCH3), 5.09 (d, J = 4.0 Hz, 1H, H‐6), 6.15 (d,
J = 8.4 Hz, 2H, ArH), 6.34 (s, 1H, H‐2), 6.41 (d,
J = 9.2 Hz, 2H, ArH), 7.05 (d, J = 8.0 Hz, 2H, ArH),
7.10–7.18 (m, 8H, ArH), 7.23 (d, J = 8.8 Hz, 2H, ArH),
10.24 (s, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 21.0, 21.1, 33.4, 51.2, 55.0, 58.0, 98.6, 108.2, 114.5,
119.0, 126.2, 126.3, 127.3, 129.0, 129.4, 131.5, 131.9,
136.1, 136.9, 137.0, 139.0, 140.0, 145.9, 155.4, 168.4.
4.19 | Ethyl (2R,6S)‐1‐(4‐methoxyphenyl)‐
4‐((4‐methoxyphenyl)amino)‐2,6‐diphenyl‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate (7f)
4.22 | Methyl (2R,6S)‐1,2,6‐tri‐p‐tolyl‐4‐(p‐
tolylamino)‐1,2,5,6‐tetrahydropyridine‐3‐
carboxylate (7i)
White solid; 82% yield (0.44 mg); mp 180–182 °C (Lit.[27]
1
179–181 °C); H NMR (400 MHz, CDCl3): δ = 1.48 (t,
J = 7.0 Hz, 3H, OCH2CH3), 2.67 (dd, J = 15.2, 2.8 Hz,
1H, H′‐5), 2.82 (dd, J = 15.2, 5.6 Hz, 1H, H″‐5), 3.69 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 4.30–4.38 (m, 1H,
OCHaHb), 4.43–4.51 (m, 1H, OCHaHb), 5.09 (d,
J = 3.2 Hz, 1H, H‐6), 6.23 (t, J = 6.0 Hz, 2H, ArH), 6.38
(s, 1H, H‐2), 6.58 (t, J = 6.6 Hz, 2H, ArH), 6.62–6.65 (m,
2H, ArH), 6.66–6.70 (m, 2H, ArH), 7.20–7.25 (m, 3H,
ArH), 7.28–7.37 (m, 7H, ArH), 10.17 (s, 1H, NH); 13C
NMR (62.9 MHz, CDCl3): δ = 14.8, 33.6, 55.4, 55.6, 55.7,
58.3, 59.5, 97.2, 113.9, 114.0, 114.5, 126.2, 126.5, 126.8,
White solid; 90% yield (0.46 mg); mp 204–207 °C (Lit.[34]
1
206–208 °C); H NMR (400 MHz, CDCl3): δ = 2.18, 2.30,
2.35, 2.37 (4 s, 12H, 4CH3), 2.76 (dd, J = 15.2, 2.4 Hz,
1H, H′‐5), 2.85 (dd, J = 15.2, 5.6 Hz, 1H, H″‐5), 3.94 (s,
3H, OCH3), 5.11 (d, J = 3.6 Hz, 1H, H‐6), 6.22 (d,
J = 8.0 Hz, 2H, ArH), 6.39 (s, 1H, H‐2), 6.46 (d,
J = 8.4 Hz, 2H, ArH), 6.91 (t, J = 9.2 Hz, 4H, ArH),
7.07–7.13 (m, 6H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH),
10.21 (s, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 20.1, 20.9, 21.0, 21.1, 33.6, 50.9, 55.0, 57.9, 97.5,

SHARGHI ET AL.
17 of 23
112.8, 124.8, 125.9, 126.3, 126.6, 128.9, 129.2, 129.4, 135.2,
135.5, 135.6, 136.5, 139.9, 141.3, 144.9, 156.6, 168.6.
4.26 | Methyl 5‐oxo‐1‐(p‐tolyl)‐4‐(p‐
tolylamino)‐2,5‐dihydro‐1H‐pyrrole‐3‐
carboxylate (10b)
White solid; 89% yield (0.30 mg); mp 177–179 °C (Lit.[44f]
177–178 °C); 1H NMR (250 MHz, CDCl3): δ = 2.34 (s, 6H,
2CH3), 3.74 (s, 3H, OCH3), 4.48 (s, 2H, CH2‐N), 7.04 (d,
J = 8.2 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H, ArH), 7.18 (d,
J = 8.5 Hz, 2H, ArH), 7.66 (d, J = 8.3 Hz, 2H, ArH), 8.02
(brs, 1H, NH); 13C NMR (62.9 MHz, CDCl3): δ = 20.9,
21.0, 48.2, 51.3, 101.8, 119.2, 123.1, 128.9, 129.6, 134.5,
134.7, 135.9, 136.3, 143.5, 163.5, 164.9.
4.23 | Ethyl (2R,6S)‐1‐(4‐fluorophenyl)‐4‐
((4‐fluorophenyl)amino)‐2,6‐di‐p‐tolyl‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate (7j)
White solid; 90% yield (0.48 mg); mp 183–185 °C (Lit.[27]
1
183–185 °C); H NMR (250 MHz, CDCl3): δ = 1.50 (t,
J = 7.1 Hz, 3H, OCH2CH3), 2.36 (s, 3H, CH3), 2.38 (s,
3H, CH3), 2.66 (dd, J = 15.0, 2.7 Hz, 1H, H′‐5), 2.88 (dd,
J = 15.2, 5.7 Hz, 1H, H″‐5), 4.30–4.40 (m, 1H, OCHaHb),
4.42–4.56 (m, 1H, OCHaHb), 5.08 (d, J = 1.5 Hz, 1H, H‐
6), 6.23–6.30 (m, 2H, ArH), 6.36 (s, 1H, H‐2), 6.43–6.50
(m, 2H, ArH), 6.75–6.85 (m, 4H, ArH), 7.10–7.26 (m, 8H,
ArH), 10.24 (s, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 14.8, 21.0, 21.1, 33.6, 55.4, 58.2, 59.7, 98.3, 113.6,
113.7, 115.1, 115.4, 115.8, 126.3, 126.6, 127.9, 128.0,
129.0, 129.4, 133.9, 134.0, 135.9, 136.9, 139.7, 140.7,
143.6, 153.1, 156.0, 156.8, 158.7, 162.6, 168.3.
4.27 | Ethyl 1‐(4‐fluorophenyl)‐4‐((4‐
fluorophenyl)amino)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10c)
White solid; 88% yield (0.32 mg); mp 170–172 °C (Lit.[44b]
1
172–173 °C); H NMR (250 MHz, CDCl3): δ = 1.54 (t,
J = 7.1 Hz, 3H, OCH2CH3), 4.51 (q, J = 7.2 Hz, 2H,
OCH2CH3), 4.77 (s, 2H, CH2‐N), 7.25–7.42 (m, 6H, ArH),
8.00–8.04 (m, 2H, ArH), 8.32 (brs, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 14.3, 48.4, 60.4, 102.9, 115.3,
115.7, 116.1, 121.1, 121.2, 124.8, 125.0, 134.5, 134.7,
143.2, 157.9, 158.1, 161.8, 162.0, 163.6, 164.6.
4.24 | Methyl (2R,6S)‐2,6‐bis(4‐
fluorophenyl)‐1‐phenyl‐4‐(phenylamino)‐
1,2,5,6‐tetrahydropyridine‐3‐carboxylate
(7k)
White solid; 87% yield (0.43 mg); mp 160–162 °C (Lit.[26]
161–162 °C); H NMR (250 MHz, CDCl3): δ = 2.77 (dd,
4.28 | Ethyl 1‐(4‐methoxyphenyl)‐4‐((4‐
methoxyphenyl)amino)‐5‐oxo‐2,5‐dihydro‐
1H‐pyrrole‐3‐carboxylate (10d)
1
J = 15.1, 2.7 Hz, 1H, H′‐5), 2.86 (dd, J = 15.1, 5.3 Hz,
1H, H″‐5), 3.95 (s, 3H, OCH3), 5.14 (d, J = 2.5 Hz, 1H,
H‐6), 6.38–6.45 (m, 3H, H‐2 and ArH), 6.50 (d,
J = 8.2 Hz, 2H, ArH), 6.66 (t, J = 7.2 Hz, 1H, ArH), 6.98
(t, J = 8.6 Hz, 4H, ArH), 7.07–7.18 (m, 7H, ArH), 7.25–
7.31 (m, 2H, ArH), 10.30 (s, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 33.8, 51.1, 54.6, 57.3, 97.7, 112.9,
114.9, 115.2, 115.3, 115.6, 116.6, 125.7, 126.0, 127.8,
127.9, 128.1, 128.2, 129.0, 137.7, 138.0, 138.1, 139.3,
139.4, 146.6, 156.1, 168.4.
Pale yellow solid; 89% yield (0.34 mg); mp 152–153 °C
(Lit.[44e] 152–154 °C); 1H NMR (250 MHz, CDCl3):
δ = 1.23 (t, J = 7.1 Hz, 3H, OCH2CH3), 3.80 (s, 6H,
2OCH3), 4.20 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.46 (s, 2H,
CH2‐N), 6.87 (q, J = 8.7 Hz, 4H, ArH), 7.09 (d,
J = 8.7 Hz, 2H, ArH), 7.66 (d, J = 9.2 Hz, 2H, ArH),8.00
(brs, 1H, NH); 13C NMR (62.9 MHz, CDCl3): δ = 14.3,
48.5, 55.4, 55.5, 60.1, 101.3, 113.6, 114.2, 121.0, 124.8,
131.7, 132.0, 143.7, 156.9, 157.0, 163.5, 164.8.
4.25 | Methyl 5‐oxo‐1‐phenyl‐4‐
(phenylamino)‐2,5‐dihydro‐1H‐pyrrole‐3‐
carboxylate (10a)
White solid; 91% yield (0.28 mg); mp 154–156 °C (Lit.[44f]
155–156 °C); 1H NMR (250 MHz, CDCl3): δ = 3.73 (s, 3H,
OCH3), 4.54 (s, 2H, CH2‐N), 7.12–7.42 (m, 8H, ArH), 7.77–
7.81 (m, 2H, ArH), 8.02 (brs, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 48.2, 51.3, 102.9, 119.2, 122.8,
124.7, 125.1, 128.4, 129.2, 138.5, 143.0, 163.8, 164.8.
4.29 | Methyl 4‐(benzylamino)‐1‐(4‐
fluorophenyl)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10e)
White solid; 87% yield (0.30 mg); mp 166–168 °C (Lit.[44e]
166–168 °C); 1H NMR (250 MHz, CDCl3): δ = 3.78 (s, 3H,
OCH3), 4.40 (s, 2H, CH2‐N), 5.10 (s, 2H, CH2‐NH), 6.80
(brs, 1H, NH), 7.03–7.12 (m, 2H, ArH), 7.20–7.35 (m,
5H, ArH), 7.66–7.74 (m, 2H, ArH).

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SHARGHI ET AL.
4.30 | Methyl 1‐(4‐bromophenyl)‐4‐((4‐
bromophenyl)amino)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10f)
4.34 | Methyl 1‐(4‐fluorophenyl)‐4‐((4‐
fluorophenyl)amino)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10j)
Yellow solid; 91% yield (0.42 mg); mp 177–179 °C (Lit.[44f]
179–180 °C); 1H NMR (250 MHz, CDCl3): δ = 3.79 (s, 3H,
OCH3), 4.50 (s, 2H, CH2‐N), 7.01 (d, J = 8.7 Hz, 2H, ArH),
7.42 (d, J = 8.5 Hz, 2H, ArH), 7.5 (d, J = 9.2 Hz, 2H, ArH),
7.68 (d, J = 9.0 Hz, 2H, ArH), 8.03 (brs, 1H, NH).
White solid; 91% yield (0.31 mg); mp 162–164 °C (Lit.[44a]
163–165 °C); 1H NMR (250 MHz, CDCl3): δ = 3.76 (s, 3H,
OCH3), 4.48 (s, 2H, CH2‐N), 6.97–7.14 (m, 6H, ArH), 7.69–
7.74 (m, 2H, ArH), 8.03 (brs, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 48.3, 51.4, 102.3, 115.1 (d,
JCF = 22.8 Hz), 115.8 (d, JCF = 22.5 Hz), 121.0 (d,
JCF = 8.0 Hz), 125.1 (d, JCF = 8.3 Hz), 134.4 (d,
JCF = 3.0 Hz), 134.7 (d, JCF = 2.9 Hz), 143.4, 158.0 (d,
JCF = 20.9 Hz), 161.9 (d, JCF = 19.6 Hz), 163.4, 164.8.
4.31 | Methyl 1‐(4‐methoxyphenyl)‐4‐((4‐
methoxyphenyl)amino)‐5‐oxo‐2,5‐dihydro‐
1H‐pyrrole‐3‐carboxylate (10g)
4.35 | Ethyl 4‐(cyclohexylamino)‐5‐oxo‐1‐
(p‐tolyl)‐2,5‐dihydro‐1H‐pyrrole‐3‐
carboxylate (10k)
Brown solid; 96% yield (0.35 mg); mp 175–177 °C (Lit.[44f]
176–177 °C); 1H NMR (250 MHz, CDCl3): δ = 3.67 (s, 3H,
OCH3), 3.74 (s, 6H, 2OCH3), 4.40 (s, 2H, CH2‐N), 6.81 (q,
J = 9.0 Hz, 4H, ArH), 7.04 (d, J = 8.7 Hz, 2H, ArH), 7.60
(d, J = 8.7 Hz, 2H), 7.95 ((brs, 1H, NH); 13C NMR
(62.9 MHz, CDCl3): δ = 48.4, 51.2, 55.4, 55.5, 100.8,
113.6, 114.2, 121.0, 125.0, 131.5, 131.9, 144.0, 156.9,
157.1, 163.3, 165.1.
White solid; 87% yield (0.30 mg); mp 105–107 °C (Lit.[44h]
1
106.4–107.4 °C); H NMR (250 MHz, CDCl3): δ = 1.10–
1.49 (m, 8H), 1.58–1.78 (m, 3H), 1.98–2.03 (m, 2H), 2.33
(s, 3H, CH3), 4.19–4.29 (m, 2H, OCH2CH3), 4.37 (s, 2H,
CH2‐N), 4.56–4.68 (m, 1H), 6.56 (brs, 1H, NH), 7.15–7.20
(m, 2H, ArH), 7.59–7.64 (m, 2H, ArH); 13C NMR
(62.9 MHz, CDCl3): δ = 14.6, 20.8, 24.7, 25.5, 34.8, 48.1,
50.6, 59.6, 100.0, 119.4, 129.5, 134.7, 136.3, 164.2, 165.4.
4.32 | Ethyl 1‐(4‐bromophenyl)‐4‐((4‐
bromophenyl)amino)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10h)
4.36 | Ethyl 1‐(4‐bromophenyl)‐4‐
(butylamino)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐
3‐carboxylate (10l)
White solid; 90% yield (0.43 mg); mp 168–170 °C (Lit.[44b]
1
169–171 °C); H NMR (250 MHz, CDCl3): δ = 1.26 (t,
J = 7.1 Hz, 3H, OCH2CH3), 4.24 (q, J = 7.2 Hz, 2H,
OCH2CH3), 4.47 (s, 2H, CH2‐N), 7.00 (d, J = 8.7 Hz, 2H,
ArH), 7.40 (d, J = 8.7 Hz, 2H, ArH), 7.48 (d, J = 9.0 Hz,
2H, ArH), 7.67 (d, J = 9.0 Hz, 2H, ArH), 8.03 (brs, 1H,
NH); 13C NMR (62.9 MHz, CDCl3): δ = 14.3, 48.1, 60.6,
104.4, 117.6, 118.0, 120.5, 124.2, 131.4, 132.1, 137.6,
137.7, 142.5, 163.6, 164.4.
White solid; 82% yield (0.31 mg); mp 93–95 °C (Lit.[44a]
94–96 °C); 1H NMR (250 MHz, CDCl3): δ = 0.94 (t,
J = 7.1 Hz, 3H, CH3), 1.28–1.61 (m, 7H, −CH2CH2CH3),
3.82 (t, J = 6.7 Hz, 2H, CH2‐NH), 4.24 (q, J = 7.0 Hz,
2H, OCH2CH3), 4.35 (s, 2H, CH2‐N), 6.59 (brs, 1H, NH),
7.44–7.49 (m, 2H, ArH), 7.64–7.68 (m, 2H, ArH); 13C
NMR (62.9 MHz, CDCl3): δ = 13.8, 14.5, 19.8, 33.3, 42.8,
47.8, 59.8, 96.4, 117.7, 120.6, 132.0, 137.9, 164.6, 165.2.
4.33 | Ethyl 1‐(4‐chlorophenyl)‐4‐((4‐
chlorophenyl)amino)‐5‐oxo‐2,5‐dihydro‐1H‐
pyrrole‐3‐carboxylate (10i)
4.37 | Methyl 1‐(4‐bromophenyl)‐4‐
(butylamino)‐5‐oxo‐2,5‐dihydro‐1H‐pyrrole‐
3‐carboxylate (10m)
White solid; 92% yield (0.36 mg); mp 168–170 °C (Lit.[44d]
168–170 °C); H NMR (250 MHz, CDCl3): δ = 1.25 (t,
Yellow solid; 84% yield (0.31 mg); mp 105–107 °C (Lit.[44f]
108–109 °C); H NMR (250 MHz, CDCl3): δ = 0.94 (t,
1
1
J = 7.1 Hz, 3H, OCH2CH3), 4.23 (q, J = 7.2 Hz, 2H,
OCH2CH3), 4.47 (s, 2H, CH2‐N), 7.05 (d, J = 8.5 Hz, 2H,
ArH), 7.23–7.35 (m, 4H, ArH), 7.72 (d, J = 9.0 Hz, 2H,
ArH), 8.04 (brs, 1H, NH); 13C NMR (62.9 MHz, CDCl3):
δ = 14.3, 48.1, 60.6, 104.1, 120.2, 124.0, 128.5, 129.2,
130.0, 130.3, 137.1, 137.2, 142.7, 163.6, 164.4.
J = 7.2 Hz, 3H, CH3), 1.40 (sextet, J = 7.0 Hz, 2H), 1.58
(quintet, J = 7.0 Hz, 2H), 3.77 (s, 3H, OCH3), 3.85 (t,
J = 7.0 Hz, 2H, CH2‐NH), 4.35 (s, 2H, CH2‐N), 7.47 (d,
J = 8.8 Hz, 2H, Ar‐H), 7.66 (d, J = 8.8 Hz, 2H, Ar‐H);
13C NMR (62.9 MHz, CDCl3): δ = 13.8, 19.8, 33.3, 42.6,
47.8, 51.0, 99.4, 117.7, 120.6, 132.0, 137.8, 164.5, 166.7.

SHARGHI ET AL.
19 of 23
4.38 | Methyl 4‐(butylamino)‐5‐oxo‐1‐(p‐
tolyl)‐2,5‐dihydro‐1H‐pyrrole‐3‐carboxylate
(10n)
4.43 | 3,5‐Dimethyl‐1‐(4‐nitrophenyl)‐1H–
pyrazole (13e)
1
Yellow solid; 92% yield (0.20 mg); mp 101–102 °C; H
NMR (250 MHz, CDCl3): δ = 2.28 (s, 3H, CH3), 2.41 (s,
3H, CH3), 6.06 (s, 1H, CH), 7.66 (d, J = 8.7 Hz, 2H,
ArH), 8.29 (d, J = 8.7 Hz, 2H, ArH); 13C NMR
(62.9 MHz, CDCl3): δ = 13.1, 13.5, 109.3, 123.4, 124.6,
139.9, 145.0, 145.5, 150.8.
White solid; 83% yield (0.25 mg); mp 88–90 °C (Lit.[44a]
89–91 °C); 1H NMR (250 MHz, CDCl3): δ = 0.94 (t,
J = 7.2 Hz, 3H, CH3), 1.41 (sextet, J = 7.0 Hz, 2H, CH2),
1.59 (quintet, J = 6.8 Hz, 2H, CH2), 2.33 (s, 3H, CH3),
3.77 (s, 3H, OCH3), 3.88 (t, J = 6.8 Hz, 2H, CH2‐NH),
4.36 (s, 2H, CH2‐N), 6.57 (brs, 1H, NH), 7.18 (d,
J = 8.2 Hz, 2H, ArH), 7.62 (d, J = 8.7 Hz, 2H, ArH); 13C
NMR (62.9 MHz, CDCl3): δ = 13.8, 19.8, 20.8, 33.3, 42.6,
48.0, 50.9, 101.5, 119.4, 129.6, 134.7, 136.2, 164.3, 165.4.
4.44 | 1‐(2‐Chlorophenyl)‐3,5‐dimethyl‐1H‐
pyrazole (13f)
1
Brown liquid; 95% yield (0.20 mg); H NMR (250 MHz,
CDCl3): δ = 2.01 (s, 3H, CH3), 2.21 (s, 3H, CH3), 5.90 (s,
1H, CH), 7.20–7.44 (m, 4H, ArH); 13C NMR (62.9 MHz,
CDCl3): δ = 11.2, 13.6, 105.5, 127.5, 129.9, 130.1, 132.5,
137.5, 141.1, 149.3.
4.39 | 3,5‐Dimethyl‐1‐phenyl‐1H‐pyrazole
(13a)
Light brown liquid;[59] 98% yield (0.17 mg); 1H NMR
(250 MHz, CDCl3): δ = 2.22 (s, 6H, 2CH3), 5.92 (s, 1H,
CH), 7.26–7.37 (m, 5H, ArH); 13C NMR (62.9 MHz,
CDCl3): δ = 12.3, 13.5, 106.9, 124.8, 127.2, 129.0, 139.4,
140.0, 148.9.
4.45 | 3,5‐Dimethyl‐1‐(o‐tolyl)‐1H–pyrazole
(13g)
Brown liquid;[57g] 93% yield (0.17 mg); 1H NMR
(250 MHz, CDCl3): δ = 1.98 (s, 6H, 2CH3), 2.22 (s, 3H,
CH3), 5.89 (s, 1H, CH), 7.14–7.25 (m, 4H, ArH); 13C
NMR (62.9 MHz, CDCl3): δ = 11.2, 13.6, 17.2, 104.9,
126.4, 127.9, 128.9, 130.8, 136.3, 138.7, 140.2, 148.4.
4.40 | 3,5‐Dimethyl‐1‐(p‐tolyl)‐1H–
pyrazole (13b)
Brown liquid;[59] 95% yield (0.18 mg); 1H NMR (250 MHz,
CDCl3): δ = 2.27 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.39 (s,
3H, CH3), 5.97 (s, 1H, CH), 7.21–7.28 (m, 4H, ArH); 13C
NMR (62.9 MHz, CDCl3): δ = 12.3, 13.5, 21.1, 106.6,
124.7, 129.5, 137.1, 137.5, 139.3, 148.7.
4.46 | 1,3,5‐Triphenyl‐1H‐pyrazole (13h)
Dark yellow solid; 88% yield (0.26 mg); mp 131–133 °C
(Lit.[59] 129–132 °C); 1H NMR (250 MHz, CDCl3):
δ = 6.84 (s, 1H, CH), 7.26–7.47 (m, 13H, ArH), 7.92–7.96
(m, 2H, ArH); 13C NMR (62.9 MHz, CDCl3): δ = 105.2,
125.3, 125.8, 127.4, 128.0, 128.3, 128.5, 128.6, 128.7,
128.9, 130.6, 133.0, 140.1, 144.4, 152.0.
4.41 | 1‐(4‐Fluorophenyl)‐3,5‐dimethyl‐1H‐
pyrazole (13c)
Brown liquid;[59] 85% yield (0.16 mg); 1H NMR (250 MHz,
CDCl3): δ = 2.24 (s, 3H, CH3), 2.26 (s, 3H, CH3), 5.95 (s,
1H, CH), 7.06–7.14 (m, 2H, ArH), 7.33–7.40 (m, 2H,
ArH); 13C NMR (62.9 MHz, CDCl3): δ = 12.1, 13.4,
106.8, 115.6, 115.9, 126.4, 126.6, 136.1, 139.4, 148.9,
159.5, 163.5.
4.47 | 3,5‐Dimethyl‐1‐(perfluorophenyl)‐
1H–pyrazole (13i)
Orange liquid;[57h] 77% yield (0.20 mg); 1H NMR
(250 MHz, CDCl3): δ = 2.14 (s, 3H, CH3), 2.27 (s, 3H,
CH3), 6.04 (s, 1H, CH); 13C NMR (62.9 MHz, CDCl3):
δ = 10.7, 13.5, 106.9, 135.7, 139.8, 142.2, 145.8, 151.7.
4.42 | 1‐(4‐Bromophenyl)‐3,5‐dimethyl‐1H‐
pyrazole (13d)
4.48 | (3,5‐dimethyl‐1H‐pyrazol‐1‐yl)(4‐
nitrophenyl)methanone (13j)
Brown liquid;[63] 88% yield (0.22 mg); 1H NMR (250 MHz,
CDCl3): δ = 2.19 (s, 6H, 2CH3), 5.90 (s, 1H, CH), 7.20–7.24
(m, 2H, ArH), 7.44–7.48 (m, 2H, ArH).
White solid; 83% yield (0.20 mg); mp 133–135 °C (Lit.[62]
1
134 °C); H NMR (250 MHz, CDCl3): δ = 2.24 (s, 3H,
13C NMR (62.9 MHz, CDCl3): δ = 12.4, 13.5, 107.4,
120.6, 126.0, 132.1, 139.0, 139.3, 149.3.
CH3), 2.66 (s, 3H, CH3), 6.10 (s, 1H, CH), 8.12 (d,
J = 9.0 Hz, 2H, ArH), 8.05 (d, J = 9.0 Hz, 2H, ArH); 13C

20 of 23
SHARGHI ET AL.
NMR (62.9 MHz, CDCl3): δ = 13.8, 14.4, 111.9, 122.9,
ORCID
132.0, 139.2, 145.4, 149.6, 153.3, 166.5.
Hashem Sharghi http://orcid.org/0000-0001-6772-3332
4.49 | 5‐Methyl‐2‐phenyl‐2,4‐dihydro‐3H‐
pyrazol‐3‐one (13k)
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Brown solid; 85% yield (0.15 mg); mp 126–128 °C (Lit.[59]
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4.50 | (2E,2′E)‐2,2′‐(Pentane‐2,4‐diylidene)
bis(1‐(2,4‐dinitrophenyl)hydrazine) (13l)
Yellow solid; 95% yield (0.44 mg); mp 178–180 °C
1
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4.51 | 2,4,7‐Trimethyl‐3H‐benzo[b] [1,4]
diazepine (15a)
Oil;[69d] 84% yield (0.16 mg); 1H NMR (250 MHz, CDCl3):
δ = 2.32 (s, 6H, 2CH3), 2.37 (s, 3H, CH3), 2.80 (s, 2H,
CH2), 7.01–7.23 (m, 3H, ArH); 13C NMR (62.9 MHz,
CDCl3): δ = 21.0, 27.6, 43.2, 126.2, 127.3, 127.4, 134.7,
138.0, 140.0, 156.9, 157.4.
4.52 | 2,4‐dimethyl‐3H‐benzo[b] [1,4]
diazepine (15b)
1
Oil;[58] 93% yield (0.16 mg); H NMR (250 MHz, CDCl3):
δ = 2.34 (s, 6H, 2CH3), 2.81 (s, 2H, CH2), 7.19–7.23 (m,
2H, ArH), 7.34–7.38 (m, 2H, ArH); 13C NMR (62.9 MHz,
CDCl3): δ = 27.7, 43.2, 124.9, 127.5, 140.2, 157.8.
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ACKNOWLEDGEMENTS
We gratefully appreciate the Shiraz University Research
Councils for the financial support of this work.

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Application and developing of iron‐doped multi‐
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