Stereoselective synthesis of spirocyclic pyrrolidines/pyrrolizidines/pyrrolothiazolidines using l-proline functionalized manganese ferrite nanorods as a novel heterogeneous catalyst

Article abstract of DOI:10.1039/d1ra00841b

An efficient, green, one-pot, and three-component protocol has been reported for the stereoselective synthesis of a new class of spiro thiazolidines. A series of spiro-heterocycle derivatives were produced stereoselectively in high yields by the reaction of 5-arylidene thiazolidine-2,4-diones, isatin, and secondary amino acids in the presence of MnCoCuFe2O4@l-proline (MCCFe2O4@l-proline) magnetic nanorods as a novel nanocatalyst. The synthesized catalyst was fully characterized for thermal stability, magnetic properties, and other physicochemical properties via numerous techniques. It was applied as an efficient and reusable catalyst for the synthesis of endo-isomers of spirocyclic pyrrolidine/pyrrolizidine/pyrrolothiazolidine derivatives in high yield. The regioselectivity and stereochemistry of these heterocyclic spiro-compounds were established by 1H, 13C, HMBC, HSQC, and COSY NMR spectroscopy techniques. The main attractive characteristics of the presented protocol are high yield, high level of diastereoselectivity, and easy recovery of catalyst without significant loss of its catalytic activity. This journal is

Full text of DOI:10.1039/d1ra00841b

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Stereoselective synthesis of spirocyclic
pyrrolidines/pyrrolizidines/pyrrolothiazolidines
using L-proline functionalized manganese ferrite
nanorods as a novel heterogeneous catalyst†
ab
Cite this: RSC Adv., 2021, 11, 14755
Malihe Akhavana and Ahmadreza Bekhradnia
*
An efficient, green, one-pot, and three-component protocol has been reported for the stereoselective
synthesis of a new class of spiro thiazolidines. A series of spiro-heterocycle derivatives were produced
stereoselectively in high yields by the reaction of 5-arylidene thiazolidine-2,4-diones, isatin, and
secondary amino acids in the presence of MnCoCuFe2O4@L-proline (MCCFe2O4@L-proline) magnetic
nanorods as a novel nanocatalyst. The synthesized catalyst was fully characterized for thermal stability,
magnetic properties, and other physicochemical properties via numerous techniques. It was applied as
an efficient and reusable catalyst for the synthesis of endo-isomers of spirocyclic pyrrolidine/
pyrrolizidine/pyrrolothiazolidine derivatives in high yield. The regioselectivity and stereochemistry of
these heterocyclic spiro-compounds were established by 1H, 13C, HMBC, HSQC, and COSY NMR
spectroscopy techniques. The main attractive characteristics of the presented protocol are high yield,
high level of diastereoselectivity, and easy recovery of catalyst without significant loss of its catalytic activity.
Received 31st January 2021
Accepted 8th March 2021
DOI: 10.1039/d1ra00841b
rsc.li/rsc-advances
which the most common representation has a positive charge
located on the nitrogen atom and a negative charge distributed
over the two carbon atoms.7 The cycloaddition of an azomethine
Introduction
Multicomponent 1,3-dipolar cycloaddition reactions play a key
role in the synthesis of ve-membered heterocyclic compounds;
also, they are one category of the most important reactions in
organic chemistry.1,2 Multicomponent 1,3-dipolar cycloaddition
ylide with a p-system involves a total of six p electrons [p4s +
p2s] and takes place by a thermally allowed, suprafacial process
in which two carbon–carbon bonds are formed on the same face
of the azomethine ylide and on the same face of the dipolar-
ophile.8 It is generally accepted that the cycloaddition involves
both carbon–carbon p-bonds being formed at the same time,
although not necessarily to the same extent. In terms of frontier
molecular orbital (FMO) theory, in which a reaction takes place
by maximizing the overlap of the HOMO and the LUMO, azo-
methine ylides can be considered to be electron-rich, and the
dominant interaction involves the HOMO of the azomethine
ylide with the LUMO of the p-system. This is borne out by the
general preference for reaction of azomethine ylides with
electron-poor alkenes.9–11
Our previous theoretical study was performed on the 1,3-
dipolar cycloaddition between the HOMO of an azomethine and
the LUMO of an alkene using density functional theory (DFT) in
combination with the 6-311++G(d,p) basis set.11 Our results
showed that a combination of FMO theory, atomic Fukui
indices, Gibbs activation free energies (DG#) and the reaction
constant, r, explains that the reactivity in the 1,3-dipolar
cycloaddition was affected by electron-withdrawing substitu-
ents on the dipolar component and enhanced the reaction
constant (r > 0), especially in more polar aprotic solvents. The
early transition state for these substituents can be inferred
reactions have found extensive application as
a high-
performance and efficient stereocontrolled and regiocon-
trolled method for the synthesis of many new heterocyclic ve-
membered nitrogen spiro scaffolds.2 Heterocyclic spirooxindole
systems contain two rings sharing one sp3 carbon, and they are
frequently used as important construction blocks in organic
synthesis. Placing the ylide dipole and the alkene dipolarophile
in the same molecule provides direct access to bicyclic products
of considerable complexity.3 The proximity of the reactants and
conformational constraints oen lead to ready cycloaddition
with very high or complete selectivity.4 For the preparation of
ve-membered cyclic amines, in particular pyrrolidines, pyrro-
lizidines, and dihydropyrroles, cycloaddition of azomethine
ylides with alkenes is very effective.2–6 Azomethine ylides have
four p electrons spread over the three-atom C–N–C unit, of
aPharmaceutical Sciences Research Centre, Department of Medicinal Chemistry,
Mazandaran University of Medical Sciences, Sari, Iran. E-mail: abekhradnia@
mazums.ac.ir; abekhradnia@gmail.com
bDepartment of Chemistry and Biochemistry, 103CBB, Montana State University,
Bozeman, MT 59717, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra00841b
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14755

View Article Online
RSC Advances
Paper
Fig. 1 Representative naturally occurring spiro-oxindole alkaloids.
based on the slope of the Hammett plot and the similarity of the with ve heterostructural motifs, including TZD and
reactants and transition state structures in various solvents.11
Due to the constrained structure of spiro compounds, the
oxindole.19–22
Heterogeneous catalysts are an important class of so
existence of the chiral central spiro carbon and the indole core magnetic materials which have high magnetic permeability,
represents an interesting pharmacophore, and these saturation magnetization, electrical resistivity and low power los-
compounds show a wide range of biological and pharmaco- ses.23 Because of the efficient recyclability and facile separation of
logical activities.9 Furthermore, a broad range of natural alka- the products, heterogeneous catalysts have gained prominent
loids contain well-known spirooxindole moieties, such as attention in economical and environmentally benign chemical
formosanine,4 pteropodine,5 coerulescine,6 strychnofoline,7 processes.24 MNRs have recently received special and signicant
rychnophyilline,4 and alstonisine,8 with highly pronounced attention that has led to many advancements, such as in drug
proved pharmacological properties (Fig. 1). For instance, spi- delivery25 and magnetic resonance imaging (MRI).25–27 Moreover, L-
rooxindoles exhibit a range of biological properties, including proline MNR-supported catalysts which were synthesized by
antimicrobial, antitumoral, and antibiotic properties, as well as coating MnCoCu ferrite nanorods with proline showed high
inhibition of human NK-1 receptor.12–14
surface areas, high catalyst loading capacity, reusability, disper-
In medicinal chemistry and drug design, TZD-containing sion, excellent yields and superior stability.28–30 In this work,
compound derivatives in medicine are also well recognized a novel MCCFe2O4@L-proline recyclable heterogeneous nanorod
for their anti-inammatory15,16 and antihypertensive17,18 activi- catalyst was prepared; it is promising due to its easy operation, low
ties. Therefore, according to the signicant biological impor- cost, low temperature, and controllable conditions, the high
tance associated with the above heterocyclic core, we became reactivity of the obtained products and the prevention of undesired
interested in the synthesis of hybrid spiro structure heterocycles side-product formation (Scheme 1).
Scheme 1 Preparation of CoCuMnFe2O4@L-proline MNRs.
14756 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Scheme 2 Green one-pot, three-component asymmetric 1,3-dipolar cycloaddition catalyzed by the CCMFe2O4@L-proline MNRs catalyst.
In continuation of our research and considering the above
reasons related to multicomponent 1,3-dipolar cycloaddition
reactions and our ongoing program for the synthesis of complex
organic compounds based on green chemistry,31–37 herein, we were
fascinated by the possibility of using green and nano chemistry to
design an efficient, reusable and diastereoselective catalyst for the
synthesis of spiro-pyrrolidines/pyrrolizidines and pyrrolothiazole
derivatives via a one-pot process involving azomethine ylides using
MCCFe2O4@L-proline MNRs (Scheme 2).
Morphological studies of the MCCFe2O4@L-proline MNRs. A
SEM image of the MCCFe2O4@L-proline MNRs is demonstrated
in Fig. 3, which provides sufficient data on the morphology features
and sizes of the nanoparticles. The SEM image clearly demonstrates
that the nanoparticles possess a rod-like morphology with 30–60 nm
width and 150–300 nm length. It can be concluded that the shape of
MCCFe2O4@L-proline is nanorods.
Fig. 4 shows TEM images of the uniform-sized particles with
rod shapes with an average size of 30 nm. It is noticeable that
the average diameter obtained from the TEM measurements is
smaller than the sizes obtained from the SEM measurements.
Results and discussion
Synthesis and characterization of the catalyst
Chemical compositions of the MCCFe2O4@L-proline MNRs
According to Scheme 1, we report a facile preparation of
MCCFe2O4@L-proline MNRs as a new, reusable and recoverable
heterogeneous catalyst. This newly synthesized catalyst was
fully characterized by various techniques, such as powder X-ray
diffraction (XRD), scanning electron microscopy (SEM), energy
dispersive X-ray analysis (EDAX), vibrating sample magnetom-
etry (VSM), and thermogravimetric (TGA) analysis. The results
obtained from these techniques conrmed the successful
preparation of this novel catalyst.
EDX spectra and elemental mapping of the MCCFe2O4@L-
proline MNRs. The EDAX analysis of the MCCFe2O4@L-proline
Structural properties of the MCCFe2O4@L-proline MNRs
XRD analysis of the MCCFe2O4@L-proline MNRs. The crys-
talline structures of the MCCFe2O4 and MCCFe2O4@L-proline
MNRs were investigated by means of XRD (Fig. 2). The positions
and relative intensities of the diffraction peaks in the XRD spectra
show invers spinel structures for the nanoparticles. All the peaks
can be indexed to the (2 2 0), (3 1 1), (222), (4 0 0), (4 2 2), (5 1 1),
(440), (620), (533) and (622) reections, which agree well with the
cubic structure of the pure spinel structure (JCPDS 74-2401).
Fig. 2 XRD patterns of the MnCoCuFe2O4@L-proline MNRs.
RSC Adv., 2021, 11, 14755–14768 | 14757
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
RSC Advances
Paper
Fig. 3 SEM images of the MnCoCuFe2O4@L-proline MNRs.
MNRs is depicted in Fig. 5. The surface layer consists of successfully synthesized. In the EDX spectrum, three peaks were
manganese, zinc, iron, copper, and oxygen; therefore, the N observed for each metal and one peak each for C and O. The
signal is present in the EDAX spectrum. According to the EDX EDX elemental mapping from the SEM analysis clearly conrms
analysis, it can be deduced that MCCFe2O4@L-proline was that MCCFe2O4@L-proline consists of Mn, Co, Cu, C, O and Fe;
14758 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Fig. 4 TEM images of the MnCoCuFe2O4@L-proline MNRs.
also, the absence of other elements indicates that MCCFe2- MNR nanoparticles. As shown in the TGA curves of the
O4@L-proline has a high purity level. MCCFe2O4@L-proline MNRs, a high amount of L-proline
FT-IR spectroscopy of the MCCFe2O4@L-proline MNRs. The (2.01 mmol gꢀ1) is immobilized on the magnetic nanoparticles
FT-IR spectra of MCCFe2O4 and the MCCFe2O4@L-proline (Fig. 8). Using carbon hydrogen nitrogen (CHN) analysis, the
MNRs in the wavenumber range of 4000–400 cmꢀ1 are depicted coating of L-proline onto the MCCFe2O4 MNRs was further
in Fig. 6. The magnetic nanoparticles were proved by the two evaluated, and the results indicated that the catalyst is
signicant absorption bands at 450 and 569 cmꢀ1, which are composed of 3.19% nitrogen, 3.06% hydrogen and 13.31%
related to the stretching vibration of metal–oxygen. Further- carbon elements.
more, the broad peaks in the region of 3100–3600 cmꢀ1 concern
O–H groups on the surface of the MCCFe2O4 nanoparticles,
Catalytic properties of the MCCFe2O4@L-proline MNRs
which can be attributed to absorbed water molecules. For the L-
proline functional group, the band perceived at 1647 cmꢀ1
,
Synthesis of 1,3-dipolar cycloaddition using MCCFe2O4@L-
which is due to the COO–Fe band, proves the complexation proline MNRs. Aer characterization of the MCCFe2O4@L-
between the carboxylate moiety of L-proline and the ions on the proline MNRs catalyst, we evaluated its catalytic activity and
surface of the magnetic nanoparticles.
found an appropriate reaction medium for the green one-pot
synthesis of spiro oxindole pyrrolidines/pyrrolizidines/
pyrrolothiazoles. By applying 1,3-dipolar cycloaddition reac-
tion conditions (Scheme 2), the catalyst in the reaction was
Physical properties
Magnetic properties of the MCCFe2O4@L-proline MNRs. The investigated by performing a model reaction of isatin 4a (1.0
magnetic properties of the prepared MNRs-supported catalyst mmol), thiazolidine-4-carboxylic acid 5a00 (1.0 mmol) and the
were studied using VSM (20 kOe magnetic eld) at room dipolarophiles of 5-arylidene thiazolidine-2,4-diones 7a (1.0
temperature (Fig. 7). According to the magnetization curves, the mmol). The model reaction behavior was studied under
saturation magnetization quantity of the MCCFe2O4@L-proline different conditions, and the results are summarized in Table 1.
MNRs was measured to be 18 emu gꢀ1
.
It can be seen that when the model reaction was carried out at
Thermal gravimetric analysis of the MCCFe2O4@L-proline 100 ꢁC in EtOH media, the yield was lower than 40% under
MNRs. A thermogravimetric analyzer (TGA) was used to conrm catalyst-free conditions (Table 1, entry 1). By using the
and evaluate the stability of the MCCFe2O4 MNPs (Fig. 8a) and CCMFe2O4@L-proline MNRs in different reactions, one
the content of organic functional groups on the surface of the regioisomer with yields of up to 80–91% was obtained. Then, we
MCCFe2O4@L-proline MNRs (Fig. 8b). The mass changes under investigated the effects of different solvents and amounts of
the temperꢀa1ture scan from 30 ꢁC to 1300 ꢁC at a heating rate of catalyst on the model reaction (Table 1, entries 2–4). Further,
20 ꢁC min and under a nitrogen ow were monitored and studies established that ethanol was the best choice among the
recorded. Thermogravimetric analysis (TGA) gives the thermal screened solvents (methanol, acetonitrile, and chloroform); it
stability of a catalyst. Therefore, the main changes in the masses leads to a fast reaction rate, high isolated yield, and selectivity.
of the samples were monitored from 260 ꢁC to 500 ꢁC. The In the presence of 4–18 mol% of catalyst in other solvents under
weight loss of 23.9% at 60–500 ꢁC may be due to the removal of reux conditions, the reaction took a longer time to complete,
absorbed water and L-proline from the MCCFe2O4@L-proline and the yields were low in EtOH; applying lower amounts of the
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14759

View Article Online
RSC Advances
Paper
Fig. 5 EDAX spectrum of the MCCFe2O4@L-proline MNRs and the corresponding EDX elemental mapping pattern results of the MCCFe2O4@L-
proline MNRs.
catalyst resulted in 70% and 85% yields of the product aer
To assess the efficiency of the catalytic activity of CCMFe2-
a long time (Table 1, entries 6 and 7). The obtained results O4@L-proline for the synthesis of spirocyclic pyrrolidines/
demonstrated that both variables affected the reaction. Using pyrrolizidines/pyrrolothiazolidines and the methodology, the
14 mol% MNPs in EtOH especially increased the yield of the obtained results from the model reactions were compared with
reaction to 91% and decreased the reaction time to 3 h with previously reported work (Table 2, entries 1–7). Recently,
enhanced regioselectivity (Table 1, entry 5). The product selec- proline (Table 2, entry 2), 4 mol% Pd (CH3CN)2Cl2, 8 mol%
tivity was not inuenced by the nature of the solvents.
CuCl, 14 mol% iPrQuinox, 40 mol% KHCO3, 50 equiv. (Table 2
14760 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Fig. 6 FTIR spectra of the CCMFe2O4 and MnCoCuFe2O4@L-proline
MNRs.
Fig. 8 TGA patterns of the (a) MnCoCuFe2O4 and (b) MnCoCuFe2-
O4@L-proline MNRs.
entry 3), TsNH2 (0.5 mmol%), AgOTf (0.5 mmol%), Au(PPh3)Cl
(0.5 mmol%) (Table 2, entry 4), Ni(COD)2 (10 mol%), PBu3
(20 mol%), Et3SiH (5 equiv.) (Table 2, entry 5), and [Cp2TiMe2]
(Table 2, entry 6) were employed for the synthesis of spirocyclic
compounds. All those methods require toxic organic solvents
with high reaction times, whereas the present procedures afford
environmental friendliness, a reusable and efficient magnetic
catalyst, low catalyst loading, good to excellent yields, and short
reaction times. These results clearly accentuate the efficiency of
this applied methodology.
According to the optimized reaction conditions in Table 1,
we extended this method to various secondary amino acids and
5-arylidenthiazolidine-2,4-dione derivatives (Table 3). In all
cases, 1,3 dipolar cycloaddition was completed in a short time
and spirooxindole derivatives were isolated in good to excellent
yields. Using this methodology in the reaction with different
secondary amino acids produced only one of the possible single
isomers with an endo-conguration. The results are shown in
Table 3 (entries 1–9), and they demonstrate that the reaction
was successfully compatible with a broad range of substituted 5-
arylidenthiazolidine-2,4-dione derivatives. In an attempt to
expand the scope of our methodology, the possibility of per-
forming the reaction with secondary amino acid derivatives was
studied for the synthesis of three types of spiro compounds.
From Table 3, it can be observed that the 1,3-dipolar cycload-
dition reaction of the 5-arylidenthiazolidine-2,4-dione deriva-
tives as potential dipolarophiles and isatin with sarcosine 5a/
thiaproline 5a00/L-proline 5a0 proceeded smoothly, and the cor-
responding pyrrolidine/pyrrolizidine/pyrrolothiazole deriva-
tives were obtained in high yields (Table 3).
Identication of products. With this catalyst, a safe and
efficient three-component reaction for the regioselective
generation of spiro-oxindole derivatives has been developed.
Initially, the required dipolarophiles were synthesized based on
our previous study by the condensation reaction of thiazolidine-
2,4-dione and rhodamine with thiophene-2-carboxaldehyde,
fural-2-carboxaldehyde and indole-3-carbaldehyde using Fe3-
O4@SiO2–NH2/Cu(II) MNPs in EtOH31 (Scheme 2).
The structures of all the products were established by IR, 1H
NMR, 13C NMR and mass spectral analyses. These studies
conrmed the spiroheterocyclic ring structures. The high ster-
eoselectivity of this cycloaddition reaction was determined by
Table 1 Optimization of the reaction conditions
Entry Catalyst (mol%) Solvent T (ꢁC) Time (h) Yielda (%)
1
2
3
4
5
6
7
8
Catalyst-free
EtOH
MeOH
CHCl3
CH3CN
EtOH
EtOH
EtOH
EtOH
80
24
9
48
24
3
9
7
3
40
67
43
52
80–91
70
85
14
14
14
14
4
80
80
80
80
8
14b
92, 92, 90, 90, 88
a
Isolated yield. b Recyclability experiments aer ve reactions.
Fig. 7 Magnetization curves of the MCCFe2O4@L-proline MNRs.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14761

View Article Online
RSC Advances
Paper
Table 2 Comparison of the catalytic activity of the CCMFe2O4@L-proline MNRs with that of other catalysts in the preparation of spirocyclic
pyrrolidines/pyrrolizidines/pyrrolothiazolidines
Entry
Catalyst/conditions
Time (min)
Yield (%)
Ref.
1
2
3
Method A: silica/MW; B: BiCl3–silica/MW; C: TiO2–silica/MW
L-Proline/toluene DMF CH3CN (1 equiv.) and rt
6–8
1200
1440
52–80
17–90
53–72
38
39
40
4 mol% Pd (CH3CN)2Cl2, 8 mol% CuCl, 14 mol% i-PrQuinox, 40 mol% KHCO3, 50
equiv. of MeOH, O2 balloon, rt, toluene/THF, 4 : 1, 24 h
4
5
6
7
TsNH2 (0.5 mmol%), AgOTf (0.5 mmol%), Au(PPh3)Cl (0.5 mmol%)/toluene and 85 ꢁC
360
72
51–85
83
41
42
43
Ni(COD)2 (10 mol%), PBu3 (20 mol%), Et3SiH (5 equiv.)/THF and 45–50 ꢁ
C
20–120
1200
540
[Cp2TiMe2]2 (5.0 mol%)/toluene and 110 ꢁ
CCMFe2O4@L-proline MNRs
C
80–91
This work
HMBC, HSQC and COSY techniques. In continuation of the d 4.67 (J ¼ 8.8 Hz) for the methine proton due to diastereotopic
synthesis of novel spiro-oxindole derivatives, through a 1,3- protons. Within the HSQC spectrum, 35.14, 46.28 and 58.70
dipolar cycloaddition, three new bonds and ve concurrent correspond to the N0–CH3, methine and methylene carbon,
stereogenic centers, including one quaternary carbon, were respectively. The selective long-range HMBC correlation and
incorporated simultaneously in a single step. The cycloaddition COSY correlation of compound 1a are given in Fig. 9.
reaction of azomethine ylides proceeded in situ via decarbox-
The characteristic methine proton (C40–H) of the pyrrolidine
ylative condensation of sarcosine (5a)/thiaproline (5a00)/L- ring showed an HMBC correlation with the C4000 (d 170.58), C2 (d
proline (5a0) with isatin (4a) to 5-arylidenthiazolidine-2,4-diones 144.33), C4 (d 137.97), C3 (d 134.76), C30 (d 74.75) and C50 (d
(7a) with a green catalyst, and a new class of spiro-substituted 58.70) carbons. The diastereotopic methylene protons (C50–
thiazolidine compounds was formed (Scheme 2). The IR spec- CH2) showed correlations with the C3 (d 134.36), C30 (d 74.75),
trum of the spiro-pyrrolidine derivative (compound 1a) gave C20 (d 798.35) C40 (d 46.28), and N10–CH3 (d 35.14) carbons, and
stretching at 3453 and 3142 cmꢀ1 for the TZD and indole NH the N10–CH3 protons showed correlations with the C20 (d 79.35)
groups, 1765 and 1723 cmꢀ1 for the two C]O groups of and C50 (d 58.70) carbons. Selected HMBC compounds from the
thiazolidine-2,4-dione and 1284 cmꢀ1 for the indole C]O combination are listed in Table 3.
1
groups, respectively. The H NMR spectrum of this compound
Based on regioselectivity analysis, the observed regioisomer
showed three singlets at d 2.07, 8.03 and 10.75, which corre- 1a via path A is more favourable because path A is plausibly
spond to the N10–CH3, indole N100–H and thiazolidine-2,4-dione favored by attractive p-interactions between aromatic rings, as
N3000–H, respectively, and the peaks that appeared as a multiplet depicted in Scheme 4. It was assumed that the reaction
in the region of d 7.01–7.66 are due to aromatic protons. Simi- proceeds through the interactions of the highest occupied
larly, the 50-CH2 pyrrolidine ring protons appeared as two trip- molecular orbital (HOMO) azomethine along with the lowest
lets at d 3.85 (J ¼ 8.4 Hz) and 3.55 (J ¼ 9.2 Hz) due to their unoccupied molecular orbital (LUMO) of alkene. The approach
coupling with benzylic protons Ha and diastereotopic protons of azomethine to alkene according to path A would lead to the
Hb and Hc. In particular, the regiochemistry proposed for this formation of 1a.
product was decided on the basis of a doublet of doublets at
The reaction scope was extended to the synthesis of
d 4.67 (J ¼ 8.8 Hz) for the C40–H proton due to its coupling with pyrrolothiazole-substituted thiazolidine-2,4-dione heterocycles
protons Hc and Hb. If another isomer had been formed, the C4– using the 5-(thiophen-2-ylmethylene) thiazolidine-2,4-dione
H would be expected to be a singlet instead of a doublet of and azomethine ylides. The IR spectrum of the 2,4-dione
doublets. The 13C NMR spectrum of this compound showed two substituted pyrrolothiazole 1b showed stretching at 3438, 3054,
peaks at d 74.75 and 79.35, reecting the two spiro carbons. The and 1703 and 1683 cmꢀ1 for the TZD and indole NH groups and
regiochemistry of this product was also conrmed by its 2D C]O groups, respectively. The 1H NMR spectrum of this
NMR spectrum. The peaks found at d 35.14, 46.28 and 58.70 compound showed two singlets at d 8.50 and 10.40 for the
correspond to the N0–CH3, methine and methylene carbons, indole N200–H and TZD N3000–H, respectively. The C10–CH2
respectively, which was conrmed on the basis of HSQC and H- protons were found at d 2.70 (J ¼ 8.8 Hz) as a triplet and d 3.00 (J
COSY correlations in the ESI les ( Fig. 5S1a and Fig. 6S1†). The ¼ 9.2 Hz, 5.6 Hz) as a doublet of doublets, respectively. The
other characteristic carbon peaks were found at d 168.07, 170.58 doublets at d 3.76 (J ¼ 5.6 Hz) and 4.17 (J ¼ 6.0 Hz) were due to
and 176.71, which correspond to the C200, C4000 and C2000 carbonyl the C30–CH2 protons. A doublet at d 4.3 4 (J ¼ 8.8 Hz) was due to
groups, respectively. The two-dimensional NMR spectra of the C70–H proton, indicating the regioselectivity of the product.
HMBC and COSY correlations were useful in the signal A multiple at d 4.81–4.85 was due to the C7a0–H proton. The
assignment of 1a, and various characteristic signals are shown aromatic protons appeared in the chemical shi region of
in Fig. 10. The H,H-COSY spectrum of this compound revealed d 6.88–7.67. The 13C NMR spectrum showed the presence of
two triplets at d 3.85 (J ¼ 8.4 Hz) and 3.55 (J ¼ 9.2 Hz), two each three carbonyl groups at 168.0, 2176.72, and 176.72 and two
for diastereotopic protons due to one of the diastereotopic spiro carbons at 79.33 and 74.73. The structure was further
protons and the methine proton, and a doublet of doublets at conrmed on the basis of 2D NMR spectral studies. The HSQC
14762 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Table 3 Multicomponent one-pot synthesis of pyrrolidine/pyrrolizidine/thiapyrrolizidine derivatives using the MNR catalysts
MP (ꢁC)
Entry
Products
Dipolarophiles
Compound
Yield (%)
Found
Reported [lit.]
153 (ref. 22)
1
1a
85
155–157
2
1b
89
158–160
—
3
4
5
1c
2a
2b
78
88
90
195–197
160–162
186–189
—
—
—
6
7
8
2c
3a
3b
91
89
87
208–210
198–200
227–230
—
—
—
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14763

View Article Online
RSC Advances
Paper
Table 3 (Contd.)
MP (ꢁC)
Found
Entry
Products
Dipolarophiles
Compound
Yield (%)
Reported [lit.]
9
3c
80
208–210
—
31.73 ppm, N-bonded methine carbon (C7a0) at 67.21 ppm,
spiro carbon (C60) at 78.38 ppm, and carbon (C4) at 138.99 ppm.
The methylene protons (C30–CH2) at d 3.45 and 3.83 showed
HMBC correlations to the methylene carbon (C10) at 31.73 ppm,
the N-bonded methane carbon at 67.21 ppm and one of the
spiro carbons (C50) at 75.02 ppm. Similarly, the methylene
protons at d 2.82 and 3.18 showed correlations with two
methine carbons (C70 and C7a0) at 30.25 ppm and 58.92 ppm,
Fig. 9 Selected HMBC and H–H COSY correlations of compound 1a. respectively. The selected HMBC correlation of compound 1b is
shown in Table 4 and Fig. 10. Based on the above spectral
details and the elemental analysis (Table 2), the structure was
conrmed to be 70-(thiophen-2-yl)-70,7a0-dihydro-10H,30H-dis-
piro[indoline-3,50-pyrrolo[1,2-c]thiazole-60,500-thiazolidine]-
2,200,400-trione (Table 5, entry 2) (1b).
The IR spectrum of the thiazolidine-2,4-dione substituted
pyrrolizidine 3c revealed peaks at 3097 cmꢀ1 (N–H stretch),
1765 cmꢀ1 (carbonyl stretch), 1645 cmꢀ1 (amide C]O stretch),
1505 cmꢀ1 (N–O asymmetric stretch) and 1336 cmꢀ1 (N–O
1
symmetric stretch). The H NMR spectrum of 3c showed three
singlets at d 12.15, 10.59, and 8.29 for the TZD N3000–H, indole
N200–H and C2–H, respectively. Nine aromatic protons in the
region of d 6.78–8.29 and one methane proton (C10–CH)
Fig. 10 Selected HMBC and H–H COSY correlations of compound 1b.
appeared as a doublet at d 3.45 (3J ¼ 9.5 Hz) and three methine
protons as multiplets at d 4.11–4.13 and d 2.59–2.63, 2.30–2.39,
and 1.70–1.75, corresponding to C7a0–CH, C50–CH2, C70–CH2,
correlation assigned the carbons C30, C70, and 7a0 to the C30–
and C60–CH2, respectively. The 13C NMR spectrum of this
CH2, C70–CH, and C7a–CH protons, respectively. The H,H-COSY
compound showed three methylene carbons that appeared at
spectrum of the compound, shown in Fig. 10, revealed a doublet
d 46.56, 24.24, and 23.68 and three methane carbons that
at d 4.54 (J ¼ 8.8 Hz), which conrmed only one nearby
appeared at d 66.97, 61.27 and 60.28. Three carbonyl carbons
hydrogen in C70; this indicated the regioselectivity of the
appeared at d 185.44, 175.89 and 174.99, corresponding to the
compound. In the long-range HMBC correlation, the charac-
carbonyls of the oxindole and TZD ring, and nine aromatic
teristic C70–H was correlated with the methylene carbon (C10) at
carbons appeared in the region of d 112.89–150.51. The
Table 4 Selected HMBC correlations of compound 1a
S. no.
Proton
Correlated carbons
1
2
N10–CH3 (s, 3H) at d 2.16
C50 (54.48), C20 (78.76)
C40–H (t, 1H, J ¼ 8.8 Hz) at d 4.92
C30 (74.52), C50 (54.48), C2 (151.38), C3 (130.55),
C4 (139.07), C4000 (178.43)
3
4
C50–CH2 (t, 1H, J ¼ 8.4 Hz) at d 3.65 (t, 1H, J ¼ 9.2
Hz) at d 4.27
C20 (78.76), C30 (74.52), C40 (46.52), N10–CH3
(34.71), C3 (130.55)
Indole N00–H (s, 1H) at d 10.84
C200 (176.18), C20 (78.76)
14764 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
Table 5 Selected HMBC correlations of compound 1b
S. no.
Proton
Correlated carbons
1
2
3
C10–CH2 (t, 1H, J ¼ 8.8 Hz) at d 2.82 (dd, 1H, J ¼ 9.2 Hz, 5.6 Hz) at d 3.18
C30–CH2 (d, 1H, J ¼ 5.6 Hz) at d 3.76 (d, 1H, J ¼ 6.0 Hz) at d 4.17
C70–H (d, 1H, J ¼ 8.8 Hz) at d 4.34
C70 (30.25), C7a0 (58.69)
C10 (35.15), C50 (79.33), C7a0 (58.69)
C10 (35.15), C60 (74.73), C7a0 (58.69)
Fig. 11 Selected HMBC and H–H COSY correlations of compound 3c.
heteronuclear single-quantum correlation assigned the carbons
C50, C60, C70, 7a, and C10 to the C50–CH2, C60–CH2, C70–CH2,
C7a–CH, and C10–CH protons, respectively. The 2D NMR
spectra of the HMBC and COSY correlations are useful in the
signal assignment of 3c, and various characteristic signals are
shown in Fig. 11. From the selected long-range HMBC correla-
tions of compound 3c shown in Table 6, the correlation between
the proton (C70–CH2) interacting with carbons C10, C7a0, C50 and
protons (C50–CH2) of the pyrrolizidine ring showed HMBC
correlations with the C60, C70 and C30 carbons. The correlation
between the protons (C70–CH2) interacting with carbons C7a0,
C50 and C10 suggests that the formation of product 3c proceeds
via path A (Scheme 3).
According to recent reports, 1,3-dipolar cycloaddition reac-
tions of azomethine ylides with dipolarophiles proceed in
a concerted manner rather than a step-wise diradical transition
state.32 Product 3c has four stereocenters, indicating the possi-
bility of 24 ¼ 16 stereoisomers (eight pairs of diastereoisomers).
Hence, the reaction is stereospecic, and the relative stereo-
chemistry of the secondary amino acid (L-proline 5a0) and
dipolarophile (5-arylidenthiazolidine-2,4-diones 7a) would
inuence the stereochemistry at the C-1, C-2, and C-3 stereo-
centers (the stereocenters of 3c are marked as 1, 2, 3, and 4 in
Scheme 3). The reaction mechanism involves the formation of
the corresponding azomethine ylide, which we have described
in three steps. The rst step, condensation of the secondary
Scheme 3 Plausible transition state for the formation of 1a, 1a0.
amino acid with the isatin, would lead to the formation of the
intermediates 7b and 7b0, with a new C–N bond that can freely
rotate. In the second step, one molecule of water is lost due to
an intramolecular rearrangement, generating two possible
intermediates 7c and 7c0 (Scheme 3).
The reaction of 7a with the ylide 7b leads to the formation of
two different diastereomers, 3c and 3c0, depending upon how
the ylide 6a approaches dipolarophile 7a (path A and path B).
The reaction proceeds through the interactions of the highest
occupied molecular orbital (HOMO) of azomethine ylide 6a with
the lowest unoccupied molecular orbital (LUMO) of dipolar-
ophile 7a. Following path A, the dipolarophile can approach 6a
from both its faces with equal feasibility to 3c. Therefore, the 3c
product with the more stabilized transition state will require
less free energy for activation. Thus, the observation that 3c0 was
Table 6 Selected HMBC correlations of compound 3c
S. no.
Proton
Correlated carbons
1
2
3
4
5
C10–CH (dd, 1H, J ¼ 9.5 Hz) at d 3.45
C50–CH2 (M, 1H) at 2.59–2.63
C70–CH2 (m, 2H) at d 2.30–2.39
C60–CH2 (m, 2H) at d 1.70–1.75
C7a–CH (m, 1H) at d 4.11–4.13
C70 (23.68), C7a (60.28)
C10 (24.24), C50 (46.56), C7a (d 60.28)
C10 (d 24.24), C60 (d 21.09), C7a (d 60.28)
C70 (23.68), C7a (60.28), C50 (46.56)
C70 (23.68), C10 (d 24.24), C30 (d 66.97), C60 (d 21.09)
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14765

View Article Online
RSC Advances
Paper
Scheme 4 Proposed transition states for the formation of 3c, 3c0, 8a and 8a0.
not formed can be demonstrated by the plausible transition of activation for this transition state. Also, the observed regio-
state, as depicted in path B. The approach of 6a to 7a through selectivity can be explained by considering the HOMO–LUMO
path B appears to be hindered by the steric hindrance between interactions of 6a and 7a. As shown in Scheme 3, either of the
the aryl moiety and isatin core, which will result in electrostatic two possible pathways (paths C and D) leads to strong steric
repulsion within these components, enhancing the free energy crowding between the aryl part of dipolarophile 7a and the
Fig. 12 The catalytic efficiency of the MCCFe2O4@L-proline MNRs in cycloaddition reactions.
14766 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry

View Article Online
Paper
RSC Advances
pyrrolidine residue of 6a in the transition states and agrees well added to 100 ml NH4OH (3 mol Lꢀ1) solution dropwise at room
with the non-observation of regioisomers 8a and 8a0 (Scheme 4). temperature, and the solution was warmed to 95 ꢁC. The ob-
Stability of the MCCFe2O4@L-proline MNRs. The recycling of tained mixture was heated for 5 h with intense stirring. Even-
catalysts is important from practical and environmental tually, 1 g of L-proline and NH4OH (25 wt%, 20 ml) were added
perspectives. Therefore, we investigated the stability, high to the mixture until the pH was raised to 11, and a black
catalytic activity and easy recovery of the catalyst from this suspensionꢁwas formed. The mixture was ltered, washed and
reaction. The reusability of the catalyst was investigated using dried at 70 C for 12 h.
a model reaction between isatin 4a (1.0 mmol), thiazolidine-4-
carboxylic acid 5a00 (1.0 mmol) and dipolarophiles of 5-
Synthesis of spiro-pyrrolidine, pyrrolizidine, and
arylidenthiazolidine-2,4-diones 7a in the presence of 0.03 g of
the catalyst at 90 ꢁC. The MNP-supported catalyst in the ethanol
readily suspends and separates from the reaction mixture. This
separation approach is not time-consuming in comparison with
standard methods (centrifugation and ltration) and prevents
the loss of heterogeneous catalyst in the process of separation.
The separated catalyst was reused in the model reaction ve
times with minor variation of its catalytic activity, and no
considerable decrease in the product yield was observed aer
repeated cycles of the reaction (run 1, 92%; run 2, 92%; run 3,
90%; run 4, 90%; run 5, 88%) (Fig. 12).
pyrrolothiazole derivatives
Isatin (1.0 mmol), sarcosine (1 mmol), and 5-arylidene-1,3-
thiazolidine-2,4-dione (1 mmol) were placed in a 10 ml round-
bottomed ask in EtOH (5 ml). Sequentially, MCCFe2O4@L-
proline MNRs (4 mol%) were added, and the resulting mixture
ꢁ
was stirred at 100 C. The reaction progress was monitored by
TLC. Aer completion of the reaction, the catalyst was separated
with an external magnet and the solvent was evaporated. The
separated catalyst was washed several times with EtOH and
water, dried under vacuum and utilized four times for the same
reaction. The nal product was puried by column chroma-
tography using n-hexane and ethyl acetate (3 to 2) as the eluent.
All novel spiro-products were identied by physical and spec-
troscopic data.
Experimental
Materials
All reagents and solvents were purchased from Merck and were
used without additional purication. The FT-IR spectra were
obtained in the region of 400–4000 cmꢀ1 as KBr pellets with
a PerkinElmer 550 spectrometer.
Conclusions
In summary, we developed an efficient, green one-pot procedure
and a new approach for the construction of pyrrolidine/
pyrrolizidine/pyrrolothiazolidine skeletons based on tandem
cycloaddition using new synthetic MCCFe2O4@L-proline nano-
rods. The nanocatalyst can be recycled and reused for the next
run without any signicant changes in its catalytic activity. This
methodology is applicable to provide spiro thiazolidines with
excellent regio- and stereoselectivity.
Instrumental measurements
Melting points were recorded with an electrothermal 9200
1
apparatus and are not corrected. H NMR (600 MHz) and 13C
NMR (150 MHz) spectra were recorded with a Bruker Advance
spectrometer with DMSO-d6 as solvent and TMS as an internal
standard. TLC was performed on silica gel polygram SILG/UV
254 nm plates. The magnetite properties of the catalyst were
analyzed using a vibrating sample magnetometer (VSM) with
a varying magnetic eld from ꢀ10 000 to 10 000 on a BHV-S5
instrument. Mass spectra were recorded with a CH7A Varian
mat Bremen instrument at 70 eV electron impact ionization, in
m/z (rel%). The X-ray powder (XRD) pattern of the catalyst was
recorded with an X-Pert Pro instrument (Cu Ka radiation, l ¼
1.54 A) in the region of 2Q ¼ 20–80ꢁ. Morphology was analyzed
by SEM (Hitachi S4160 scanning electron microscope). Ther-
mogravimetric analysis (TGA) curves were obtained using a PL-
STA 1500 device manufactured by Thermal Sciences with
a heating rate of 10 ꢁC minꢀ1 over a temperature limited area of
Conflicts of interest
The authors declare that they have no conict of interest.
Acknowledgements
This work was supported by the National Institute for Medical
Research Development (NIMAD) [grant number 971338]. Also,
the authors gratefully acknowledge the support for this work
received from the Mazandaran University of Medical Sciences
“Professor's Projects and Sabbatical Funds”.
ꢁ
30–1300 C under N2 atmosphere.
References
Preparation of L-proline-coated MCCFe2O4 magnetic
nanorods
1 I. Coldham and R. Huon, Chem. Rev., 2005, 105, 2765–2810.
2 G. S. Kumar, R. Satheeshkumar, W. Kaminsky, J. Platts and
K. J. R. Prasad, Tetrahedron Lett., 2014, 55, 5475–5480.
3 G. Periyasami, R. Raghunathan, G. Surendiran and
N. Mathivanan, Bioorg. Med. Chem. Lett., 2008, 18, 2342–
2345.
The nano-catalyst was prepared by taking advantage of chemical
co-precipitation. Firstly, a solution of FeCl3$6H2O (0.541 g, 2
mmol), MnCl2$2H2O (0.0809 g, 0.5 mmol), CuCl2$2H2O
(0.0426 g, 0.25 mmol), and CoCl2$6H2O (0.0595 g, 0.25 mmol) in
150 ml distilled water was prepared. Then, this solution was
4 C. Marti, Eur. J. Org. Chem., 2003, 2209–2229.
© 2021 The Author(s). Published by the Royal Society of Chemistry
RSC Adv., 2021, 11, 14755–14768 | 14767

View Article Online
RSC Advances
Paper
5 A. Ilenia Alfano, A. Zampella, E. Novellino, M. Brindisi and 23 M. Afradi, S. A. Pour, M. Dolat and A. Yazdani-Elah-Abadi,
H. Lange, React. Chem. Eng., 2020, 5, 2091–2100. Appl. Organomet. Chem., 2018, 32, e4103.
6 A. Dandia, S. Kumari, S. Maheshwari and P. Soni, 24 R. Jahanshahi and B. Akhlaghinia, RSC Adv., 2016, 6, 29210–
Experimental and Theoretical Approach. 2017, vol. 3, p. 39. 29219.
7 L. E. Carloni, S. Mohnani and D. Bonifazi, Eur. J. Org. Chem., 25 S. A. Pour, H. R. Shaterian, M. Afradi and A. Yazdani-Elah-
2019, 44, 7322–7334. Abadi, J. Magn. Magn. Mater., 2017, 438, 85–94.
8 R. L. Garnick and P. W. Le Quesne, J. Am. Chem. Soc., 1978, 26 N. Lee and T. Hyeon, Chem. Soc. Rev., 2012, 41, 2575–2589.
100, 4213–4219.
9 P. Saraswat, G. Jeyabalan, M. Z Hassan, M. U. Rahman and
N. K. Nyola, Synth. Commun., 2016, 46, 1643–1664.
27 P. Thakur, R. Sharma, M. Kumar, S. C. Katyal, N. S. Negi,
N. Thakur and P. Sharma, Mater. Res. Express, 2016, 3,
075001.
10 B. Yu, D. Q. Yu and H. M Liu, Eur. J. Med. Chem., 2015, 97, 28 A. Ponti and G. Molteni, Eur. J. Org. Chem., 2020, 39, 6173–
673–698. 6191.
11 A. R. Bekhradnia, S. Arshadi and S. A. Siadati, Chem. Pap., 29 T. P. Loh, L. C. Feng, H. Y. Yang and J. Y. Yang, Tetrahedron
2014, 2, 283–290. Lett., 2002, 43, 8741–8743.
12 C. Mhiri, S. Boudriga, M. Askri, M. Knorr, D. Sriram, 30 R. Arulmurugan, B. Jeyadevan, G. Vaidyanathan and
P. Yogeeswari and C. Strohmann, Bioorg. Med. Chem. Lett.,
2015, 25, 4308–4313.
S. Sendhilnathan, J. Magn. Magn. Mater., 2005, 288, 470–477.
31 M. Akhavan, N. Foroughifar, H. Pasdar, A. Khajeh-Amiri and
A. Bekhradnia, Transition Met. Chem., 2017, 42, 543–552.
32 C. E. P. Galvis and V. V. Kouznetsov, Org. Biomol. Chem.,
2013, 11, 7372–7386.
13 F. Rouatbi, M. Askri, F. Nana, G. Kirsch, D. Sriram and
P. Yogeeswari, Tetrahedron Lett., 2016, 57, 163–167.
14 G. Bhaskar, Y. Arun, C. Balachandran, C. Saikumar and
P. T. Perumal, Eur. J. Med. Chem., 2012, 51, 79–91.
15 M. Akhavan, N. Foroughifar, H. Pasdar and A. Bekhradnia,
33 Z. Esam, M. Akhavan, A. R. Bekhradnia, M. Mohammadi and
S. Tourani, Catal. Lett., 2020, 8, 1–20.
Green Synthesis, Combinatorial Chemistry
Throughput Screening, 2019, vol. 22, pp. 716–727.
&
High 34 Z. Esam, M. Akhavan and A. R. Bekhradnia, Appl. Organomet.
Chem., 2021, 35, DOI: 10.1002/aoc.6005.
16 C. D. Barros, A. A. Amato, T. B. de Oliveira, K. B. R. Iannini, 35 S. N. Azizi, M. J. Chaichi, P. Shakeri and A. Bekhradnia, J.
A. L. da Silva, T. G. da Silva and F. D. A. R. Neves, Bioorg. Med.
Chem., 2010, 11, 3805–3815.
17 V. Mamakou, I. Eleheriadou, N. Katsiki, K. Makrilakis,
Fluoresc., 2013, 23, 227–235.
36 E. Vessally, A. Hosseinian, L. Edjlali, A. Bekhradnia and
M. D. Esrali, Curr. Org. Synth., 2017, 14, 557–567.
K. Tsious and N. Tentolouris, Curr. Vasc. Pharmacol., 37 T. Tamoradi, M. Masoumeh and M. Mohammadi,
2018, 16(1), 70–78. ChemistrySelect, 2020, 5, 5077–5081.
18 R. Mishra, K. K. Jha, S. Kumar and I. Tomer, Der Pharma 38 A. S. Babu and R. Raghunathan, Tetrahedron, 2007, 63, 8010–
Chem., 2011, 3, 38–54. 8016.
19 R. Murugan, S. Anbazhagan and S. S. Narayanan, Eur. J. Med. 39 I. Ibrahem, R. Rios, J. Vesely and A. Cordova, Tetrahedron
Chem., 2009, 44, 3272–3279. Lett., 2007, 48, 6252–6257.
20 A. Y. Barkov, N. S. Zimnitskiy, V. Y. Korotaev, I. B. Kutyashev, 40 R. Jana, T. P. Pathak, K. H. Jensen and M. S. Sigman, Org.
´
V. S. Moshkin and V. Y. Sosnovskikh, Tetrahedron, 2016, 72,
6825–6836.
Lett., 2012, 14, 4074–4077.
41 M. Shi, L. P. Liu and J. Tang, Org. Lett., 2006, 8, 4043–4046.
21 S. U. Maheswari, K. Balamurugan, S. Perumal, P. Yogeeswari 42 X. Q. Tang and J. Montgomery, J. Am. Chem. Soc., 1999, 121,
and D. Sriram, Bioorg. Med. Chem. Lett., 2010, 24, 7278–7282. 6098–6099.
22 P. Dhanalakshmi, S. S. Babu, S. Thimmarayaperumal and 43 I. Bytschkov, H. Siebeneicher and S. Doye, Eur. J. Org. Chem.,
S. Shanmugam, RSC Adv., 2015, 5, 33705–33719.
2003, 2003, 2888–2902.
14768 | RSC Adv., 2021, 11, 14755–14768
© 2021 The Author(s). Published by the Royal Society of Chemistry