A sequential multicomponent reaction (SMCR) strategy: Synthesis of novel pyrazolo-1,4-dioxaspiro[4,5]decane grafted spiro-indenoquinoxaline pyrrolidine heterocycles

Article abstract of DOI:10.1080/00397911.2021.1919901

A facile and expedient one-pot sequential five-component synthesis of highly substituted trispiro-pyrrolidine heterocycles is described. The key step involves [3 + 2]-cycloaddition of azomethine ylide. This multicomponent reaction (MCR) strategy provides a mild reaction condition, high yield of the products, high regioselectivity, and operational simplicity to assemble complex structural entity in a single operation. The structure of product was confirmed by IR, ¹H-NMR, ¹³C-NMR, and high-resolution mass spectroscopic analysis. A theoretical insight is provided through MM2 calculation for the formation of the observed products.

Full text of DOI:10.1080/00397911.2021.1919901

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A sequential multicomponent reaction (SMCR)
strategy: Synthesis of novel pyrazolo-1,4-
dioxaspiro[4,5]decane grafted spiro-
indenoquinoxaline pyrrolidine heterocycles
Gavaskar Deivasigamani & Suresh Babu Adukamparai Rajukrishnan
To cite this article: Gavaskar Deivasigamani & Suresh Babu Adukamparai Rajukrishnan
(2021) A sequential multicomponent reaction (SMCR) strategy: Synthesis of novel pyrazolo-1,4-
dioxaspiro[4,5]decane grafted spiro-indenoquinoxaline pyrrolidine heterocycles, Synthetic
Communications, 51:13, 2063-2076, DOI: 10.1080/00397911.2021.1919901
To link to this article: https://doi.org/10.1080/00397911.2021.1919901
View supplementary material
Published online: 12 May 2021.
Submit your article to this journal
Article views: 58
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lsyc20

R
SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 13, 2063–2076
https://doi.org/10.1080/00397911.2021.1919901
A sequential multicomponent reaction (SMCR) strategy:
Synthesis of novel pyrazolo-1,4-dioxaspiro[4,5]decane
grafted spiro-indenoquinoxaline pyrrolidine heterocycles
Gavaskar Deivasigamania and Suresh Babu Adukamparai Rajukrishnanb
b
aSchool of Basic Sciences, Vels University, Chennai, India; Department of Chemistry, University of
Calicut, Calicut, India
ABSTRACT
ARTICLE HISTORY
Received 7 November 2020
A facile and expedient one-pot sequential five-component synthesis
of highly substituted trispiro-pyrrolidine heterocycles is described.
The key step involves [3 þ 2]-cycloaddition of azomethine ylide. This
multicomponent reaction (MCR) strategy provides a mild reaction
condition, high yield of the products, high regioselectivity, and oper-
ational simplicity to assemble complex structural entity in a single
operation. The structure of product was confirmed by IR, 1H-NMR,
13C-NMR, and high-resolution mass spectroscopic analysis. A theoret-
ical insight is provided through MM2 calculation for the formation of
the observed products.
KEYWORDS
Azomethine ylide; pyrazolo-
1,4-dioxa-spiro[4,5]decane;
indenoquinoxaline; multi-
component reaction (MCR);
spiro-pyrrolidines
GRAPHICAL ABSTRACT
H
O
H
N
N
N
O
O
R
R
R
NH2
NH2
OH
OH
CH3
NH-CH2-COOH
MeOH
Reflux
N
NH2NH2.H2O
5
O
O
HN
O
O
R
6a-e
4
3
2
1a-e
X
R =
X = H, Cl, OMe, Br, F
Introduction
A multicomponent reaction (MCR) can be simply classified as a reaction in which three
or more components are combined together in a single reaction vessel to produce a final
product or products displaying features of all inputs and thus offer greater possibilities
for molecular diversity per step with a minimum of synthetic time and effort.
Multicomponent reactions offer a convenient strategy for the rapid elegant and conver-
gent construction of complex and structurally diverse organic molecules in a single oper-
ation resulting in substantial minimization of waste, labor, time, and cost[1,2] and play a
vital role in combinatorial and diversity-oriented synthesis.[3] MCRs result in high atom
and step economy. MCRs are more advantageous than conventional approach which
CONTACT Suresh Babu Adukamparai Rajukrishnan
arsborg@gmail.com
Department of Chemistry, University of
Calicut, Calicut, India
Supplemental data for this article can be accessed on the publisher’s website
ß 2021 Taylor & Francis Group, LLC

2064
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
generally involves the use of multistep reaction sequence which is typically associated
with low yields, high cost, tedious isolation, and purification of the resulting products.
One of the major challenges often encountered in modern drug discovery program is the
design of highly efficient chemical reactions for accessing structurally complex and
diverse compounds, possessing important biological activities, in a minimum number of
synthetic steps. MCR strategy can be useful in this regard which has emerged as an
advanced tool for sustainable organic synthesis. Among MCRs, the intermolecular
[3þ 2]-cycloaddition of azomethine ylides to olefinic dipolarophiles[4] constitutes a facile
approach for the efficient assembly of five-membered heterocyclic rings of biological
importance particularly pyrrolidines and spiro-pyrrolidines due to their occurrence in a
large number of natural products.[5] Spiropyrrolidines act as potential antileukemic,[6]
anticonvulsant[7] antiviral,[8] local anesthetic,[9] and anti-inflammatory agents.[10]
Quinoxalines, indazoles, and pyrazoles are important classes of nitrogen-containing het-
erocycles with broad spectrum of biological activities such as anti-viral,[11 anti-cancer,[12]
anti-inflammatory,[13] anti-tubercular,[14] anti-leishmanial,[15] anti-malarial,[16] and anti-
depressant activities.[17] Recently, some of the quinoxaline derivatives such as brimonidine
and varenicline have been approved by the food and drug administration for the treat-
ment of glaucoma[18] and anti-smoking therapy.[19] Some of the synthetic and naturally
occurring biologically significant spiro-pyrrolidine, quinoxaline, pyrazole, and dioxalane
derivatives are shown (Fig. 1). The potential pharmaceutical significance of these
backbones has led to a demand for the synthesis of hybrid systems incorporating all these
significant entities in a single molecule.
Results and discussion
In continuation of our research in the area of cycloaddition reactions and with renewed
interest in such complex spiro-pyrrolidine heterocycles,[20,21] we herein report for the
first time, a mild, rapid, and a facile one-pot sequential five-component synthesis of
highly substituted trispiroheterocyles containing 1,4-dioxa-spiro[4,5]decane, pyrrolidine,
indenoquinoxaline, and pyrazole moieties using various unusual 7, 9-bis-[(E)-arylmethy-
lidene]-1.4-dioxa-spiro[4,5]-decan-8-one derivatives, 1,2-phenylenediamine, ninhydrin,
sarcosine, and hydrazine hydrate (Scheme 1).
The one-pot sequential five-component reaction involving ninhydrin 2, 1,2-phenyle-
nediammine 3, sarcosine 4, dipolarophile 1a, and hydrazine hydrate 5 proceeded at
reflux temperature in methanol, to give pyrazolo-1,4-dioxa-spiro[4,5]decane grafted
spiro-indenoquinoxaline pyrrolidine 6a. The multistep sequence of events involves,
initial heterocyclization of phenylenediamine 3 with ninhydrin 2 giving indenoquinox-
line-11-one 7[22] which further condensed with sarcosine 4 to produce 1,3-dipole, azo-
methine ylide 10 via thermal decarboxylation of 9.[20a,b,23] The azomethine ylide 10
undergoes cycloaddition across one of the exocyclic double bond of the dipolarophile
1a to afford the intermediate product 11 which undergoes cyclization with hydrazine to
give the final product 6a in good yield (Scheme 2).
Thus, the IR spectrum of 1-N-methyl-spiro[7.30’]-3,3a,4,5,6,7-hexahydro-2H-indazole-3-
(p-methoxyphenyl)–spiro-[5.20]-10,30-dioxalane-spiro[20’.110’’]-indeno-[1,2-b]-quinoxaline-4-
(p-methoxyphenyl)-pyrrolidine 6a revealed the complete disappearance of carbonyl group

R
SYNTHETIC COMMUNICATIONSV
2065
Me
H
N
H
N
O
HO
N
O
O
CH3
H3C
MeO
CO2CH3
CH3
NH
O
NMe
N
H
Mitraphylline
(-)-Horsfiline
(+)-Elacomine
N
N
O
O
N
N
O
N
O
CH3
CH3
CH3
CH3
H3C
H3C
H3C
O
O
CH3
Cl
CH3
O
O
CH3
CH3
Cl
Itraconazole
Isoacorone
Acorone
H3C
N
CH3
N
NH2
O
CH3
N
N
OHC
H3C
N
F
N
HN
N
Cl
HN
N
N
F
H3C
Cl
CH3
NHSO2CH3
CH3 Cl
HN
COOCH3
Encorafenib
Cinachyrazole A
Crizotinib
CH3
O
N
H
O
CH3
N
N
N
N
H
O
CH3
N
O
S
O
O
O
O
Br
H
CH3
N
O
S
H
N
H
N
N
N
N
N
N
N
N
H
O
NH
O
CH3
N
CH3
O
N
N
Brimonidine
Vareniciline
Triostin A
Figure 1. Some synthetic and naturally occurring biologically significant molecules having
spiro-pyrrolidine, spiro[4,5]decane, dioxalane, pyrazole, and quinoxaline moieties.
of cyclohexanone and exhibited a peak at 1605 and 3317 cmꢀ1due to the C ¼ N and NH
1
group of the pyrazole ring. The H NMR spectrum of the product 6a exhibited a singlet at
d 1.77 ppm due to -NCH3 pyrrolidine protons. The two pyrrolidine-NCH2 protons
exhibited triplets at d 3.55 and d 4.14. The pyrrolidine ring proton attached to the aryl
moiety exhibited a doublet of doublet at d 5.14 ppm. The two methoxy groups on the
aryl moiety exhibited a singlet at d 3.79 and 3.84. The pyrazole ring proton attached to the
aryl moiety exhibited a doublet at d 4.28. The -CH ring proton fused to the pyrazole moi-
ety exhibited a multiplet in the region d 2.04 ꢀ 2.10. The -NH ring proton exhibited a sing-
let at 6.02 ppm. The aromatic rings protons exhibited a doublet at d 6.84, d 6.95, d 7.84,
triplet at d 7.26, d 7.49, d 8.09 and multiplet in the region d 7.61-7.74 and d 8.22-8.26. No
trace of the other regioisomer 7a was observed. If the other regioisomer 7a had been
formed, the benzylic proton attached to the pyrrolidine ring would have appeared as a

2066
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
H
O
H
O
O
NH2
NH2
OH
OH
R
R
CH3
NH-CH2-COOH
NH2NH2.H2O
5
O
O
4
3
1a-e
2
MeOH
Reflux
N
R
N
N
R
N
N
N
N
N
HN
R
HN
R
O
O
O
O
7a-e
6a-e
X
R =
X = OMe (6a); H (6b); Cl (6c); Br (6d); F (6e)
Scheme 1. Synthesis of pyrazolo-1,4-dioxa-spiro[4,5]decane grafted spiro-indenoquinoxaline pyrroli-
dines 6a–e.
1
singlet in the H NMR spectrum of 7a and this was not observed (Scheme 1). The off-res-
onance proton decoupled 13C spectrum of 6a exhibited peaks at 34.63 and 39.04 ppm due
to the pyrrolidine NCH3 and NCH2 carbons.[21a] The two methoxy carbon resonated at
55.31 and 55.46 ppm. The two spirocarbon resonated at 73.26 and 78.18 ppm. The spiro
carbon of the dioxalane ring resonated at 108.33 ppm (Table 1).[24] The C ¼ NH carbon of
the indazole ring resonated at 155.92 ppm and the signals of all other carbons appeared at
appropriate chemical shifts in agreement with the proposed structure. The formation of the
product is confirmed by mass spectral and elemental analysis. The high-resolution mass
spectrum of 6a showed a molecular ion peak (Mþ) at 665.7738. The regiochemical out-
1
come of the cycloaddition is also confirmed by the H-NMR and single-crystal analysis of
one of the similar intermediate in the isatin series [24] (Fig. S5, Supplementary file).
Even with an excess of 1,3-dipole (generated from excess of ninhydrin 2, 1,2-phenyl-
enediamine 3, sarcosine 4) and prolonged reaction times as evidenced by thin-layer
chromatography (TLC), the reaction failed to proceed to give the bis-adduct 13a
(Scheme 2). Thus, the addition occurs at only one of the exocyclic double bonds. This
may be due to the steric hinderance of the spiro-indenoquinoxaline pyrrolidine ring
which prevents the attack of 1,3-dipole on the other exocyclic double bond. The forma-
tion of bis-adduct 13a was ruled out from the high-resolution mass spectrum analysis.

R
SYNTHETIC COMMUNICATIONSV
2067
NH2
NH2
O
CH3
NH-CH2-COOH
4
O
O
O
H3C
HO
O
O
N
OH
OH
OH
N
-H2O
H2O
3
O
N
CH3OH, Reflux
-2H2O
N
N
8
2
O
H3C
O
O
N
H3C
H2O
H3C
N
O-
H3C
N
O
N
-CO2
N
-H2O
O-
N
N
N
N
N
N
N
10
R
9
H
O
H
R
R
N
O
N
N
H
R
O
O
O
O
1a-e
11a-e
NH2NH2.H2O
5
H
R
N
N
N
O
R
R
N
N
N
O
R
N
N
O
O
N
N
HN
O
R
N
R
N
O
O
O
N
6a-e
12a-e
13 a-e
Scheme 2. Mechanism for the formation of the product 6a–e from azomethine ylide 10 and dipolaro-
phile 1a–c followed by annulation with hydrazine hydrate 5.
Table 1. 13C NMR values of spiro carbons.
S. no
C2 pyrrolidine ring
C3 pyrrolidine ring
Dioxalane ring
6a
6b
6c
6d
6e
73.26
72.81
72.84
72.56
72.44
78.18
78.09
78.12
78.16
78.12
108.33
107.79
108.00
107.34
108.20
In order to optimize and improve the yield of the product, the reaction was also car-
ried out in various other solvents (Table 2). The results showed that even under reflux-
ing condition for prolonged time in toluene (12 h), there was not much significant
increase in the isolated yield of product (23%). However, in refluxing methanol, better
chemical yield of the product was obtained (reaction time: 3.6 h.; isolated chemical yield:
79%) due to the better solubility of all the reactants favoring the easy formation of
azomethine ylide 10. Hence, methanol was chosen as solvent for invariably conducting
the one-pot sequential MCR with various other dipolarophiles (1b–e), ninhydrin 2,

2068
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
Table 2. Optimization of solvent effect on the model reaction involving dipolarophiles 1a, 1,2-
phenylenediamine 2, ninhydrin 3, sarcosine 4, and hydrazine hydrate 5.
b
Entry
Solvent
Time (h)
Yield (%)
c
1
2
3
4
5
6
Toluene
12
23
60
54
66
73
79
1,4-dioxane
Tetrahydrofuran
Acetonitrile
Ethanol
6.0
6.0
3.3
3.8
3.6
Methanol
(a) Reaction condition: 1a, 2, 3, 4, 5 (1 mmol) in solvent (20 mL) at reflux temperature; T(h): Time in hours, (b)Yield of
the isolated product in percentage, (c) The reaction was carried out using a Dean–Stark apparatus.
Table 3. One-pot sequential five-component reaction of dipolarophiles 1a–e, 1,2-phenylenediamine
2, ninhydrin 3, sarcosine 4, and hydrazine hydrate 5.
Methanol
T (h)
Entry
R
Reflux Y (%)
Melting point (oC)
6a
6b
6c
6d
6e
OMe
H
Cl
Br
F
3.6
3.4
3.3
3.5
3.0
79
83
86
84
88
197–200
188–190
166–167
158–159
174–175
T(h): time in hours, Y (%): yield of the product in percentage
1,2-phenylenediamine 3, sarcosine 4, and hydrazine hydrate 5 affording pyrazolo-1,4-
dioxa-spiro[4,5]decane grafted spiro-indenoquinoxaline pyrrolidines (6b–e) in good
yield (Table 3).
A sequential one-pot five-component is implemented in order to have the pyrazolo-
1,4-dioxa-spiro[4,5]decane and indenoquinoxaline moiety on the pyrrolidine platform.
When all the five components were added in one-pot and refluxed in methanol, mixture
of unidentified inseparable products was obtained. Alternatively, when changes in the
sequential addition were brought by the addition of hydrazine hydrate 5 with the dipo-
larophile 1a followed by the addition of ninhydrin 2 and 1,2-phenylenediammine 3, the
product 6a was formed in poor yield (20%). Hence, this methodology was abandoned.
Molecular mechanics (MM2)
Molecular mechanics or force-field method use classical type models to predict the
energy of a molecule as a function of its conformation. This allows predictions of equi-
librium geometries and transition states and also relative energies between conformers
or between different molecules. Molecular mechanics can be used to supply the poten-
tial energy for molecular dynamics computations on large molecules. In our study,
molecular mechanics (MM2) calculations have been carried out to rationalize the for-
mation of the spiroheterocyclic hybrid 6a–e.[25,26] The energy minimized structure is
expressed in kcal/mol. Through the MM2 calculations, it is observed that the total
energy of the product 6a–e formed, ranges from 63 to 81 kcal/mole (Fig. 2). Depending
upon the various substituents on the hybrid heterocycle, the total energy of the individ-
ual product is different. The total energy of the possible regioisomer 12a–e ranges from
74 to 90 kcal/mole (Fig. 3) whereas the total energy of the bis-cycloadduct 13a–e ranges
from 1010 to 1190 kcal/mole which is extremely large (Fig. 4). From the overall com-
parison of the total energy of the product formed 6a–e, its possible regioisomer 12a–e

R
SYNTHETIC COMMUNICATIONSV
2069
Figure 2. Energy minimized structure of the product 6a–e.
and the bis-cycloadduct 13a–e, it is evident that the expected product 6a–e formed has
minimum energy when compared to the 12a–e and 13a–e favoring its formation as
shown in Figs. 2–4, respectively.
Conclusion
In conclusion, we have synthesized a series of novel pyrazolo-1,4-dioxa-spiro[4,5]decane
grafted spiro-indenoquinoxaline pyrrolidines via a facile one-pot sequential five-component
reaction involving [3 þ 2]- cycloaddition reaction of azomethine ylides to various 7, 9-bis-

2070
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
Figure 3. Energy minimized structure of 12a–e.
[(E)-arylmethylidene]-1.4-dioxa-spiro[4,5]-decan-8-one derivatives followed by ring
annulation using hydrazine hydrate. The synthesized compounds carry diverse substitution
pattern by choice. This method offers several advantages including its operational simpli-
city, selectivity with enhanced reaction rate in a one-pot five-component approach, mild
reaction conditions, easy workup, affording the desired products from readily and cheaply
available starting materials in a single step. A theoretical approach is provided for the for-
mation of the product. The biological studies on these novel compounds are in progress
and will be published elsewhere. We believe that this methodology will be useful for mod-
ern drug discovery program involving MCRs.

R
SYNTHETIC COMMUNICATIONSV
2071
Figure 4. Energy minimized structure of 13a–e.
Experimental section
General considerations
All melting points are uncorrected. IR spectra were recorded on a SHIMADZU 8300
1
series FT-IR instrument. H NMR spectra were recorded in CDCl3 using TMS as an
internal standard on a BRUKER 300 spectrometer at 300 MHz. 13C NMR was recorded
on a BRUKER 300 spectrometer at 75 MHz. High-resolution mass spectra were recorded
on a JEOL-GC-MATE II mass spectrometer (70 Energy eV, Quadrapole double-focusing
mass analyzer with photomultiplier tube detector). Column chromatography was per-
formed on silica gel (ACME, 100–200 mesh). Solvents were reagent grade and were

2072
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
purified according to standard procedures. The starting materials cyclohexanone mono-
acetal ketal, benzaldehyde, and its derivatives, 1,2-phenylenediamine, ninhydrin, sarco-
sine, hydrazine hydrate were purchased commercially and used as such. Cyclohexanone
monoacetal ketal-based dipolarophiles were synthesized as per the literature
procedures.[27]
Representative procedure for the synthesis of pyrazolo-1,4-dioxa-spiro[4,5]decane
grafted trispiro-indenoquinoxaline pyrrolidine heterocycles 6a-e
A mixture of ninhydrin (1 mmol) and 1,2-phenylenediamine (1 mmol) was refluxed for
10 min in 10 ml of methanol followed by the addition of sarcosine (1 mmol). To this
mixture, a solution of dipolarophile 1a (1 mmol) in 10 ml of methanol was added. The
mixture was refluxed until completion of the reaction as evidenced by TLC in petrol-
eum ether-ethyl acetate mixture (3.5:1.5) and visualization was accomplished in an iod-
ine chamber. Then to the reaction mixture, hydrazine hydrate (1 mmol) was added and
refluxed for 1 h. After the completion of the reaction as evidenced by TLC, the solvent
was removed under reduced pressure and the crude product 6a was further purified by
column chromatography using petroleum ether-ethyl acetate mixture (4:1) as eluent.
Spectral data of the representative product
1-N-Methyl-spiro-[2.110]oxindole-spiro[3.700][300-(p-methoxyphenyl)]-1,4 -dioxospiro[400,500]
00 00
decane-D1 ,7 a-hexahydro-2H-indazole-4-(p-methoxyphenyl)-pyrrolidine 6a Color: green
(amorphous solid); IR (KBr): (ꢀC ¼ N) 1605, (ꢀNH) 3317 cmꢀ1
,
1H NMR (CDCl3/
1
300 MHz): H NMR (CDCl3/300 MHz): d 1.01–1.19 (m, 2H), 1.38–1.46 (m, 1H), 1.77 (s,
3H, -NCH3), 2.06–2.10 (m, 1H), 2.17–2.21 (m, 2H), 2.87 (q, J¼ 5.7 Hz, 1H), 3.00 (q,
J¼ 5.7 Hz, 1H), 3.19 (q, J¼ 6.0 Hz, 1H), 3.55 (t, J¼ 8.2 Hz, 1H), 3.79 (s, 3H, -OMe), 3.84
(s, 3H, -OMe), 4.14 (t, J¼ 10.0 Hz, 1H), 4.28 (d, J¼ 13.2 Hz, 1H), 5.14 (dd, J¼ 7.6 Hz,
3.3 Hz, 1H), 6.02 (bs, 1H, -NH), 6.84 (d, J¼ 8.4 Hz, 2H), 6.95 (d, J¼ 8.4 Hz, 2H), 7.26 (t,
J¼ 8.4 Hz, 2H), 7.49 (t, J¼ 7.3 Hz, 1H), 7.61–7.74 (m, 5H), 7.84 (d, J¼ 7.8 Hz, 1H), 8.09
(t, J¼ 4.9 Hz, 2H), 8.22–8.26 (m, 1H); 13C NMR (CDCl3/75 MHz): d 30.92, 34.63, 39.04,
40.42, 49.85, 52.02, 55.31, 55.46, 59.45, 63.64, 64.45, 73.26, 78.18, 108.33, 121.03, 128.39,
128.79, 128.84, 129.02, 129.24, 129.68, 131.32, 131.57, 132.07, 132.30, 139.30, 140.24,
141.20, 147.55, 155.92, 157.99, 158.52, 159.22, 163.91 ppm; HRMS calculated for
C41H39N5O4: 665.7738, Found: 665.7739 (Mþ).
Acknowledgments
Funding University Grants Commission (UGC) (No F.4-5/2018 (FRP-Start-up-Grant) (Cycle IV)
(BSR) dated June 2019. Author ARS thanks University Grants Commission (UGC) for the start-
up grant under UGC-Faculty Recharge Programme and DG thanks Vels University for the sup-
port and encouragement..

R
SYNTHETIC COMMUNICATIONSV
2073
References
[1] (a) Trost, B. M. The Atom Economy-a Search for Synthetic Efficiency. Science 1991, 254,
1471–1477. DOI: 10.1126/science.1962206. (b) Schreiber, S. L. Target-Oriented and
Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 287, 1964–1969.
DOI: 10.1126/science.287.5460.1964.(c) Trost, B. M. Atom Economy—a Challenge for
Organic Synthesis: Homogeneous Catalysis Leads the Way. Angew. Chem. Int. Ed. Engl.
1995, 34, 259–281. DOI: 10.1002/anie.199502591.
[2] (a) Bonne, D.; Dekhane, M.; Zhu, J.-P. Modulating the Reactivity of alpha-isocyanoace-
tates: multicomponent synthesis of 5-methoxyoxazoles and furopyrrolones. Angew. Chem.
Int. Ed. Engl. 2007, 46, 2485–2488. DOI: 10.1002/ange.200605005. DOI: 10.1002/anie.
€
200605005. (b) Domling, A.; Ugi, I. Ugi, I. Multicomponent Reactions with Isocyanides.
Angew. Chem. Int. Ed. 2000, 39, 3168–3210. DOI: 10.1002/1521-3773(20000915)
39:18<3168::AID-ANIE3168>3.0.CO;2-U.(c) Domling, A. Recent Developments in
Isocyanide Based Multicomponent Reactions in Applied Chemistry. Chem. Rev 2006, 106,
17–89. DOI: 10.1021/cr0505728.(d) Wang, Q.-F.; Hui, L.; Hou, H.; Yan, C.-G. Synthesis of
Zwitterionic Salts of Pyridinium-Meldrum Acid and Barbiturate through Unique Four-
component Reactions. J. Comb. Chem. 2010, 12, 260–265. DOI: 10.1021/cc900161z.(e)
Burke, M. D.; Schreiber, S. L. A. A Planning Strategy for Diversity-oriented Synthesis.
Angew. Chem. Int. Ed. Engl. 2004, 43, 46–58. DOI: 10.1002/anie.200300626.(f) Tan, D. S.
Diversity-Oriented Synthesis: Exploring the Intersections between Chemistry and Biology.
Nat. Chem. Biol. 2005, 1, 74–84. DOI: 10.1038/nchembio0705-74.
ꢀ
€
[3] (a) Graebin, C. S.; Ribeiro, F. V.; Rogerio, K. R.; Kummerle, A. E. Multicomponent
Reactions for the Synthesis of Bioactive Compounds: A Review. Curr. Org. Synth. 2019,
16, 855–869. DOI: 10.2174/1570179416666190718153703. (b) Cimarelli, C.
Multicomponent Reactions. Molecules 2019, 24, 2372. DOI: 10.3390/molecules24132372.(c)
Pavlinov, I.; Gerlach, E. M.; Aldrich, L. N. Next Generation Diversity-Oriented Synthesis:
A Paradigm Shift from Chemical Diversity to Biological Diversity. Org. Biomol. Chem.
2019, 17, 1608–1623. DOI: 10.1039/c8ob02327a.(d) Liu, T.; Jia, W.; Xi, Q.; Chen, Y.;
Wang, X.; Yin, D. Diversity-Oriented Synthesis of Heterocycles: Al(OTf)3-Promoted
Cascade Cyclization and Ionic Hydrogenation. J. Org. Chem. 2018, 83, 1387–1393. DOI:
10.1021/acs.joc.7b02894.(e) Guarnieri-Ibanez, A.; Medina, F.; Besnard, C.; Kidd, S. L.;
Spring, D. R.; Lacour, J. Diversity-Oriented Synthesis of Heterocycles and Macrocycles by
Controlled Reactions of Oxetanes with a-Iminocarbenes. Chem. Sci. 2017, 8, 5713–5720.
DOI: 10.1039/C7SC00964J.(f) Spandl, R. J.; Bender, A.; Spring, D. R. Diversity-Oriented
Synthesis; a Spectrum of Approaches and Results. Org. Biomol. Chem. 2008, 6, 1149–1158.
DOI: 10.1039/b719372f.(g) Spring, D. R. Diversity-Oriented Synthesis; a Challenge for
Synthetic Chemists. Org. Biomol. Chem. 2003, 1, 3867–3870. DOI: 10.1039/B310752N.(h)
Burke, M. D.; Berger, E. M.; Schreiber, S. L. Generating Diverse Skeletons of Small
Molecules Combinatorially. Science 2003, 302, 613–618. DOI: 10.1126/science.1089946.
[4] (a) Lledo, D.; Grindlay, G.; Sansano, J. M. 1,3-Dipolar Cycloadditions of Stabilized
Azomethine Ylides and Electrophilic Alkenes Mediated by a Recyclable TSILꢁAgOAc
Catalyst. Eur. J. Org. Chem. 2019, 25, 4095–4100. DOI: 10.1002/ejoc.201900724; (b)
Gulevskaya, A. V.; Nelina-Nemtseva, J. I. 1,3-Dipolar Cycloaddition Reactions of
Azomethine Ylides and Alkynes. Chem. Heterocycl. Comp. 2018, 54, 1084–1107. DOI: 10.
1007/s10593-019-02398-5.(c) Hashimoto, T.; Maruoka, K. Recent Advances of Catalytic
Asymmetric 1,3-Dipolar Cycloadditions. Chem. Rev. 2015, 115, 5366–5412. DOI: 10.1021/
cr5007182.(d) Pandey, G.; Banerjee, P.; Gadre, S. R. Construction of Enantiopure
Pyrrolidine Ring System via Asymmetric [3 þ 2]-Cycloaddition of Azomethine Ylides.
Chem. Rev. 2006, 106, 4484–4517. DOI: 10.1021/cr050011g.
[5] (a) O’Hagan, D. Pyrrole, Pyrrolidine, Pyridine, Piperidine, Andtropane Alkaloids. Nat.
Prod. Rep. 2000, 17, 435–446. DOI: 10.1039/a707613d. (b) Chupakhin, E.; Babich, O.;
Prosekov, A.; Asyakina, L.; Krasavin, M. Spirocyclic Motifs in Natural Products. Molecules
2019, 24, 4165. DOI: 10.3390/molecules24224165.

2074
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
[6] (a) Kumar, A.; Gupta, G.; Srivastava, S.; Bishnoi, A. J.; Saxena, R.; Kant, R.; Khanna, R. S.;
Maulik, P. R.; Dwivedi, A. Novel Diastereoselective Synthesis of Spiropyrrolidine-Oxindole
Derivatives as Anti-Breast Cancer Agents. RSC Adv. 2013, 3, 4731–4735. DOI: 10.1039/
c3ra21595d. (b) Abou-Gharbia, M. A.; Doukas, P. H. Synthesis of Tricyclic Aryl Spiro
Compounds as Potential Antileukemic and Anticonvulsant Agents. Heterocycles 1979, 12,
637–640. DOI: 10.3987/R-1979-05-0637.
[7] (a) Maurya, R. A.; Nayak, R.; Reddy, C. N.; Kapure, J. S.; Nanubolu, J. B.; Singarapu,
K. K.; Ajitha, M.; Kamal, A. Regio- and Stereoselective Synthesis of Novel
Spiropyrrolidines through 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides and
2-Styrylquinazolin-4(3H)-Ones. RSC Adv. 2014, 4, 32303–32311. DOI: 10.1039/
C4RA03508A. (b) Obniska, J.; Zagorska, A. Synthesis and Anticonvulsant Properties of
New N-[(4-Arylpiperazin-1-yl)-Methyl] Derivatives of 3-Aryl Pyrrolidine-2,5-Dione and 2-
Aza-Spiro[4.4]Nonane-1,3-Dione. Farmaco 2003, 58, 1227–1234. DOI: 10.1016/S0014-
827X(03)00187-3.
[8] (a) De Clercq, E. Antiviral Agents Active against Influenza a Viruses. Nat Rev Drug
Discov. 2006, 5, 1015–1025. DOI: 10.1038/nrd2175. (b) Stylianakis, I.; Kolocouris, A.;
Kolocouris, N.; Fytas, G.; Foscolos, G. B.; Padalko, E.; Neyts, J.; De Clercq, E.
Spiro[Pyrrolidine-2,20-Adamantanes]: Synthesis, Anti-Influenza Virus Activity and
Conformational Properties. Bioorg. Med. Chem. Lett. 2003, 13, 1699–1703. DOI: 10.1016/
S0960-894X(03)00231-2.
[9] (a) Buciova, L.; Cizmarik, J.; Sedlarova, E.; Racanska, E. Preparation, Local Anaesthetic
and Antiarrhythmic Activity of Pyrrolidinomethylcyclohexyl Esters of Alkoxysubstituted
Phenyl Carbamic Acids. Pharmazie 1995, 50, 566–567. (b) Kornet, M. J.; Thio, A. P.
Oxindole-3-Spiropyrrolidines and -Piperidines. Synthesis and Local Anesthetic Activity.
J. Med. Chem. 1976, 19, 892–898. DOI: 10.1021/jm00229a007.
[10] Hussein, E. M.; Abdel-Monem, M. I. Regioselective Synthesis and anti-Inflammatory
Activity of Novel Dispiro[Pyrazolidine-4,30-Pyrrolidine-20,300-Indoline]-200,3,5-Triones.
Arkivoc 2011, 2011, 85–98. DOI: 10.3998/ark.5550190.0012.a07.
[11] (a) Montana, M.; Montero, V.; Khoumeri, O.; Vanelle, P. Quinoxaline Derivatives as
Antiviral Agents. A Systematic Review. Molecules 2020, 25, 2784–2803. DOI: 10.3390/mol-
ecules25122784. (b) Janus, S. L.; Magdif, A. Z.; Erik, B. P.; Claus, N. Synthesis of
Triazenopyrazole Derivatives as Potential Inhibitors of HIV-1. Monatsh. Chem. 1999, 130,
1167–1173. DOI: 10.1007/PL00010295.(c) Singh Jadav, S.; Nayan Sinha, B.; Pastorino, B.;
de Lamballerie, X.; Hilgenfeld, R.; Jayaprakash, V. Identification of Pyrazole Derivative as
an Antiviral Agent against Chikungunya through HTVS. Lddd. 2015, 12, 292–301. DOI:
10.2174/1570180811666141001005402.
[12] (a) Kaushal, T.; Srivastava, G.; Sharma, A.; Negi, A. S. An Insight into Medicinal
Chemistry of Anticancer Quinoxalines. Bioorg. Med. Chem. 2019, 27, 16–35. DOI: 10.
1016/j.bmc.2018.11.021.; (b) Bennani, F. E.; Doudach, L.; Cherrah, Y.; Ramli, Y.;
Karrouchi, K.; Ansar, M.; Faouzi, M. E. Overview of Recent Developments of Pyrazole
Derivatives as an Anticancer Agent in Different Cell Line. Bioorg. Chem. 2020, 97,
103470–103470. DOI: 10.1016/j.bioorg.2019.103470.
[13] (a) Shen, Q.-K.; Gong, G.-H.; Li, G.; Jin, M.; Cao, L.-H.; Quan, Z.-S. Discovery and
Evaluation
of
Novel
Synthetic
5-Alkyl-4-Oxo-4,5-Dihydro-[1,2,4]Triazolo[4,3-
a]Quinoxaline-1-Carbox-Amide Derivatives as anti-Inflammatory Agents. J. Enzyme.
Inhib. Med. Chem. 2020, 35, 85–95. DOI: 10.1080/14756366.2019.1680658. (b) Bekhit, A.
A.; Hymete, A.; Bekhit, A. A.-D. A.; Damtew, A.; Aboul-Enein, H.-Y. Pyrazoles as
Promising Scaffold for the Synthesis of anti-Inflammatory and/or Antimicrobial Agent: A
Review. Mini Rev. Med. Chem. 2010, 10, 1014–1033. DOI: 10.2174/1389557511009011014.
ꢀ
DOI: 10.2174/1389557511009011014.;(c) Aran, V. J.; Ochoa, C.; Boiani, L.; Buccino, P.;
ꢀ
ꢀ
Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Montero, D.; Nogal, J. J.; Gomez-Barrio, A.; et al.
Synthesis and Biological Properties of New 5-Nitroindazole Derivatives. Bioorg. Med.
Chem. 2005, 13, 3197–3207. DOI: 10.1016/j.bmc.2005.02.043.(d) Hassan, G. S.; Rahman,
D. E. A.; Abdelmajeed, E. A.; Refaey, R. H.; Salem, M. A.; Nissan, Y. M. New Pyrazole

R
SYNTHETIC COMMUNICATIONSV
2075
Derivatives: Synthesis, anti-Inflammatory Activity, Cycloxygenase Inhibition Assay and
Evaluation of mPGES. Eur. J. Med. Chem. 2019, 171, 332–342. DOI: 10.1016/j.ejmech.
2019.03.052.
[14] (a) Wang, T.; Tang, Y.; Yang, Y.; An, Q.; Sang, Z.; Yang, T.; Liu, P.; Zhang, T.; Deng, Y.;
Luo, Y. Discovery of Novel anti-Tuberculosis Agents with Pyrrolo[1,2-a]Quinoxaline-
Based Scaffold. Bioorg. Med. Chem. Lett. 2018, 28, 2084–2090. DOI: 10.1016/j.bmcl.2018.
04.043.; (b) Pandit, U.; Dodiya, A. Synthesis and Antitubercular Activity of Novel
Pyrazole–Quinazolinone Hybrid Analogs. Med. Chem. Res. 2013, 22, 3364–3371. DOI: 10.
1007/s00044-012-0351-0.
^
[15] (a) Cogo, J.; Cantizani, J.; Cotillo, I.; Sangi, D. P.; Correa, A. G.; Ueda-Nakamura, T.;
ꢀ
Filho, B. P. D.; Martın, J. J.; Nakamura, C. V. Quinoxaline Derivatives as Potential
Antitrypanosomal and Antileishmanial Agents. Bioorg. Med. Chem. 2018, 26, 4065–4072.
DOI: 10.1016/j.bmc.2018.06.033.; (b) Razzaghi-Asl, N.; Sepehri, S.; Ebadi, A.; Karami, P.;
Nejatkhah, N.; Johari-Ahar, M. Insights into the Current Status of Privileged N-
Heterocycles as Antileishmanial Agents. Mol. Divers. 2020, 24, 525–569. DOI: 10.1007/
s11030-019-09953-4.
[16] (a) Kumar, G.; Tanwar, O.; Kumar, J.; Akhter, M.; Sharma, S.; Pillai, C. R.; Alam, M. M.;
Zama, M. S. Pyrazole-Pyrazoline as Promising Novel Antimalarial Agents: A Mechanistic
Study. Eur. J. Med. Chem. 2018, 149, 139–147. DOI: 10.1016/j.ejmech.2018.01.082. (b)
ꢀ
Bonilla-Ramirez, L.; Rios, A.; Quiliano, M.; Ramirez-Calderon, G.; Beltran-Hortelano, I.;
ꢀ
Franetich, J. F.; Corcuera, L.; Bordessoulles, M.; Vettorazzi, A.; Lopez de Cerain, A.; et al.
Novel Antimalarial Chloroquine- and Primaquine-Quinoxaline 1,4-di-N-Oxide Hybrids:
Design, Synthesis, Plasmodium Life Cycle Stage Profile, and Preliminary Toxicity Studies.
Eur. J. Med. Chem. 2018, 158, 68–81. DOI: 10.1016/j.ejmech.2018.08.063.
[17] (a) Gupta, D.; Radhakrishnan, M.; Thangaraj, D.; Kurhe, Y. Antidepressant and Anti-anx-
iety Like Effects of 4i (N-(3-chloro-2-methylphenyl) Quinoxalin-2-carboxamide), a Novel
5-HT3 Receptor Antagonist in Acute and Chronic Neurobehavioral Rodent Models. Eur.
J. Pharmacol. 2014, 735, 59–67. DOI: 10.1016/j.ejphar.2014.04.008. (b) Mohammed, A. A.;
Gamal, E. A. A.; Alaa, A. H. Synthesis of Novel Pyrazole Derivatives and Evaluation of
Their Antidepressant and Anticonvulsant Activities Euro. J. Med. Chem. 2009, 44,
3480–3487. DOI: 10.1016/j.ejmech.2009.01.032.
[18] Danylkova, N. O.; Alcala, S. R.; Pomeranz, H. D.; McLoon, L. K. Neuroprotective Effects
of Brimonidine Treatment in a Rodent Model of Ischemic Optic Neuropathy. Exp. Eye
Res. 2007, 84, 293–301. DOI: 10.1016/j.exer.2006.10.002.
[19] Mohanasundaram, U. M.; Chitkara, R.; Krishna, G. Smoking Cessation Therapy with
Varenicline. Int. J. Chron. Obstruct. Pulmon. Dis. 2008, 3, 239–251. DOI: 10.2147/copd.
s1848.
[20] (a) Gavaskar, D.; Suresh Babu, A. R.; Raghunathan, R.; Dharani, M.; Balasubramanian, S.
An Expedient Sequential One-Pot Four Component Synthesis of Novel Steroidal Spiro-
Pyrrolidine Heterocycles in Ionic Liquid. Steroids 2016, 109, 1–6. DOI: 10.1016/j.steroids.
2016.02.010. (b) Gavaskar, D.; Suresh Babu, A. R.; Raghunathan, R.; Dharani, M.;
Balasubramanian, S. Ionic Liquid Accelerated Multicomponent Sequential Assembly of
Ferrocene Grafted Spiro-Heterocycles. J. Organomet. Chem. 2014, 768, 128–135. DOI: 10.
1016/j.jorganchem.2014.06.015.(c) Babu, A. R. S.; Raghunathan, R.; Kumaresan, K.;
Raaman, N. Synthesis, Characterization and anti-Microbial Activity of Novel
Dispirooxindolopyrrolizidines. Curr. Chem. Biol. 2009, 3, 112–123. DOI: 10.2174/
2212796810903010112.(d) Suresh Babu, A. R.; Raghunathan, R.; Madhivanan, R.;
Ompraba, G.; Velmurugan, D. Raghu, R Synthesis, Characterization, anti-Microbial
Activity and Docking Studies of Novel Dispirooxindolopyrrolidines. Curr. Chem. Biol.
2008, 2, 312–320. DOI: 10.2174/187231308785739729.
[21] (a) Suresh Babu, A. R.; Gavaskar, D.; Raghunathan, R. An Expedient Ultrasonic Assisted
One-Pot Four Component Synthesis of Novel Ferrocene Grafted Pyrrolidine Heterocycles
via [3 þ 2]- Cycloaddition of Azomethine Ylides. J. Organomet. Chem. 2013, 745–746,
409–416. DOI: 10.1016/j.jorganchem.2013.08.014. (b) Sureshbabu, A. R.; Raghunathan, R.;

2076
G. DEIVASIGAMANI AND S. B. A. RAJUKRISHNAN
Satiskumar, B. K. A Facile Synthesis of Ferrocene Grafted N-Methyl-Spiropyrrolidines
through 1,3-Dipolar Cycloaddition of Azomethine Ylides. Tetrahedron Lett. 2009, 50,
2818–2821. DOI: 10.1016/j.tetlet.2009.03.175.(c) Suresh Babu, A. R.; Raghunathan, R.;
Baskaran, S. An Expedient Synthesis of Ferrocene Grafted Spirooxindolopyrrolizidines via
[3 þ 2]-Cycloaddition of Azomethine Ylides. Tetrahedron 2009, 65, 2239–2243. DOI: 10.
1016/j.tet.2009.01.044.
[22] Ghalib, R. M.; Hashim, R.; Sulaiman, O.; Hemamalini, M.; Fun, H. K. 11H-Indeno-[1,2-
b]Quinoxalin-11-One. Acta Cryst. 2010, E 66, o1494. DOI: 10.1107/s1600536810019252.
[23] Suresh Babu, A. R.; Gavaskar, D.; Raghunathan, R. A Facile Synthesis of Novel Ferrocene
Grafted Spiro-Indeoquinoxaline Pyrrolizidines via One Pot Multicomponent [3 þ 2]
Cycloaddition of Azomethine Ylide. Tetrahedron Lett. 2012, 53, 6676–6681. DOI: 10.1016/
j.tetlet.2012.09.104.
[24] Gavaskar, D.; Suresh Babu, A. R. An Easy Access to Highly Substituted
Trispiroheterocycles – Synthesis of Novel Pyrazolo-1,4-Dioxa-Spiro[4,5]Decane Grafted
Spiro-Oxindolopyrrolidines via a Sequential Multicomponent Reaction. Synth. Commun.
2021, 51, 1066–1075. DOI: 10.1080/00397911.2020.1866613.
[25] (a) Rappe, A. K.; Casewit, C. L. Molecular Mechanics across Chemistry; University Science
Books: Sausalito, CA, 1997. http://www.chm.colostate.edu/mmac; (b) Leach, A. R.
Molecular Modelling, Principles and Applications; chapter 3; Addison Wesley Longman:
Essex, 1996.;(c) Burkert, U.; Allinger, N. L. “Molecular Mechanics,” ACS Monograph 177;
American Chemical Society: Washington, DC, 1982.
[26] Almansour, A. I.; Arumugam, N.; Kumar, R. S. An Efficient, Sustainable Approach to the
Chemo and Regioselective Synthesis of Novel Spiroindenoquinoxaline Grafted Piperidone
Hybrid Heterocycles. J. King. Saud. Univ-Sci. 2020, 32, 3059–3064. DOI: 10.1016/j.jksus.
2020.08.013.
[27] Dimmock, J. R.; Padmanilayam, M. P.; Zello, G. A.; Nienaber, K. H.; Allen, T. M.; Santos,
C. L.; De Clercq, E.; Balzarini, J.; Manavathu, E. K.; Stables, J. P. Cytotoxic Analogues of
2,6-Bis(Arylidene)Cyclohexanones. Eur. J. Med. Chem. 2003, 38, 169–177. DOI: 10.1016/
s0223-5234(02)01444-7.