[Bmim]br accelerated one-pot three-component cascade protocol for the construction of spirooxindole?pyrrolidine heterocyclic hybrids

Article abstract of DOI:10.3390/molecules25204779

Our synthetic approach for the assembly of structurally complex spirooxindole heterocyclic hybrids was based on an ionic liquid, [bmim]Br mediated one-pot three-component cascade reaction strategy involving 1,3-dipolar cycloaddition reaction of N-1-(2-pyridinylmethyl)-3, 5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones and azomethine ylide generated in situ from isatin and L-phenyl alanine, affording a series of spirooxindole–pyrrolidine heterocyclic hybrids in good-to-excellent yields. In addition to serving as the reaction medium, [bmim]Br also functioned as a catalyst in this cycloaddition reaction and hence accelerated the reaction rate affording the cycloadducts in short reaction time.

Full text of DOI:10.3390/molecules25204779

molecules
Article
[
Bmim]Br Accelerated One-Pot Three-
Component Cascade Protocol for the Construction
of Spirooxindole–Pyrrolidine Heterocyclic Hybrids
1
,
1
1
Raju Suresh Kumar * , Dhaifallah M. Al-thamili , Abdulrahman I. Almansour ,
Natarajan Arumugam 1 and Necmi Dege 2
1
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia; daife54321@hotmail.com (D.M.A.-t.); almansor@ksu.edu.sa (A.I.A.);
anatarajan@ksu.edu.sa (N.A.)
Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayıs University, Samsun 55139, Turkey;
2
necmid@omu.edu.tr
*
Correspondence: sraju@ksu.edu.sa or drrajusureshkumar@gmail.com
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Antonio Massa
Received: 30 September 2020; Accepted: 13 October 2020; Published: 18 October 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Our synthetic approach for the assembly of structurally complex spirooxindole
heterocyclic hybrids was based on an ionic liquid, [bmim]Br mediated one-pot three-component
cascade reaction strategy involving 1,3-dipolar cycloaddition reaction of N-1-(2-pyridinylmethyl)-3,
5
-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones and azomethine ylide generated in situ from
isatin and L-phenyl alanine, affording a series of spirooxindole–pyrrolidine heterocyclic hybrids in
good-to-excellent yields. In addition to serving as the reaction medium, [bmim]Br also functioned
as a catalyst in this cycloaddition reaction and hence accelerated the reaction rate affording the
cycloadducts in short reaction time.
Keywords: one-pot cascade reactions; 1,3-dipolar cycloaddition; ionic liquid; selectivity;
spirooxindole–pyrrolidines
1
. Introduction
A swift construction of molecular complexity from easily available and simple starting precursors
advances the field of chemistry. One-pot multicomponent cascade reactions are highly effective and
prevailing protocols that incorporate multiple bond-forming events, thus constituting an attractive
division of organic chemistry and attaining great interest, as these reactions permit the construction
of molecules with noteworthy structural complexity from simple and easily available starting
materials [1–4]. These one-pot cascade reactions have advantages such as atom economy, operational
simplicity, and high reaction efficiency, in addition affording better overall yields when compared
with the classical single-step transformations [
of intermediates, consequently leading to reduction in pollution and, as a result, come under the
category of green chemistry [ ]. Specifically, these reactions are useful for the construction of vastly
5]. These reactions avoid the isolation and purification
6
functionalized and valuable building blocks comprising several stereogenic centers, and also for the
synthesis of biologically intriguing natural products and heterocyclic compounds.
1
,3-dipolar cycloaddition is a powerful synthetic approach for the formation of a variety of
heterocycles; this eco-compatible synthetic procedure has recently received a great deal of attention
and considerable progress has been achieved in this area [ ]. 1,3-dipolar cycloaddition reaction
7–9
of azomethine ylides with activated electron deficient alkenes offers a proficient methodology for
synthesizing pyrrolidine heterocyclic hybrids in a regio- and stereoselective fashion [10–12].
Molecules 2020, 25, 4779; doi:10.3390/molecules25204779
www.mdpi.com/journal/molecules

Molecules 2020, 25, 4779
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Ionic liquids play a most important role in advancing synthetic chemistry and in recent past years
have gained immense attention as green solvents, catalysts, and reagents due to their identifications
and tunable characteristics. Moreover, their high thermal and chemical stability, negligible vapor
pressure, good solvating ability, non-coordinating nature, and ease of recyclability make them a good
choice for diverse chemical reactions. It is noteworthy to mention that ionic liquids act both as solvents
and catalysts in diverse transformations [13–15].
The major advantage of spiroheterocycles is their inherent three-dimensional nature and associated
ability to project functionality in all three dimensions. Noteworthy interactions of a ligand with a
three-dimensional binding site can be achieved more easily with a spirocyclic core than with planar
aromatic systems [16]. Due to their wide occurrence in many natural products, highly functionalized
spirooxindole pyrrolidines have gained much importance and are the central skeleton for several
alkaloids and pharmacologically important compounds [17
in the synthesis of spiroheterocyclic hybrids derived through one-pot cascade reaction [19
,
18]. In recent years, we have been involved
23]. Herein,
–
we commence exploring the synthesis of structurally complex highly substituted pyrrolidines through
ionic liquid mediated cascade reaction and report the results in this article.
2
. Results and Discussion
The methodology for the synthesis of spirooxindole heterocyclic hybrids is based on a
one-pot three-component cascade reaction strategy employing N-1-(2-pyridinylmethyl)-3,5-bis[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones 5a , isatin 6, and L-proline involving a key
,3-dipolar cycloaddition reaction, as outlined in Scheme 1. The starting precursors 5a were
prepared as reported by us earlier [24] through the alkylation of compounds 3a with an equivalent
amount of 2-(chloromethyl)pyridine hydrochloride in the presence of K CO as shown in Scheme 1.
–
h
7
1
–h
–h
2
3,
To begin with the one-pot three-component cycloaddition reaction, primarily in order to optimize the
reaction conditions, a characteristic reaction was performed involving 5e, isatin 6, and l-phenylalanine
7
(
with different solvents viz. ethanol, methanol, dioxane, methanol:dioxane (1:1 v/v), and acetonitrile
Table 1). The reaction of isatin and L-phenylalanine via decarboxylative condensation afforded
the azomethine ylide which, in turn, added regioselectivity to 5e. In a representative reaction, an
equimolar mixture of 5e , and was dissolved in 5 mL of ethanol and heated under reflux with
6
7
,
6
7
constant stirring for 6 h. When all the starting substrates had been consumed completely, as obvious
from thin-layer chromatography (TLC) analysis, the reaction mixture was poured into ice cold water
(50 mL). The solid, thus precipitated, was filtered and washed with water to obtain 8e in 67% yield.
The reactions in methanol and dioxane afforded moderate and good yield (45 and 85%) of 8e, while the
product was obtained only in traces in acetonitrile. Among these solvents, the reaction in methanol
afforded a better yield of the product 8e (85%) when compared to other solvents. As the prime
objective in current organic synthesis is to develop new synthetic methods employing green solvents,
we planned to conduct the same reaction in an ionic liquid, [bmim]Br. As expected, an excellent yield
of 8e (92%) has been observed in [bmim]Br in a considerably shorter reaction time (1 h) (Scheme 1,
Table 1). Then, all other reactions employing dipolarophiles with different substitutions on the aryl
rings were executed with the ionic liquid. Good yields of the products were observed irrespective of
the substitutions on the aryl ring of 5.
A careful structural elucidation of the spirooxindole–pyrrolidine heterocyclic hybrids
was accomplished with the help of spectroscopic data considering a representative case, 8e
(
vide Supplementary Material). In the IR spectrum of 8e, the key infrared absorption peaks at
−
1
1
υmax 2359, 2342, 1713, and 1589 cm is referred to N-H, C=O, and C=C groups. In the H-NMR
spectrum, the H-4 proton appears as a doublet at 4.24 ppm (J = 11.0 Hz), while the H-5 proton appears
as a multiplet at 4.58–4.63 ppm. H-6 protons appear as doublet of doublets at 2.74 ppm (J = 14.5,
8
.0 Hz) and 3.04 ppm (J = 14.5, 2.5 Hz). C,H-COSY correlation of H-4, H-5 and H-6 protons assigns the
carbon signals at 54.44, 61.07, and 38.90 ppm to C-4, C-5, and C-6, respectively. The two doublets at
0
2
.08 and 3.61 ppm were due to the piperidone ring protons 2 -CH , whereas the other ring protons
2

Molecules 2020, 25, 4779
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0
(
6 -CH ) appeared as a doublet of doublets and a doublet at 2.92 ppm (J = 14.5, 2.5 Hz) and 3.41 ppm
2
(
7
J = 14.5 Hz). The doublets at 3.36 ppm (J = 13.0 Hz) and 3.79 ppm (J = 13.5Hz) were assigned to
0
-CH . From HMQC spectra, the carbon signals at 56.67, 53.94, and 63.70 ppm were assigned to
2
0
0
0
C-2 , C-6 , and C-7 , respectively. The carbonyl carbons of oxindole and piperidone rings appear at
1
1
13
80.33 ppm and 199.05 ppm. The selected H and C chemical shifts of 8e are shown in Figure 1.
The structure of other cycloadducts was also derived by similar considerations.
Scheme 1. Synthesis of spirooxindole–pyrrolidine heterocyclic hybrids 8a–h.
Table 1. Solvent optimization for the synthesis of spirooxindole–pyrrolidine heterocyclic hybrid 8e.
◦
Yield a (%)
Entry
Solvents
Temp ( C)
Time (h)
1
2
3
Ethanol
Methanol
Dioxane
80
70
100
6
2
10
67
85
45
Methanol:
Dioxane
Acetonitrile
4
100
10
51
5
6
80
100
10
1
Traces
92
[bmim]Br
a
Isolated yield.

Molecules 2020, 25, 4779
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Figure 1. Selected H and 13C-NMR chemical shifts of 8e.
1
The structure of one of the cycloadduct 8b was further confirmed by the single crystal X-ray
analysis (Figure 2) [25].
Figure 2. Oak Ridge Thermal Ellipsoid Plot (ORTEL) diagram of 8e.
A feasible mechanistic pathway for the assembly of spirooxindole–pyrrolidine hybrids 8a
shown in Scheme 2. Firstly, the reaction of isatin and L-phenylalanine affords the imine
the elimination of a molecule of water, and the hydrogen bonding interaction of [bmim]Br with the
carbonyl group of isatin facilitates the attack of -NH of L-phenylalanine. Again, the hydrogen bonding
–
h
is
6
7
9
via
2
interaction of [bmim]Br with the -C=O group of the cyclic intermediate 10 derived from
formation of azomethine ylide 11 via decarboxylation. The interaction of [bmim]Br with the carbonyl
group perhaps stimulates the exocyclic double bond, allowing the addition of azomethine ylide 11
and resulting in the construction of 8a . It is evident from Scheme 2 that the association of ionic
liquid with both the starting substrates and intermediates could be responsible for the rate acceleration
furnishing the heterocyclic hybrids 8a in excellent yields in a shorter reaction time. This one-pot
three-component cascade reaction progressed in a highly regio- and stereocontrolled fashion, affording
a sole diastereoisomer of the cycloadduct 8a . The spirooxindole–pyrrolidine heterocyclic hybrids
9 facilitates the
5
–
h
–
h
–h

Molecules 2020, 25, 4779
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were constructed via a route which involved the creation of two C-C and one C-N bonds with four
contiguous stereocenters.
Scheme 2. Feasible mechanistic pathway for the formation of spirooxindole–pyrrolidine hybrids 8a–h.
3
. Materials and Methods
The reagents and solvents employed in the existing study were got from commercial dealers.
All the reactions were observed by thin-layer chromatography (TLC) on silica gel. Melting points of the
synthesized compounds were measured using open capillary tubes and are uncorrected. NMR spectra
were recorded on a Jeol 500 MHz instrument (Tokyo, Japan) while the FT-IR spectra were documented
on a Perkin Elmer system 2000 FT-IR instrument (KBr) (Shelton, AL, USA). Mass spectra of these
compounds were measured on a DART-ToF-MS mass spectrometer (Jeol, MA, USA). Elemental analyses
of the synthesized compounds were done on a Perkin Elmer 2400 Series II Elemental CHNS analyzer
(Waltham, MA, USA).
0
0
General Procedure for the Synthesis of 4-(Aryl)-5-benzylpyrrolo(spiro [2.3”]oxindole)-spiro[3.3 ]-5 -
0
0
(
arylmethylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one 8a–h
An equimolar mixture of N-1-(2-pyridinylmethyl)-3,5-bis[(E)-arylmethylidene]tetrahydro-
4
(1H)-pyridinone
5
, isatin
6
, and phenylalanine
7
in 100 mg of [bmim]Br was heated with constant
◦
stirring at 100 C. Progress of this cycloaddition reaction was monitored after every 15 min time

Molecules 2020, 25, 4779
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interval, and TLC analysis of the reaction mixture revealed the complete disappearance of the starting
materials at 1 h of reaction time. Ethyl acetate (10 mL) was added to the reaction mixture, followed by
stirring for 15 min. The ethyl acetate layer was then washed with water (50 mL) and evaporated under
reduced pressure. The residue was dried in vacuo and purified by column chromatography, eluting
with a 6:4 petroleum ether–ethyl acetate mixture to afford the product 8 in good yield.
00 0 0 0
-Phenyl-5-benzylpyrrolo(spiro[2.3 ]-oxindole)-spiro-[3.3 ]-5 -(phenylmethylidene)-1 -N-
pyridinylmethyl)piperidin-4 -one (8a): Obtained as white solid (90%); mp = 98–100 C; IR (KBr):
4
0
◦
(
2
(
6
2
−
1
1
0
358, 2341, 1712, 1589 cm ; H-NMR (500 MHz, CDCl ):
δ
H
2.04 (d, 1H, J = 12.5 Hz, 2 -CH ), 2.75
3
2
0
dd, 1H, J = 14.5, 8.0 Hz, 6-CH ), 2.90 (dd, 1H, J = 14.0, 2.5 Hz, 6 -CH ), 3.03 (dd, 1H, J = 14.0, 3.0 Hz,
-CH ), 3.34 (d, 1H, J = 13.0 Hz, 7 -CH ), 3.40 (d, 1H, J = 14.0 Hz, 6 -CH ), 3.61(dd, 1H, J = 12.5, 2.0 Hz,
-CH ), 3.75 (d, 1H, J = 14.0 Hz, 7 -CH ) 4.26 (d, 1H, J = 11.0 Hz, 4-CH), 4.61–4.64 (m,1H, 5-CH), 6.56
2
2
0
0
2
2
2
0
0
2
2
(
(
d, 1H, J = 7.5 Hz, ArH), 6.86–7.04 (m, 8H, ArH), 7.15–7.25 (m, 10H, ArH), 7.32–7.46 (m, 4H, ArH), 7.88
s, 1H, NH), 8.40–8.42 (m, 1H, ArH). 13C-NMR (125 MHz, CDCl3):
δ
C
39.08, 53.80, 54.78, 56.73, 61.10,
63.58, 67.86, 71.95, 109.06, 122.04, 122.17, 123.26, 126.35, 126.73, 127.04, 128.25, 128.42, 128.56, 128.69,
1
28.90, 129.23, 129.45, 129.87, 130.01, 133.18, 134.93, 136.28, 137.30, 137.72, 138.46, 141.44, 149.01, 157.45,
+
1
80.38, 199.19. Mass: 617 [M ]. Anal. calc. for C H N O : C, 79.84; H, 5.88; N, 9.08. Found: C, 79.95;
41
36
4
2
H, 5.72; N, 9.21%.
0 0
-(2-Methylphenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(2-methylphenyl-
4
0
0
methylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8b): Obtained as white solid (90%); mp =
◦
−1
1
1
08–111 C; IR (KBr): 2357, 2338, 1710, 1588 cm ; H-NMR (500 MHz, CDCl ):
δ
H
2.02 (d, 1H, J = 12.5
3
0
Hz, 2 -CH ), 2.09 (s, 3H, CH ), 2.27 (s, 3H, CH ), 2.78 (dd, 1H, J = 13.5, 8.0 Hz, 6-CH ), 2.85 (dd, 1H, J =
2
3
3
2
0
0
0
1
1
1
5.0, 2.5 Hz, 6 -CH ), 2.95 (dd, 1H, J = 14.0, 4.0 Hz, 6-CH ), 3.19–3.24 (m, 2H, 7 -CH , 6 -CH ), 3.44 (d,
H, J = 12.5 Hz, 2 -CH ), 3.60 (d, 1H, J = 14.0 Hz, 7 -CH ), 4.44 (d, 1H, J = 9.5 Hz, 4-CH), 4.76–4.81 (m,
2
2
2
2
0
0
2
2
H, 5-CH), 6.64 (d, 2H, J = 8.0 Hz, ArH), 6.78 (d, 1H, J = 8.0 Hz, ArH), 6.86–6.93 (m, 2H, ArH), 6.97–7.27
(
m, 13H, ArH), 7.37–7.40 (m, 1H, ArH), 7.50 (s, 1H, ArH), 7.82 (d, 1H, J = 7.5 Hz, ArH), 7.95 (s, 1H,
NH), 8.35–8.37 (m, 1H, ArH). 13C-NMR (125 MHz, CDCl3):
δ
C
20.08, 21.30, 39.78, 51.99, 54.55, 58.33,
63.30, 64.22, 65.50, 73.60, 109.24, 122.05, 122.38, 122.64, 125.52, 126.11, 126.23, 126.72, 126.85, 128.23,
1
1
6
28.35, 128.51, 128.75, 129.15, 129.20, 130.15, 130.42, 132.51, 134.02, 136.16, 136.64, 137.36, 137.84, 138.13,
+
38.92, 141.85, 148.98, 157.69, 178.88, 199.49. Mass: 645 [M ]. Anal. calc. for C H N O : C, 80.10; H,
43
40
4
2
.25; N, 8.69. Found: C, 80.29; H, 6.33; N, 8.55%.
0
0
4
-(2-Methoxyphenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(2-methoxy-
0
0
phenylmethylidene) 1 -N-(pyridinylmethyl)piperidin-4 -one (8c): Obtained as reddish brown
solid (84%); mp = 90–93 C; IR (KBr): 2358, 2341, 1710, 1587 cm ; H-NMR (500 MHz, CDCl ):
◦
−1
1
δ
H
3
0
2
.06 (d, 1H, J = 12.5 Hz, 2 -CH ), 2.81 (dd, 1H, J = 13.0, 8.0 Hz, 6-CH ), 2.87 (dd, 1H, J = 14.0, 2.5 Hz,
2
2
0
0
6
-CH ), 2.97 (dd, 1H, J = 14.0, 4.0 Hz, 6-CH ), 3.35–3.44 (m, 1H, 7 -CH ), 3.46 (s, 3H, OCH ), 3.49–3.57
2
2
2
3
0 0 0
m, 1H, 6 -CH ), 3.70 (s, 3H, OCH ), 3.74 (d, 1H, J = 12.5 Hz, 2 -CH ), 3.83 (d, 1H, J = 13.5 Hz, 7 -CH ),
2 3 2 2
(
4
.04 (d, 1H, J = 9.0 Hz, 4-CH), 4.70–4.80 (m,1H, 5-CH), 6.64 (d, 2H, J = 7.5 Hz, ArH), 6.80 (d, 1H, J = 8.0
Hz, ArH), 6.89–6.98 (m, 2H, ArH), 7.00–7.43 (m, 14H, ArH), 7.53 (s, 1H, ArH), 7.84 (d, 1H, J = 7.0 Hz,
ArH), 7.96 (s, 1H, NH), 8.38–8.41 (m, 1H, ArH). 13C-NMR (125 MHz, CDCl3):
δ
C
39.81, 52.03, 54.72,
5
5.41, 55.89, 58.51, 63.43, 64.31, 66.02, 73.64, 109.30, 122.36, 122.71, 122.85, 125.53, 126.07, 126.32, 127.12,
1
1
7
27.56, 128.34, 128.55, 128.91, 128.97, 129.61, 130.25, 130.44, 132.63, 134.12, 136.13, 136.42, 137.43, 140.56,
+
41.73, 148.99, 157.72, 158.10, 160.95, 178.97, 199.55. Mass: 677 [M ]. Anal. calc. for C H N O : C,
43
40
4
4
6.31; H, 5.96; N, 8.28. Found: C, 76.42; H, 5.80; N, 8.39%.
-(3-Nitrophenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(3-nitrophenyl
0
0
4
0
0
methylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8d): Obtained as white solid (88%);
mp = 100–103 C; IR (KBr): 2360, 2341, 1711, 1587 cm ; H-NMR (500 MHz, CDCl ):
◦
−1
1
δ 1.96 (d, 1H, J
H
3
0 0 0
12.0 Hz, 2 -CH ), 2.87–2.97 (m, 3H, 6-CH , 6 -CH ), 3.29 (d, 1H, J = 15.0 Hz, 7 -CH ), 3.34 (d, 1H, J =
2 2 2 2
=
0 0 0
3.0 Hz, 6 -CH ), 3.58 (d, 1H, J = 13.0 Hz, 2 -CH ), 3.73 (d, 1H, J = 13.0 Hz, 7 -CH ), 4.33 (d, 1H, J = 11.0
2 2 2
1
Hz, 4-CH), 4.66–4.70 (m, 1H, 5-CH), 6.64 (d, 1H, J = 7.5 Hz, ArH), 6.89–7.18 (m, 11H, ArH), 7.31–7.68
13
(
m, 6H, ArH), 7.81 (s, 1H, NH), 8.01–8.21 (m, 3H, ArH), 8.43–8.51 (m, 1H, ArH). C-NMR (125 MHz,

Molecules 2020, 25, 4779
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CDCl3):
δ 39.77, 53.34, 54.40, 56.30, 61.91, 63.20, 67.80, 71.81, 109.47, 122.17, 122.50, 122.66, 123.25,
C
1
1
23.35, 123.60, 123.67, 124.09, 124.54, 126.54, 126.64, 128.47, 129.32, 129.76, 134.21, 134.42, 135.26, 135.37,
35.97, 136.32, 136.48, 136.61, 137.72, 140.02, 141.69, 148.42, 149.29, 156.51, 179.96, 198.52. Mass: 707
+
[M ]. Anal. calc. for C H N O : C, 69.68; H, 4.85; N, 11.89. Found: C, 69.80; H, 4.94; N, 11.72%.
41 34 6 6
0 0
-(4-Methylphenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(4-methylphenyl-
4
0
0
methylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8e): Obtained as white solid (92%); mp = 95–98
◦
−1
1
C; IR (KBr): 2359, 2342, 1713, 1589 cm ; H-NMR (500 MHz, CDCl ):
δ 2.08 (d, 1H, J = 12.5 Hz,
H
3
0
2
-CH ), 2.26 (s, 3H, CH ), 2.36 (s, 3H, CH ), 2.74 (dd, 1H, J = 14.5, 8.0 Hz, 6-CH ), 2.92 (dd, 1H, J =
2 3 3 2
0
0
1
1
1
4.5, 2.5 Hz, 6 -CH ), 3.04 (dd, 1H, J = 14.5, 2.5 Hz, 6-CH ), 3.36 (d, 1H, J = 13.0Hz, 7 -CH ), 3.41 (d,
2
2
2
0
0
0
H, J = 14.5 Hz, 6 -CH ), 3.61(d, 1H, J = 12.5 Hz, 2 -CH ), 3.79 (d, 1H, J = 13.5Hz, 7 -CH ), 4.24 (d,
2
2
2
H, J = 11.0 Hz, 4-CH), 4.58–4.63 (m,1H, 5-CH), 6.55 (d, 1H, J = 8.0 Hz, ArH), 6.81 (d, 2H, J = 8.0 Hz,
ArH), 6.86–7.24 (m, 14H, ArH), 7.32 (d, 2H, J = 7.5 Hz, ArH), 7.46–7.49 (m, 1H, ArH), 7.68 (s, 1H, NH),
8
6
.44–8.46 (m, 1H, ArH). 13C-NMR (125 MHz, CDCl3):
3.70, 67.50, 71.94, 108.91, 121.89, 122.03, 123.12, 126.19, 126.58, 128.28, 128.71, 128.95, 129.17, 129.33,
δ 21.11, 21.28, 38.90, 53.94, 54.44, 56.67, 61.07,
C
1
1
29.60, 129.74, 130.14, 131.97, 132.03, 132.10, 134.49, 136.19, 136.45, 137.33, 138.48, 138.98, 141.30, 148.90,
+
57.48, 180.33, 199.05. Mass: 660 [M ]. Anal. calc. for C H N O : C, 80.10; H, 6.25; N, 8.69. Found:
43
40
4
2
C, 80.23; H, 6.17; N, 8.81%.
0 0
-(4-Chlorophenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(4-chlorophenyl-
methylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8f): Obtained as yellow solid (87%);
4
0
0
◦
−1
1
mp = 93–96 C; IR (KBr): 2359, 2340, 1712, 1588 cm ; H-NMR (500 MHz, CDCl ):
δ
1.99 (d, 1H, J =
3
H
0
0
1
1
3
2.5 Hz, 2 -CH ), 2.75 (dd, 1H, J = 14.5, 8.0 Hz, 6-CH ), 2.88 (dd, 1H, J = 14.5, 2.5 Hz, 6 -CH ), 2.98 (dd,
H, J = 14.5, 3.5 Hz, 6-CH ), 3.32–3.37 (m, 2H, 6 -CH , 7 -CH ), 3.57 (dd, 1H, J = 13.0, 2.5 Hz, 2 -CH ),
.76 (d, 1H, J = 13.0 Hz, 7 -CH ), 4.21 (d, 1H, J = 11.0 Hz, 4-CH), 4.54–4.59 (m, 1H, 5-CH), 6.55 (d, 1H, J
2
2
2
0
0
0
2
0
2
2
2
2
=
8.5 Hz, ArH), 6.78–6.89 (m, 5H, ArH), 6.97–7.38 (m, 14H, ArH), 7.48–7.52 (m, 1H, ArH), 7.63 (s, 1H,
NH), 8.45–8.46 (m, 1H, ArH). 13C-NMR (125 MHz, CDCl3):
δ
C
39.16, 53.67, 53.93, 56.63, 61.30, 63.54,
67.75, 71.81, 109.10, 122.02, 122.34, 123.30, 126.45, 126.69, 128.45, 128.57, 128.72, 128.99, 129.39, 131.19,
1
32.88, 133.23, 133.46, 136.01, 136.31, 138.10, 138.45, 141.43, 149.24, 157.21, 180.09, 198.85. Mass: 685
+
[M ]. Anal. calc. for C H Cl N O : C, 71.82; H, 5.00; N, 8.17. Found: C, 71.74; H, 5.12; N, 8.26%.
41 34 2 4 2
0 0
-(4-Fluorophenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(4-fluorophenyl-
4
0
0
methylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8g): Obtained as white solid (89%);
mp = 98–101 C; IR (KBr): 2357, 2339, 1712, 1588 cm ; H-NMR (500 MHz, CDCl ):
◦
−1
1
δ
H
2.00 (d, 1H, J =
3
0
0
13.0 Hz, 2 -CH ), 2.76 (dd, 1H, J = 14.0, 7.5 Hz, 6-CH ), 2.89 (dd, 1H, J = 15.0, 3.0 Hz, 6 -CH ), 2.99
2
2
0
2
0
(dd, 1H, J = 14.0, 3.5 Hz, 6-CH ), 3.32–3.36 (m, 2H, 6 -CH , 7 -CH ), 3.56 (dd, 1H, J = 12.5, 2.0 Hz,
2
2
2
0
0
2
-CH ), 3.75 (d, 1H, J = 13.0 Hz, 7 -CH ), 4.22 (d, 1H, J = 11.0 Hz, 4-CH), 4.54–4.59 (m, 1H, 5-CH), 6.55
2
2
(
7
(
d, 1H, J = 8.0 Hz, ArH), 6.85–6.92 (m, 8H, ArH), 6.97–7.10 (m, 5H, ArH), 7.14–7.22 (m, 4H, ArH),
.36–7.40 (m, 2H, ArH), 7.45–7.49 (m,1H, ArH), 7.73 (s, 1H, NH), 8.43–8.44 (m, 1H, ArH). 13C-NMR
125 MHz, CDCl3): 39.20, 53.71, 54.03, 56.64, 61.43, 63.57, 67.62, 71.90, 109.08, 115.30, 115.47, 122.02,
δ
C
1
1
22.28, 123.27, 126.42, 126.68, 128.43, 128.94, 129.10, 129.39, 130.10, 131.91, 131.97, 133.05, 133.60, 136.22,
36.27, 138.27, 141.51, 149.16, 157.28, 160.20, 161.20, 180.33, 199.08. Mass: 653 [M ]. Anal. calc. for
+
C H F N O : C, 75.44; H, 5.25; N, 8.58. Found: C, 75.58; H, 5.36; N, 8.49%.
4
1
34
2
4
2
0 0
4-(2,4-Dichlorophenyl)-5-benzylpyrrolo(spiro[2.3”]oxindole)spiro[3.3 ]-5 -(2,4-dichloro-
0
0
phenylmethylidene)-1 -N-(pyridinylmethyl)piperidin-4 -one (8h): Obtained as yellow solid
◦ −1
88%); mp = 103–106 C; IR (KBr): 2358, 2341, 1711, 1588 cm ; H-NMR (500 MHz, CDCl ): δ 2.11 (d,
3 H
1
(
1
1
0 0
H, J = 12.5 Hz, 2 -CH ), 2.87–2.91 (m, 1H, 6-CH ), 2.94–3.00 (m, 2H, 6 -CH , 6-CH ), 3.09 (d, 1H, J =
2 2 2 2
0
0
0
2.5 Hz, 7 -CH ), 3.15 (d, 1H, J = 15.0 Hz, 6 -CH ), 3.23 (d, 1H, J = 13.0 Hz, 2 -CH ), 3.54 (d, 1H, J = 14.0
Hz, 7 -CH ) 4.58 (d, 1H, J = 9.5 Hz, 4-CH), 4.68–4.73 (m,1H, 5-CH), 6.63–6.65 (m, 2H, ArH), 6.73 (d, 1H,
2
2
2
0
2
J = 8.5 Hz, ArH), 6.86–7.42 (m, 14H, ArH), 7.67 (s, 1H, NH), 7.82–7.85 (m, 2H, ArH), 8.37–8.38 (m, 1H,
ArH). 13C-NMR (125 MHz, CDCl3):
δ 40.41, 52.79, 54.61, 57.79, 63.62, 64.40, 64.68, 74.50, 109.36, 122.22,
C
122.40, 122.87, 126.33, 126.62, 126.82, 127.10, 127.41, 128.32, 128.87, 128.95, 129.07, 129.80, 130.48, 131.72,

Molecules 2020, 25, 4779
8 of 9
1
7
32.98, 133.69, 133.99, 135.23, 135.93, 136.30, 136.61, 138.21, 141.64, 149.08, 157.39, 177.86, 198.72. Mass:
+
55 [M ]. Anal. calc. for C H Cl N O : C, 65.26; H, 4.27; N, 7.43. Found: C, 65.41; H, 4.38; N, 7.51%.
41
32
4
4
2
4
. Conclusions
In conclusion, we have constructed a series of novel spirooxindole–pyrrolidine heterocyclic
hybrids employing an ionic liquid accelerated one-pot three-component cascade reaction protocol
involving a key 1,3-dipolar cycloaddition reaction. Azomethine ylide generated in situ from isatin and
phenylalanine reacted with a new class of functionalized dipolarophiles affording the cycloadducts.
The ionic liquid served both as the reaction medium and catalyst and thus accelerated the reaction rate,
affording good yields of the products. The structural elucidation of these compounds was done by
NMR spectroscopy and mass spectrometric data and further confirmed by X-ray diffraction analysis.
Investigation of anticancer potential of these structurally intriguing spiroheterocycles will be the subject
of our future research.
Supplementary Materials: The following are available online. Figures S1–S7: NMR and FT-IR spectra of a
representative compound.
Author Contributions: Conceptualization, R.S.K.; investigation, D.M.A.-t., R.S.K., A.I.A., N.A., and N.D.; writing
original draft preparation, R.S.K.; supervision, R.S.K. and A.I.A.; funding acquisition, A.I.A. All authors have read
and agreed to the published version of the manuscript.
Funding: The project was supported by Researchers Supporting Project number (RSP-2020/231), King Saud
University, Riyadh, Saudi Arabia.
Conflicts of Interest: Authors declare no conflict of interests.
References
1
.
Guo, H.C.; Ma, J.A. Catalytic asymmetric tandem transformations triggered by conjugate additions.
Angew. Chem. Int. Ed. 2006, 45, 354–366. [CrossRef] [PubMed]
2
.
Volla, C.M.R.; Atodiresei, I.; Rueping, M. Catalytic C-C bond-forming multi-component cascade or domino
reactions: Pushing the boundaries of complexity in asymmetric organocatalysis. Chem. Rev. 2014, 114,
2
390–2431. [CrossRef] [PubMed]
Zhu, C.; Ma, S. Efficient carbazole synthesis via Pd/Cu-cocatalyzed cross-coupling/isomerization of
-allyl-3-iodoindoles and terminal alkynes. Org. Lett. 2014, 16, 1542–1545. [CrossRef]
3
.
.
2
4
Kanbayashi, N.; Takenaka, K.; Okamura, T.; Onitsuka, K. Asymmetric auto-tandem catalysis with a
planar-chiral ruthenium complex: Sequential allylic amidation and atom-transfer radical cyclization.
Angew. Chem. Int. Ed. 2013, 52, 4897–4901. [CrossRef] [PubMed]
5
6
.
.
Tietze, L.F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2
006; p. 672.
Sheldon, R.A. Fundamentals of green chemistry: Efficiency in reaction design. Chem. Soc. Rev. 2012, 41,
437–1451. [CrossRef]
1
7
8
.
.
Kobayashi, S.; Jorgensen, A.K. Cycloaddition Reactions in Organic Synthesis; Wiley: Weinheim, Germany, 2002.
Kanagaraju, G.; Thangamani, A. Design and synthesis of spiro derivatives containing a thiophene ring and
evaluation of their anti-microbial activity. Orient. J. Chem. 2014, 30, 1619–1630. [CrossRef]
9
.
Dhanalakshmi,
One-pot chemo/regio/stereoselective
spiro-oxindoles/pyrrolizines/-pyrrolidines from
3705–33719. [CrossRef]
P.;
Sriram
Babu,
S.;
generation
-aroylidineketene dithioacetals. RSC Adv. 2015, 5,
Thimmarayaperumal,
S.;
Shanmugam,
of functionalized
S.
of library
a
α
3
1
1
0. Ahrendt, K.A.; Williams, R.M. A concise asymmetric synthesis of the ADE fragment of nakadomarin A.
Org. Lett. 2004, 6, 4539–4541. [CrossRef] [PubMed]
1. Boruah, M.; Konwar, D.; Sharma, S.D. KF/Al O mediated 1,3-dipolar cycloaddition of azomethine ylides:
2
3
A novel and convenient procedure for the synthesis of highly substituted pyrrolidines. Tetrahedron Lett.
007, 48, 4535–4537. [CrossRef]
2. Pandey, G.; Banerjee, P.; Gadre, S.R. Construction of enantiopure pyrrolidine ring system via asymmetric
3+2]-cycloaddition of azomethine ylides. Chem. Rev. 2006, 106, 4484–4517. [CrossRef]
2
1
[

Molecules 2020, 25, 4779
9 of 9
1
1
3. Zhang, Z.C. Catalysis in Ionic Liquids. Adv. Catal. 2006, 49, 153–237. [CrossRef]
4. Plechkova, N.V.; Seddon, K.R. Application of ionic liquids in the chemical industry. Chem. Soc. Rev. 2008, 37,
23–150. [CrossRef]
5. Greaves, T.L.; Drummond, C.J. Protic ionic liquids: Properties and application. Chem Rev. 2008, 108, 206–237.
CrossRef]
1
1
1
1
[
6. Carreira, E.M.; Fessard, T.C. Four-membered ring-containing spirocycles: Synthetic strategies and
opportunities. Chem. Rev. 2014, 114, 8257–8322. [CrossRef] [PubMed]
7. Daly, J.W.; Spande, T.F.; Whittaker, N.; Hignet, R.J.; Feigl, D.; Nishimori, N.; Tokuyama, T.;
Myers, C.W. Alkaloids from dendrobatid frogs: Structures of two omega-hydroxy congeners of
3-butyl-5-propylindolizidine and occurrence of 2,5-disubstituted pyrrolidines and a 2,6-disubstituted
piperidine. J. Nat. Prod. 1986, 49, 265–280. [CrossRef]
1
1
2
8. Hilton, S.T.; Ho, T.C.T.; Pljevaljcic, G.; Jones, K. A new route to spirooxindoles. Org. Lett. 2000, 2, 2639–2641.
[CrossRef] [PubMed]
9. Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Kotresha, D.; Balakrishna, J.P. Caspase dependent apoptotic
activity of polycyclic cage-like heterocyclic hybrids. Saudi J. Biol. Sci. 2020, in press. [CrossRef]
0. Kumar, R.S.; Almansour, A.I.; Arumugam, N. In vitro mechanistic investigation of polycyclic cage-like
heterocyclic hybrid possessing diverse pharmacophoric units. J. King Saud Univ. Sci. 2020, 32, 2406–2413.
[CrossRef]
2
2
2
1. Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Mohammad, F.; Kotresha, D.; Menendez, J.C.
Spirooxindole-pyrrolidine heterocyclic hybrids promotes apoptosis through activation of caspase-3.
Bioorg. Med. Chem. 2019, 27, 2487–2498. [CrossRef]
2. Kumar, R.S.; Almansour, A.I.; Arumugam, N.; Periyasami, G.; Athimoolam, S.; Ranjith Kumar, R.;
Asad, M.; Asiri, A.M. Dipolar cycloaddition based multi-component reaction: Synthesis of spiro tethered
acenaphthylene–indolizine–pyridinone hybrids. Tetrahedron Lett. 2018, 59, 3336–3340. [CrossRef]
3. Almansour, A.I.; Kumar, R.S.; Beevi, F.; Shirazi, A.N.; Osman, H.; Ismail, R.; Choon, T.S.; Sullivan, B.;
McCaffery, K.; Nahhas, A.; et al. Facile, Regio- and Diastereoselective Synthesis of Spiro-Pyrrolidine and
Pyrrolizine Derivatives and Evaluation of Their Antiproliferative Activities. Molecules 2014, 19, 10033–10055.
[CrossRef] [PubMed]
2
2
4. Al-thamili, D.M.; Almansour, A.I.; Arumugam, N.; Mohammad, F.; Kumar, R.S. Functionalized
N-Pyridinylmethyl Engrafted Bisarylmethylidenepyridinones as Anticancer Agents. Processes 2020, 8, 1154.
[CrossRef]
5. Crystallographic Data for 8b has been Deposited with the Cambridge Crystallographic Data Centre as
Supplementary Publication Number CCDC 1991074. Available online: http://www.ccdc.cam.ac.uk/conts/
retrieving.html (accessed on 17 March 2020).
Sample Availability: Samples of the compounds 8a–h are available from the authors.
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(