Microwave Assisted Neat Synthesis of Spiropyrrolidine Library

Article abstract of DOI:10.1002/jhet.3247

A new class of functionalized nitrothiophene containing spirropyrrolidines has been synthesized with high regioselectivity in moderate to excellent yields via microwave assisted solvent-free-three component 1,3-dipolar cycloaddition reaction of in situ ge

Full text of DOI:10.1002/jhet.3247

Month 2018
Microwave Assisted Neat Synthesis of Spiropyrrolidine Library
*
Balakrishna Kalluraya,
Sahana Mallya, and Anish Kumar K
Department of Studies in Chemistry, Mangalore University, Mangalagangothri 574199, Karnataka, India
*
E-mail: bkalluraya@gmail.com
Received March 8, 2018
DOI 10.1002/jhet.3247
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A new class of functionalized nitrothiophene containing spirropyrrolidines has been synthesized with high
regioselectivity in moderate to excellent yields via microwave assisted solvent-free-three component 1,3-
dipolar cycloaddition reaction of in situ generated azomethineylides with various substituted chalcones as
dipolarophiles. The structures of the newly synthesized compounds were established by analytical and spec-
tral analysis. The product yields were slightly improved and reaction times were reduced to a great extent
under microwave condition.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
spiropyrrolidines, nitrothiophene ring systems are also
important class of biologically active ring systems.
Organic reactions under solvent-free conditions have
considerable attraction because of its environmental
benign nature, no solvent consumption and easy work up
procedure [1]. These natures made it important in both
industry and academics. Expectations of an organic
chemist in his reaction are simplicity, selectivity, and less
reaction time. Microwave assisted synthesis has mostly
fulfilled these expectations [1].
Azomethineylides are one of the important dipole,
which reacts with olefins to give pyrrolidine derivatives
[2–6]. Because of its significant pharmacological and
biological activities, spiropyrrolidine derivatives are
found in many natural products and synthetic medicines
[7–17]. Spirotryprostatin B and Gelsemine are the
representative examples for the natural products
containing spiropyrrolidine skeleton. Spirotryprostatin B
is an indole alkaloid found in the Aspergillusfumigatus
fungus. It has great importance as anti-cancer drug [18].
Gelsemine, apart from its toxicity, recent research
showed that its derivatization may offer drugs for the
treatment of xenobiotic-induced or diet-induced oxidative
stress. It is an indole alkaloid isolated from flowering
plants of the genus Gelsemium [19]. In addition to
In continuation of our research on the synthesis of
biologically active heterocycles and in view of the study
of effect of electronegative nitro group on the
regiochemistry of the cycloadducts formed [20–22],
herein, we report the microwave assisted solvent free one
pot three component regioselective and stereoselective
synthesis
of
novel
nitrothiophene
substituted
spiropyrrolidines through [3 + 2] cycloaddition reaction
of azomethineylide generated in situ from ninhydrin and
sarcosine to nitrothiophenechalcones. The presence of
nitro group on dipolarophile reverses the reactivity of α
and β positions, making the β- position of 5-nitro-2-
thienyl chalcone electron rich which results in the
regioselective synthesis of compounds 4 in this case.
RESULTS AND DISCUSSION
Initially in order to obtain optimal reaction conditions
for the synthesis of (30R,40R)-40-(4-substituted benzoyl)-
10-methyl-30-(5-nitro-2-thienyl)
spiro
[indene-2,20-
pyrrolidine]-1,3-dione 4a–k derivatives, we investigated
the one pot, three component reaction between ninhydrin
© 2018 Wiley Periodicals, Inc.

B. Kalluraya, S. Mallya, and A. Kumar K
Vol 000
1, sarcosine 2, and 1-(p-tolyl)-3-(5-nitro thienyl)prop-2-en-
1-one 3a using different solvents under refluxing
condition. It is found that the reaction in ethanol
furnished excellent yield of 86% in short reaction time
compared to other solvents. Ethanol even gave
remarkable advantage in the product separation compared
to other solvents.
As per the result of solvent optimization earlier, for all
further reactions, we used ethanol as solvent; and all the
reactants were used in equimolar ratio to obtain the
optimum yield (Scheme 1).
The condition of microwave irradiation with solvent-
free techniques was used to facilitate the cycloaddition
and to generate 1,3-dipole in situ conditions, thus
improving product yields and reduction in reaction time.
When we subjected the reaction to microwave
irradiation in ethanol, there was a slight increase in the
yield of the product. However, when the reaction was
performed by microwave irradiation under solvent-free
neat conditions, we obtained 4a–k in excellent yields.
The results are summarized in Table 1.
The observed change in regiochemistry of the product 4
during cycloaddition than expected [12,14,15] indicates
the importance of electronegative nitrothiophene moiety
in the vicinity of the double bond of chalcone. In
presence of 5-nitro-2-thienyl group, β-carbon of the
chalcone becomes electron rich due to the presence of
electron withdrawing nitro group attached to thiophene
ring, which results in the formation of compounds 4 (The
possible attack is shown with solid arrows, the other
possible attack, which is not favored, is shown by dotted
arrows). This result was similar to our earlier observation
with respect to chalcones carrying nitrofuran moiety [22],
which indicates that the change of hetroatom from
oxygen to sulfur did not affect the regiochemistry of
product, which further proved that it was the presence of
electron withdrawing nitro group that caused the change
in regioselectivity.
The structures of newly synthesized spiropyrrolidines
1
were elucidated using IR, H NMR, 13C NMR, HMBC,
CHN analysis, and mass spectroscopy. The analytical and
spectral data are in consistency with the proposed
structure. Thus, in the IR spectrum of spiropyrrolidine
4b, the three carbonyl absorption bands were observed at
1660 (Ar–C=O), 1703 (C=O of ninhydrine below the
plane), and 1741 cmꢀ1 (C=O of ninhydrine above the
plane), respectively. The 1H NMR spectrum of
compound 4b showed a doublet at δ 4.86 ppm
(J = 9.6 Hz) for Ha, multiplet at δ 4.73 ppm for Hb, a
doublet of doublet at δ 3.43 ppm (J = 8.8 Hz, J = 6.4 Hz)
for Hc, and a doublet of doublet at 3.92 ppm (J = 8.8 Hz,
J = 6.4 Hz) for Hd, respectively. The aromatic protons
appeared around δ 7.3–8.1 ppm as multiplet, the protons
of nitrothienyl ring appeared at δ 6.74 and 7.61 ppm,
The plausible mechanism for regioselective formation of
spiropyrrolidines is given in Scheme 2.
As described in Scheme 2, the 1,3-dipole generated in
situ from decarboxylative cyclocondensation of ninhydrin
1 and sarcosine 2 reacted readily with the dipolarophiles
3a–k under refluxing conditions in absolute ethanol
medium to give only one regioisomer as cycloadducts
4a–k. The required dipolarophiles, 1-aryl-3-(5-
nitrothienyl) propenones 3a–k were prepared according
to literature procedure by acid catalyzed Claisen–Schmidt
condensation of 5-nitrothiophenaldehyde diacetate with
substituted acetophenones.
Scheme 1. Synthesis of novel spiropyrrolidines.
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Microwave Assisted Neat Synthesis of Spiropyrrolidine Library
Table 1
Comparison of the reaction time, yields for thermal, microwave-assisted, and solvent-free microwave-assisted [3 + 2]-cycloaddition reactions of pyrrol-
idine derivatives 4a–k.
Conventional method
Microwave irradiation in ethanol
Neat microwave irradiation
Compound
Substituent R
Time (h)
Yield (%)
Time (min)
Yield (%)
Time (min)
Yield (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
p-CH3
H
p-OH
p-Cl
m-OH
p-Br
p-OMe
p-F
4
5
2.5
3.5
3
2
6
3.2
8
4
86
84
87
81
85
88
73
89
76
87
88
9
11
7
8
6
5
13
7
15
11
6
88
84
88
82
86
89
76
91
77
87
90
6
7
4
5
4.5
3
10
5
11
8
89
86
88
84
86
91
78
92
81
89
90
p-NO2
m-Br
o-Cl
4j
4k
2
3.5
Scheme 2. Mechanism for the regioselectiveformation of spiropyrrolidine.
respectively, as doublets and N-CH3 protons of
spiropyrrolidine ring appeared at δ 2.31 ppm as a singlet.
The 13C NMR spectrum of 4b showed peak at δ
77.47 ppm due to spiro carbon whereas the two C=O of
ninhydrin ring appeared at δ 200.0 and 203.3 ppm while
C=O of benzoyl group appeared at δ 196.4 ppm.
Furthermore, the molecular ion peak at m/z 447.1 [M++1]
confirms the formation of product 4b.
The regiochemistry of the product was established from
the HMBC spectra. As indicated in HMBC data of 4b
(Fig. 1), the benzoyl C=O group at δ 196.35 ppm
correlates with all the four protons attached to the
pyrrolidine ring (Ha, Hb, Hc, Hd) protons showing that
the correct regiochemistry of the product is as shown in
structure. If the other possible regioisomer had formed, a
long-range coupling between the benzoyl C=O group and
Hc/Hd would not have been observed. Similarly, the
HMBC spectrum of compound 4f is given in Figure 2.
EXPERIMENTAL
Thin layer chromatography was used to analyze the
reaction progress and purity of the compounds
synthesized. Melting points were determined by open
glass capillary method and were uncorrected. IR spectra
were obtained in KBr discs on a Shimadzu-8400 FTIR
spectrophotometer, 1H-NMR spectra were recorded on
Bruker spectrometer (400 MHz) in CDCl3 using TMS as
an internal standard, and 13C-NMR spectra were recorded
on Bruker spectrometer (100 MHz) in CDCl3 as solvent.
Mass spectra were recorded on Waters Micromass Q-
Journal of Heterocyclic Chemistry
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B. Kalluraya, S. Mallya, and A. Kumar K
Vol 000
Figure 1. HMBC spectrum of compound 4b.
Figure 2. HMBC spectrum of compound 4f.
TofMicromass spectrometer. CHN analysis was carried out
on ElementarVario-EL III model analyzer.
The required dipolarophiles, 1-aryl-3-(5-nitrothienyl)
propenones 3a–k were prepared according to literature
refluxed in ethanol (10 mL) at 100–120°C until the
disappearance of the starting material as evidenced by the
thin-layer chromatography (TLC). After the completion
of reaction, the reaction mixture was concentrated in
vaccuo, the residue was subjected to column
chromatography using hexane: ethyl acetate (6:4) as
procedure
by
acid
catalyzed
Claisen–Schmidt
condensation of 5-nitrothiophenaldehyde diacetate with
substituted acetophenones and are characterized by
literature references.
eluent
and
recrystallized
from
ethanol:
dimethylformamide (DMF) (2:1) to give the products.
Method B (microwave method). A mixture of chalcone
(1 mmol), ninhydrin (1 mmol), and sarcosine (1.1 mmol)
were ground into fine powdery mass using pestle and
mortar. It was then taken in a two neck round bottom
flask fitted with the condenser and 10 mL of ethanol was
General procedure for the synthesis of (30R,40R)-40-(4-
substituted benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2,20-pyrrolidine]-1,3-dione
4a–k. Method
A
(conventional method). A mixture of chalcone (1 mmol),
ninhydrin (1 mmol), and sarcosine (1.1 mmol) was
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Microwave Assisted Neat Synthesis of Spiropyrrolidine Library
added to it. Then, the reaction mass was subjected to
microwave irradiation at 300 W and 100°C in CATA-R
microwave synthesizer until the disappearance of the
starting materials as evidenced by the TLC. After the
completion of reaction, the reaction mixture was
concentrated in vaccuo, the residue was subjected to
column chromatography using hexane: ethyl acetate (6:4)
as eluent and recrystallized from ethanol: DMF (2:1) to
give the products.
40-(4-Hydroxy benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2,20-pyrrolidine]-1,3-dione (4c, C24H18N2O6S).
Dark brown crystals (88%), mp: 166–167°C; H NMR
1
(400 MHz, CDCl3): δ 4.76 (d, 1H, Ha, J = 10.4 Hz),
4.53–4.59 (m, 1H, Hb), 3.29 (dd, 1H, Hc, J = 6.0 Hz,
J = 9.4 Hz), 3.88 (dd, 1H, Hd, J = 9.6 Hz, J = 10.8 Hz),
2.34 (s, 3H, N-CH3), 6.74 (d, 1H, nitrothienyl-3H,
J = 4.1 Hz), 7.45 (d, 1H, nitrothienyl-4H, J = 4.2 Hz),
6.91 (br s, 1H, ArOH),7.20–8.10 (m, 8H, Ar-H) ppm;
13C NMR (100 MHz, CDCl3): δ 32.4, 36.8 (N-CH3),
40.6, 47.5, 58.6, 77.4 (spiro carbon), 122.3, 125.9, 128.4,
129.8, 132.6, 136.7, 140.8, 143.5, 146.8, 148.3, 195.0,
199.9, 202.4 ppm; IR (KBr): = 1668 (C¼O), 1706
(C¼O), 1740 (C¼O) cmꢀ1; MS (70 eV): m/z = 463.64
(M++1); Anal. Calcd: C, 62.33; H, 3.92; N, 6.06. Found:
Method C (neat microwave method).
A mixture of
chalcone (1 mmol), ninhydrin (1 mmol), and sarcosine
(1.1 mmol) were ground using pestle and mortar for
uniform mixing. The reaction mass was subjected to
microwave irradiation under solvent-free conditions at
300 W and 100°C in CATA-R microwave synthesizer
until the disappearance of the starting materials as
evidenced by the TLC. After the completion of reaction,
the reaction mixture was extracted with ethanol, the
residue left over was filtered and subjected to column
chromatography using hexane: ethyl acetate (6:4) as
eluent and recrystallized from ethanol: DMF (2:1) to give
C, 62.36; H, 3.95; N, 6.08.
40-(4-Chloro benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2,20-pyrrolidine]-1,3-dione (4d, C24H17ClN2O5S).
Dark brown amorphous (84%), mp: 174–176°C; 1H
NMR (400 MHz, CDCl3):
δ 4.82 (d, 1H, Ha,
J = 10.1 Hz), 4.60–4.68 (m, 1H, Hb), 3.40 (dd, 1H, Hc,
J = 6.2 Hz, J = 9.1 Hz), 3.88 (dd, 1H, Hd, J = 9.2 Hz,
J = 10.9 Hz), 3.24 (s, 3H, N-CH3), 6.72 (d, 1H,
nitrothienyl-3H, J = 4.1 Hz), 7.48 (d, 1H, nitrothienyl-
4H, J = 4.4 Hz), 7.48–8.00 (m, 8H, Ar-H) ppm; 13C
NMR (100 MHz, CDCl3): δ 36.3 (N-CH3), 40.2, 49.4,
52.5, 57.7, 77.3 (spiro carbon), 122.4, 123.4, 127.4,
129.2, 129.8, 133.8, 136.4, 137.9, 140.6, 144.9, 150.3,
195.6, 200.4, 202.2 ppm; IR (KBr): = 1665 (C¼O),
the products.
Characterization data of compounds 4a–k. 40-(4-Methyl
benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro [indene-2,20-
pyrrolidine]-1,3-dione (4a, C25H20N2O5S).
Yellowish
brown crystals (89%), mp: 188–189°C; 1H NMR
(400 MHz, CDCl3): δ 4.73 (d, 1H, Ha, J = 9.9 Hz), 4.64–
4.71 (m, 1H, Hb), 3.29 (dd, 1H, Hc, J = 5.2 Hz,
J = 9.2 Hz), 3.87 (dd, 1H, Hd, J = 9.2 Hz, J = 10.9 Hz),
2.22 (s, 3H, N-CH3), 2.43 (s, 3H, p-methyl), 6.84 (d, 1H,
nitrothienyl-3H, J = 4 Hz), 7.62 (d, 1H, nitrothienyl-4H,
J = 4 Hz), 7.33–8.00 (m, 8H, Ar-H) ppm; 13C NMR
(100 MHz, CDCl3): δ 21.3, 35.7 (N-CH3), 39.8, 48.4,
50.6, 56.8, 78.1 (spiro carbon), 99.5, 122.4, 126.6, 128.3,
129.3, 132.7, 136.9, 140.3, 144.3, 146.9, 149.6, 195.9,
199.5, 202.2 ppm; IR (KBr): = 1670 (C¼O), 1706
(C¼O), 1744 (C¼O) cmꢀ1; MS (70 eV): m/z = 461.72
(M++1); Anal. Calcd: C, 65.20; H, 4.38; N, 6.08. Found:
1701 (C¼O), 1737 (C¼O) cmꢀ1
; MS (70 eV):
m/z = 481.97: 483.97 (3:1) (M++1); Anal. Calcd: C,
59.94; H, 3.56; N, 5.82. Found: C, 59.96; H, 3.61; N, 5.85.
40-(3-Hydroxy benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2,20-pyrrolidine]-1,3-dione (4e, C24H18N2O6S).
Yellowish brown crystals (86%), mp: 208–209°C; 1H
NMR (400 MHz, CDCl3):
δ 4.78 (d, 1H, Ha,
J = 10.0 Hz), 4.58–4.64 (m, 1H, Hb), 3.32 (dd, 1H, Hc,
J = 5.8 Hz, J = 8.8 Hz), 3.91 (dd, 1H, Hd, J = 8.9 Hz,
J = 10.8 Hz), 2.32 (s, 3H, N-CH3), 5.81 (br s, 1H,
ArOH), 6.94 (d, 1H, nitrothienyl-3H, J = 4.3 Hz), 7.63
(d, 1H, nitrothienyl-4H, J = 4.3 Hz), 7.30–8.06 (m, 8H,
Ar-H) ppm; 13C NMR (100 MHz, CDCl3): δ 36.9 (N-
CH3), 41.3, 48.4, 49.9, 52.4, 55.2, 57.3, 77.4
(spirocarbon), 121.7, 122.9, 123.7, 124.6, 128.9, 129.3,
130.1, 132.2, 133.9, 134.6, 136.6, 138.9, 141.3, 143.5,
150.4, 155.7, 195.4, 199.4, 202.8 ppm; IR (KBr):
= 1687 (C¼O), 1710 (C¼O), 1742 (C¼O) cmꢀ1; MS
(70 eV): m/z = 463.42 (M++1); Anal. Calcd: C, 62.33; H,
C, 65.24; H, 4.36; N, 6.11.
40-(Benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro [indene-
2,20-pyrrolidine]-1,3-dione (4b, C24H18N2O5S).
Dark
brown crystals (86%), mp: 186–187°C; 1H NMR
(400 MHz, CDCl3): δ 4.86 (d, 1H, Ha, J = 10.2 Hz),
4.69–4.75 (m, 1H, Hb), 3.44 (dd, 1H, Hc, J = 6.4 Hz,
J = 8.9 Hz), 3.92 (dd, 1H, Hd, J = 9.5 Hz,
J = 10.7 Hz), 2.31 (s, 3H, N-CH3), 6.74 (d, 1H,
nitrothienyl-3H, J = 4.2 Hz), 7.49 (d, 1H, nitrothienyl-
4H, J = 4.3 Hz), 7.30–8.01 (m, 9H, Ar-H) ppm; 13C
NMR (100 MHz, CDCl3): δ 36.4 (N-CH3), 49.3, 51.6,
57.2, 77.5 (spiro carbon), 122.9, 123.4, 126.5, 128.6,
128.9, 133.9, 135.6, 136.4, 137.1, 140.9, 141.8, 147.2,
150.5, 196.4, 200.0, 203.3 ppm; IR (KBr): = 1660
(C¼O), 1703 (C¼O), 1741 (C¼O) cmꢀ1; MS (70 eV):
m/z = 447.10 (M++1); Anal. Calcd: C, 64.56; H, 4.06;
N, 6.27. Found: C, 64.59; H, 4.07; N, 6.30.
3.92; N, 6.06. Found: C, 62.35; H, 3.93; N, 6.04.
40-(4-Bromo benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4f, C24H17BrN2O5S).
1
Dark Yellow crystals (91%), mp: 206–207°C; H NMR
(400 MHz, CDCl3): δ 4.82 (d, 1H, Ha, J = 10.1 Hz),
4.60–4.67 (m, 1H, Hb), 3.40 (dd, 1H, Hc, J = 6.2 Hz,
J = 9.1 Hz), 3.89 (dd, 1H, Hd, J = 9.2 Hz, J = 10.9 Hz),
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B. Kalluraya, S. Mallya, and A. Kumar K
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2.30 (s, 3H, N-CH3), 6.73 (d, 1H, nitrothienyl-3H,
(KBr): = 1670 (C¼O), 1708 (C¼O), 1742 (C¼O) cmꢀ1
;
J = 4.2 Hz), 7.49 (d, 1H, nitrothienyl-4H, J = 4.2 Hz),
7.64–8.01 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz,
CDCl3): δ 36.4 (N-CH3), 40.2, 49.3, 51.6, 54.1, 57.1,
69.7, 77.4 (spirocarbon), 122.9, 123.5, 123.5, 126.6,
128.3, 129.3, 130.0, 132.3, 134.4, 136.4, 136.9, 139.9,
140.9, 141.8, 146.8, 150.7, 195.4, 200.4, 203.3 ppm; IR
MS (70 eV): m/z = 492.63 (M++1); Anal. Calcd: C, 58.65;
H, 3.49; N, 8.55. Found: C, 58.69; H, 3.45; N, 8.56.
40-(3-Bromo benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4j, C24H17BrN2O5S).
Brown crystals (89%), mp: 182–184°C; 1H NMR
(400 MHz, CDCl3): δ 4.74 (d, 1H, Ha, J = 10.0 Hz),
4.58–4.65 (m, 1H, Hb), 3.27 (dd, 1H, Hc, J = 6.3 Hz,
J = 9.2 Hz), 3.78 (dd, 1H, Hd, J = 9.2 Hz, J = 10.7 Hz),
2.27 (s, 3H, N-CH3), 6.73 (d, 1H, nitrothienyl-3H,
J = 4.2 Hz), 7.52 (d, 1H, nitrothienyl-4H, J = 4.2 Hz),
7.40–8.10 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz,
CDCl3): δ 36.3 (N-CH3), 47.1, 51.3, 52.0, 55.5, 77.4
(spirocarbon), 111.4, 114.1, 121.6, 122.4, 123.6, 125.4,
132.8, 132.9, 135.4, 136.8, 140.0, 141.7, 150.4, 152.8,
198.5, 199.9, 202.2 ppm; IR (KBr): = 1672 (C¼O),
(KBr): = 1676 (C¼O), 1707 (C¼O), 1741 (C¼O) cmꢀ1
;
MS (70 eV): m/z = 523.20 (1:1) (M++1)/(M++3); Anal.
Calcd: C, 54.87; H, 3.26; N, 5.33. Found: C, 54.86; H,
3.28; N, 5.32.
40-(4-Methoxy benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4g, C25H20N2O6S).
1
Dark Yellow crystals (78%), mp: 164–165°C; H NMR
(400 MHz, CDCl3): δ 4.74 (d, 1H, Ha, J = 10.6 Hz),
4.62–4.68 (m, 1H, Hb), 3.29 (dd, 1H, Hc, J = 6.8 Hz,
J = 10.8 Hz), 3.86 (dd, 1H, Hd, J = 9.1 Hz, J = 10.9 Hz),
2.28 (s, 3H, N-CH3), 3.87 (s, 3H, OMe), 6.84 (d, 1H,
nitrothienyl-3H, J = 4.2 Hz), 7.63 (d, 1H, nitrothienyl-
4H, J = 4.2 Hz), 6.90–8.10 (m, 8H, Ar-H) ppm; 13C
NMR (100 MHz, CDCl3): δ 37.9 (N-CH3), 47.7, 51.6,
52.4, 55.6, 57.8, 77.7 (spirocarbon), 121.5, 121.9, 122.9,
128.4, 130.6, 134.5, 140.7, 152.3, 155.9, 165.3, 195.9,
199.9, 202.5 ppm; IR (KBr): = 1667 (C¼O), 1701
(C¼O), 1742 (C¼O) cmꢀ1; MS (70 eV): m/z = 477.52
(M++1); Anal. Calcd: C, 63.02; H, 4.23; N, 5.88. Found:
1704 (C¼O), 1740 (C¼O) cmꢀ1
; MS (70 eV):
m/z = 525.71: 527.71 (1:1) (M++1)/(M++3); Anal. Calcd:
C, 54.87; H, 3.26; N, 5.33. Found: C, 54.84; H, 3.25; N,
5.34.
40-(2-Chloro benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4k, C24H17ClN2O5S).
Yellow amorphous (90%), mp: 167–168°C; 1H NMR
(400 MHz, CDCl3): δ 4.83 (d, 1H, Ha, J = 10.0 Hz),
4.57–4.63 (m, 1H, Hb), 3.34 (dd, 1H, Hc, J = 6.4 Hz,
J = 9.2 Hz), 3.94 (dd, 1H, Hd, J = 9.2 Hz,
J = 10.3 Hz), 2.36 (s, 3H, N-CH3), 6.75 (d, 1H,
nitrothienyl-3H, J = 4.2 Hz), 7.58 (d, 1H, nitrothienyl-
4H, J = 4.2 Hz), 7.20–8.10 (m, 8H, Ar-H) ppm; 13C
NMR (100 MHz, CDCl3): δ 36.8 (N-CH3), 46.4, 50.2,
52.5, 55.1, 76.9 (spirocarbon), 111.6, 121.3, 122.5,
124.3, 126.9, 128.5, 132.6, 133.9, 137.2, 137.9, 141.9,
143.2, 152.9, 195.9, 199.8, 202.1 ppm; IR (KBr):
= 1670 (C¼O), 1708 (C¼O), 1742 (C¼O) cmꢀ1; MS
(70 eV): m/z = 481.93: 483.93 (3:1) (M++1); Anal.
Calcd: C, 59.94; H, 3.56; N, 5.82. Found: C, 59.94; H,
3.59; N, 5.84.
C, 63.04; H, 4.25; N, 5.86.
40-(4-Fluoro benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4h, C24H17FN2O5S).
Yellow crystals (92%), mp: 194–195°C; 1H NMR
(400 MHz, CDCl3): δ 4.76 (d, 1H, Ha, J = 10.0 Hz),
4.52–4.59 (m, 1H, Hb), 3.29 (dd, 1H, Hc, J = 6.2 Hz,
J = 9.2 Hz), 3.86 (dd, 1H, Hd, J = 9.2 Hz,
J = 10.8 Hz), 2.32 (s, 3H, N-CH3), 6.92 (d, 1H,
nitrothienyl-3H, J = 4.2 Hz), 7.68 (d, 1H, nitrothienyl-
4H, J = 4.3 Hz), 7.20–8.10 (m, 8H, Ar-H) ppm; 13C
NMR (100 MHz, CDCl3): δ 36.7 (N-CH3), 40.4, 49.7,
52.5, 57.6, 77.8 (spirocarbon), 111.6, 121.3, 122.6,
132.4, 135.7, 140.3, 140.9, 141.7, 152.9, 195.3, 199.9,
202.0 ppm; IR (KBr): = 1676 (C¼O), 1706 (C¼O),
1744 (C¼O) cmꢀ1; MS (70 eV): m/z = 465.63 (M++1);
Anal. Calcd: C, 62.06; H, 3.69; N, 6.03. Found: C,
CONCLUSION
In summary, an efficient and solvent-free “green
chemistry” approach was developed for the
regioselective synthesis of new class of functionalized
spiropyrrolidines 4a–k containing nitrothiophene moiety
in good to excellent yields, by one-pot, three-component
1,3-dipolar cycloaddition of in situ generated
azomethineylides with 1-aryl-3-(5-nitrothiophenyl) prop-
2-en-1-ones 3a–k. This process is capable of generating
spiropyrrolidines containing nitrothiophene moiety with
62.07; H, 3.67; N, 6.08.
40-(4-Nitro benzoyl)-10-methyl-30-(5-nitro-2-thienyl) spiro
[indene-2, 20-pyrrolidine]-1,3-dione (4i, C24H17N3O7S).
Yellow amorphous (81%), mp: 168–169°C; 1H NMR
(400 MHz, CDCl3): δ 4.72 (d, 1H, Ha, J = 10.0 Hz), 4.54–
4.60 (m, 1H, Hb), 3.24 (dd, 1H, Hc, J = 6.4 Hz,
J = 9.2 Hz), 3.78 (dd, 1H, Hd, J = 9.2 Hz, J = 10.7 Hz),
2.28 (s, 3H, N-CH3), 6.94 (d, 1H, nitrothienyl-3H,
J = 4.2 Hz), 7.61 (d, 1H, nitrothienyl-4H, J = 4.2 Hz),
7.30–8.00 (m, 8H, Ar-H) ppm; 13C NMR (100 MHz,
CDCl3): δ 36.2 (N-CH3), 41.3, 46.6, 52.5, 56.6, 77.7
(spirocarbon), 111.9, 121.7, 122.5, 129.2, 132.6, 133.6,
137.8, 138.9, 141.5, 153.2, 195.9,199.3, 200.7 ppm; IR
novel regiochemistry in
a
single step reaction,
minimizing the need for organic solvents, simplifying the
work-up process, increasing reaction rates with improved
product yields and thus providing green reaction
conditions.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Microwave Assisted Neat Synthesis of Spiropyrrolidine Library
[13] Ghandi, M.; Yari, A.; Tabatabaei Rezaei, S. J.; Taheri, A.Tet-
rahedron Lett 2009, 50, 4724.
[14] Babu, A. R. S.; Raghunathan, R.; Mathivanam, R.;
Omprabha, G.; Velmurugan, D.; Raghu, R.Current Chemical Biology
2008, 2, 312.
Acknowledgments. The authors are thankful to the Head, SAIF,
Panjab University, Chandigarh for spectral and elemental
analysis. S. Mallya is also thankful to University Grants
Commission, New Delhi for Senior Research Fellowship.
[15] Babu, A. R. S.; Raghunathan, R.; Kumaresan, K.; Raaman, N.
Current Chemical Biology 2009, 3, 112.
[16] Freeman-Cook, K. D.; Reiter, L. A.; Noe, M. C.; Antipas, A.
S.; Danley, D. E.; Datta, K.; Downs, J. T.; Eisenbeis, S.; Eskra, J. D.;
Garmene, D. J.; Greer, E. M.; Griffiths, R. J.; Guzman, R.; Hardink, J.
R.; Jannat, F.; Jones, C. S.; Martinelli, G. J.; Mitchell, P. G.; Laird, E.
R.; Liras, J. L.; Lopresti-Morrow, L. L.; Pandit, J.; Reilly, U. D.; Robert-
son, D.; Vaughn-Bowser, M. L.; Wolf-Gouviea, L. A.; Yocum, S. A.
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Additional supporting information may be found online
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet