Synthesis of novel spirofused spiropyrrolidine 1,3-indanedione derivatives via 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1007/s13738-019-01793-1

The successful synthesis of novel spirofused spiropyrrolidine 1,3-indanedione derivatives using 1,3-dipolar cycloaddition reactions is reported. 1-Benzyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones prepared via Kn?evenagel condensation of 1-b

Full text of DOI:10.1007/s13738-019-01793-1

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01793-1
ORIGINAL PAPER
Synthesis of novel spirofused spiropyrrolidine 1,3‑indanedione
derivatives via 1,3‑dipolar cycloaddition reactions
Mehdi Ghandi1 · Marziyeh Eshaghi Kenari1 · Alireza Abbasi1
Received: 6 February 2019 / Accepted: 7 October 2019
© Iranian Chemical Society 2019
Abstract
The successful synthesis of novel spirofused spiropyrrolidine 1,3-indanedione derivatives using 1,3-dipolar cycloaddi-
tion reactions is reported. 1-Benzyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridinones prepared via Knöevenagel
condensation of 1-benzyl-4-piperidinone with aromatic aldehydes underwent a one-pot, three-component reaction with
benzylamines and ninhydrin in ethanol to aford the desired products.
Keywords 1,3-Dipolar cycloaddition · Spirofused spiropyrrolidine 1 · 3-Indanedione · 1-Benzyl-4-piperidinone
Introduction
1-methyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-
pyridinones [21]. Subsequently, these derivatives were used
as dipolarophiles in reaction with isatin and benzylamines
[9].
Multicomponent reactions (MCRs) are known as cor-
nerstones which can be used for the synthesis of biologi-
cally interesting compounds [1–3]. These reactions, which
frequently occur not through a single-step procedure, but
rather by several sequential cascade or domino reactions,
are powerful one-step access to products of high complex-
ity and diversity [4, 5]. Advantages such as simplicity, high
efciency and atom economy with the preparation of com-
plex “druglike” heterocycles in one-pot procedure can be
mentioned for these reactions [6–8].
Since the serendipitous discovery of ninhydrin
(1,2,3-indanetriones) [1] by Siegfried Ruhemann in 1910, it
is best known for its reactions with amino acids and amines
to give the colored compounds known as Ruhemann’s pur-
ple [22]. Grigg and co-worker established the intermediacy
of 1,3-dipoles in the formation of Ruhemann’s purple [23],
since reaction of ninhydrin 1 with the α-amino acids 2 in
methanol in the presence of N-phenylmaleimide (4) aforded
the cycloadducts 5 stereospecifcally via an endo-transition
state involving dipoles 3 (Scheme 1a). Moreover, heating
a mixture of ninhydrin (1), benzylamines (6) and N-meth-
ylmaleimide (8) in acetonitrile furnished the cycloadduct
9 stereospecifcally through endo-transition state involving
dipoles 7 (Scheme 1b) [24]. Recall that the dipole intermedi-
ates cannot be isolated since they are generated in situ in a
solution in the presence of dipolarophiles [25].
1,3-Dipolar cycloaddition is a strategic method for the
construction of fve-membered ring heterocycles [9–11],
natural products and alkaloids [12]. Within the cycload-
dition reactions, 1,3-dipolar cycloaddition of azomethine
ylides with alkenes [13] is one of the most efcient and reli-
able strategies for the construction of functionalized fve-
membered pyrrolidines which exhibit antiviral [14], local
anesthetic [15] and antileukemic activities [16].
On the other hand, spiro compounds represent a
class of naturally occurring substances exhibiting pro-
nounced biological properties [17, 18]. Due to the inter-
esting biological activities of piperidine [19, 20], this
substructure has been used before in the synthesis of
Inspired by the known properties of spiro compounds as
well as piperidine together with the importance of pyrroli-
dines and in continuation of our own interest in this domain
[26–29], herein we report a one-pot three-component access
to novel spirofused spiropyrrolidine 1,3-indanedione deriva-
tives via 1,3-dipolar cycloaddition reaction between 1-ben-
zyl-3,5-bis[(E)-arylmethylidene]tetrahydro-4(1H)-pyridi-
nones, benzyl amines and ninhydrin.
* Mehdi Ghandi
ghandi@khayam.ut.ac.ir
1
School of Chemistry, College of Science, University
of Tehran, P.O. Box 14155 6455, Tehran, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
(a)
(b)
Scheme 1 Synthesis of cycloadducts 5 and 9 from ninhydrin (1) and the in situ generated azomethine ylides 3 and 7 from a amino acids 2 and b
benzylamines 6
General procedure for the preparation of 13a–i
Experimental
A mixture containing ninhydrin 1 or isatin 14 (0.5 mmol),
dipolarophiles 12a–e (0.5 mmol) and benzylamines 6a–d
(0.5 mmol) in EtOH (3 mL) was stirred at refux for 2 to 6 h.
After completion as indicated by TLC, the solid was fltered,
washed with EtOH and recrystallized from acetone–ethanol
mixture to aford 13a–i and 15.
General information
All commercially available chemicals and reagents were
purchased from Merck Chemical Company and used with-
out further purifcation. Melting points were determined
with an Electrothermal model 9100 apparatus and uncor-
rected. IR spectra were recorded on a Bomem B100 series
spectrophotometer, in cm−1. 1H and 13C NMR spectra were
recorded on a Bruker DRX-300-ADVANCE spectrometer
at 500 (1H) and 125 MHz (13C). Mass spectra of the prod-
ucts were obtained with an HP (Agilent Technologies)
5937 Mass Selective Detector. Elemental analyses were
carried out by a CHN-Rapid Heraeus elemental analyzer
(Wellesley, MA).
1″‑Benzyl‑5″‑((E)‑benzylidene)‑4′,5′‑diphenyldispiro[indene
‑2,2′‑pyrrolidine‑3′,3″‑piperidine]‑1,3,4’’‑trione (13a)
White solid, Yield 0.225 g (73%), mp 220–222 °C; IR
(KBr) (ꢀmax, cm−1) 3340 (NH), 1697(CO), 1595 (C=C);
1H NMR (500 MHz, DMSO-d6) ꢀH =2.19 (d, J=12.4 Hz,
1H, –NCH), 2.80–2.83 (dd, J=2.8, 15.1 Hz, 1H, –NCHPh),
3.14 (d, J = 15.1 Hz, 1H, –NCHPh), 3.28 (d, J = 12.4 Hz,
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Journal of the Iranian Chemical Society
1H, –NCH), 3.61 (d, J =12.6 Hz, 1H, –CHC=C), 3.60–3.66
(dd, J = 2.3, 12.6 Hz, 1H, –CHC=C), 3.7 (bs, 1H, –NH),
4.30 (d, J=11.4 Hz, 1H, –CHPh), 5.30 (d, J=11.4 Hz, 1H,
–CHNH), 6.86–7.83 (m, 25H, Ar); 13C NMR (125 MHz,
DMSO-d6) ꢀc = 52.2, 53.6, 57.6, 60.3, 63.1, 69.7, 70.0,
122.9, 123.4, 127.5, 127.9, 128.2, 128.4, 128.5, 128.9,
129.8, 130.2, 130.3, 130.6, 132.7, 134.2, 135.9, 136.0,
136.4, 136.8, 139.5, 143.0, 143.5, 196.5, 198.0, 198.9;
EI-MS m/z (%): 614 (M+,1) 365 (86), 188 (52), 161 (69),
91(100), Anal. Calc for C42H34N2O3 (614.26): C 81.84, H
5.53, N 4.66%. Found: C 81.45, H 5.64, N 4.74%.
5′‑(Benzo[d] [1, 3] dioxol‑5‑yl)‑1″‑benzyl‑4′‑(pyridin‑3‑yl)‑5″
‑(pyridin‑3‑ylmethylene)dispiro[indene‑2,2′‑pyrrolidine‑3′,
3″‑piperidine]‑1,3,4″‑trione (13d)
White solid, Yield 0.195 g (59%), mp 188–190 °C; IR (ꢀ
1
max, cm−1) 3340 (NH), 1699 (CO); H NMR (500 MHz,
DMSO-d6), ꢀH =2.21 (d, J=12.4 Hz, 1H, CHN), 2.90–2.93
(dd, J=2.8, 15.1 Hz, 1H, –NCHPh), 3.12 (d, J=15.1 Hz,
1H, –NCHPh), 3.32 (d, J = 12.4 Hz, 1H, –CHN), 3.64 (d,
J=12.8 Hz, 1H, –CHC=C), 3.71–3.74 (dd, J=2.2, 12.8 Hz,
1H, –CHC=C), 3.8 (bs, 1H, –NH), 4.33 (d, J = 11.3 Hz,
1H, –CHpy), 5.31 (d, J = 11.3 Hz, 1H, –CHNH), 5.96 (d,
J=3.4 Hz, 2H, –OCH2O), 6.76 (d, J=7.9 Hz, 1H, Ar), 6.84
(s, 1H, Ar), 6.99–7.36 (m, 19H, Ar); 13C NMR (125 MHz,
DMSO-d6), ꢀC = 51.9, 53.1, 55.4, 60.1, 62.6, 69.3, 79.0,
101.3, 108.0, 121.5, 122.9, 123.5, 123.7, 123.8, 128.0,
128.6, 130.0, 130.2, 131.5, 133.4, 134.5, 135.6, 136.0,
136.6, 137.1, 137.3, 137.9, 139.2, 143.1, 147.0, 147.7,
148.8, 150.1, 151.2, 151.4, 196.2, 197.6, 199.0; EI-MS m/z
(%): 660 (1, M+), 367 [16], 339 [15], 276 (39, 91 (100);
Anal. Calc for C41H32N4O5 (660.24): C 74.53, H 4.88, N
8.48%. Found: C 74.72, H 4.69, N 8.65%.
1’’‑Benzyl‑5’’‑((E)‑benzylidene)‑5’‑(4‑fuorop
henyl)‑4’‑phenyldispiro[indene‑2,2’‑pyrroli‑
dine‑3’,3’’‑piperidine]‑1,3,4’’‑trione (13b)
White solid, Yield 0.175 g (55%), mp 198–200 °C; IR
(KBr) (ꢀmax,cm−1) 3342 (NH), 1697 (CO), 1593 (C=C);
1H NMR(500 MHz, DMSO-d6) ꢀH = 2.22 (d, J = 12.4 Hz,
1H, –CHN), 2.80–2.84 (dd, J=2.7, 15.2 Hz, 1H, –NCHPh),
3.15 (d, J = 15.2 Hz, 1H, –NCHPh), 3.62–3.72 (m, 3H,
–CHN, –CH2C=C), 3.84 (d, J=7.5 Hz, 1H, –NH), 4.35 (d,
J=11.3 Hz, 1H, –CHPh), 5.31–5.34 (dd, J=6.65, 11.3 Hz,
1H, –CHNH), 6.84–7.84 (m, 24H, Ar); 13C NMR(125 MHz,
DMSO-d6) ꢀC = 30.2, 30.3, 30.4, 30.5, 30.6, 30.8, 69.7,
115.0, 116.2, 123.4, 123.5, 124.0, 127.4, 127.6, 127.9,
128.2, 128.52–128.5, 128.6, 128.8, 129.1, 129.4,130.0,
130.2,130.3, 130.6, 130.8, 135.0–136.0, 136.8, 138.1, 138.7,
142.4, 143.0, 205.6, 206.4, 207.2; EI-MS m/z (%): 632 (M+,
1), 393 [29], 129 [30], 91 (100), 65 [12]; Anal. Calc for:
C42H33FN2O3 (632.24): C 79.73, H 5.26, N 4.43%. Found:
C 79.83, H 5.05, N 4.56%.
1″‑Benzyl‑5″‑((E)‑4–CHlorobenzylidene)‑4′‑(4–CHloropheny
l)‑5′‑phenyldispiro[indene‑2,2′‑pyrrolidine‑3′,3″‑piperidine]
‑1,3,4″‑trione (13e)
White solid, Yield 0.250 g (73%), mp 217–219 °C; IR
(KBr) (ꢀmax, cm−1) 3342 (NH), 1697 (CO), 1593 (C=C);
1H NMR (500 MHz, DMSO-d6) ꢀH =2.18 (d, J=12.4 Hz,
1H, –CHN), 2.84–2.87 (dd, J=2.8, 15.0 Hz, 1H, –NCHPh),
3.12 (d, J=15.0 Hz, 1H, –NCHPh), 3.28–3.31 (dd, J=1.5,
J=12.4 Hz, 1H,–CHN), 3.61 (d, J=12.6 Hz, 1H, –CHC=C),
3.67 (d, J = 12.6 Hz, 1H, –CHC=C), 3.85 (s, 1H, –NH),
4.41 (d, J=11.2 Hz, 1H, –CHPhCl), 5.29 (d, J =11.2 Hz,
1H, –CHNH), 6.83 (s, 1H, Ar), 6.93 (d, J=8.1 Hz, 2H, Ar),
7.17–7.83 (m, 20H, Ar); 13C NMR (125 MHz, DMSO-d6)
ꢀC =52.0, 53.4, 56.9, 60.2, 63.2, 69.5, 78.91, 122.9, 123.4,
127.7, 128.0, 128.1, 128.5, 128.6, 128.9, 129.2, 130.2,
132.1, 132.3, 132.5, 133.1, 133.3, 134.4, 134.9, 135.4,
135.7, 136.0, 136.6, 139.3, 143.0, 143.2, 196.4, 197.8,
198.8. EI-MS m/z (%): 684 (M+, 1), 249 (100), 220 (50),
165 (70), 89 (75); Anal. Calc for C42H32Cl2N2O3 (682.18):
C 73.79, H 4.72, N 4.10%. Found: C 73.52, H 4.76, N 4.21%.
1″‑Benzyl‑5′‑phenyl‑4′‑(pyridin‑3‑yl)‑5″‑(pyridin‑3‑ylmethy
lene)dispiro[indene‑2,2′‑pyrrolidine‑3′,3″‑piperidine]‑1,3,4
″‑trione (13c)
White solid, Yield 0.260 g (84%), mp 218–220 °C; IR(KBr)
1
(ꢀmax, cm−1) 3336 (NH), 1698 (CO), 1595 (C=C); H
NMR (500 MHz, DMSO-d6) ꢀH =2.19 (d, J=12.4 Hz, 1H,
–CHN), 2.91–2.94 (dd, J=2.8, 15.2 Hz, 1H, –NCHPh), 3.11
(d, J = 15.2 Hz, 1H, –NCHPh), 3.33 (d, J = 12.4 Hz, 1H,
–CHN), 3.63 (d, J=12.8 Hz, 1H, –CHC=C), 3.76–3.87 (m,
2H, –CH C=C, NH), 4.40 (d, J=11.4 Hz, 1H, –CHpy), 5.37
(d, J=11.4 Hz, 1H, –CHNH), 6.85 (s, 1H, Ar), 7.19–8.44
(m, 22H, Ar); 13C NMR (125 MHz, DMSO-d6) ꢀC = 51.8,
53.2, 55.2, 60.0, 62.9, 69.4, 78.9, 122.9, 123.5, 123.7, 123.8,
127.8, 128.0, 128.1, 128.6, 130.1, 130.2, 131.5, 133.4,
134.5, 135.5, 136.0, 136.6, 137.3, 137.8, 139.1, 139.2,
143.0, 143.1, 148.9, 150.1, 151.2, 151.3, 196.2, 197.7,
198.8; EI-MS m/z (%): 616 (M+,1), 249 (39), 233 (68), 105
(97), 77 (100), 51 (48); Anal. Calc for C40H32N4O3 (616.25):
C 77.90, H 5.23, N 9.08%. Found: C 77.69, H 5.10, N 9.27%.
1″‑Benzyl‑5″‑((E)‑4‑chlorobenzylidene)‑4’‑(4‑chlorophenyl)
‑5′‑(4‑fuorophenyl)dispiro[indene‑2,2′‑pyrrolidine‑3’,3″‑pip
eridine]‑1,3,4″‑trione (13f)
White solid, Yield 0.160 g (42%), mp 202–204 °C; IR
(KBr) (ꢀmax, cm−1) 3343 (NH), 1698 (CO), 1595 (C=C);
1H NMR (500 MHz, DMSO-d6) ꢀH =2.18 (d, J=12.4 Hz,
1H, –CHN), 2.84–2.87 (dd, J=2.8, 15.2 Hz, 1H, –NCHPh),
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Journal of the Iranian Chemical Society
3.10 (d, J = 15.2 Hz, 1H, –NCHPh), 3.30 (d, J = 12.4 Hz,
1H, –CHN), 3.61 (d, J=12.7 Hz, 1H, –CHC=C), 3.67 (dd,
J = 2.3, 12.7 Hz, 1H, –CHC=C), 3.70 (s, 1H, –NH), 4.33
(d, J = 11.3 Hz, 1H, –CHPhCl), 5.31 (d, J= 11.3 Hz, 1H,
–CHNH), 6.85 (s, 1H, CH=), 6.86–7.84 (m, 20H, Ar); 13
C
NMR (125 MHz, DMSO-d6) ꢀC = 52.2, 53.0, 53.3, 60.5,
64.6, 69.08, 79.3, 123.0, 123.4, 125.6, 127.3, 127.3, 127.8,
128.1, 128.1, 128.4, 128.5, 128.7, 128.5, 129.6,130.0, 130.3,
133.8, 135.7, 136.0, 136.5, 137.5, 138.2, 139.4, 142.7, 143.3,
195.1, 197.4, 198.7; IE-Ms m/z (%): 626 (M+,1), 377 (68),
202 (46), 121 [33], 91 (100); Anal. Calc for C38H30N2O3S2
(626.17): C 72.82, H 4.82, N 4.47; S 10.23%. Found C
72.75, H 4.74, N 4.40, S 10.19%.
–CHNH), 6.80 (s, 1H, CH=), 7.08–7.82 (m, 21H, Ar); 13
C
NMR(125 MHz, DMSO-d6) ꢀC = 56.7, 58.1, 61.8, 65.0,
67.1, 74.2, 83.8, 119.9, 120.1, 127.7, 128.2, 132.7, 133.3,
133.6, 134.6, –134.7, 135.0, 136.9, 137.1, 137.1, 137.8,
139.2, 139.4, 138.0–140.4, 140.2, −140.8, 141.3, 144.1,
144.3, 144.3, 147.8, 165.7, 167.6, 201.1, 202.4, 203.5;
IE-MS m/z (%): 701 (M+,1), 267 (100), 238 [35], 183 (61),
146 (40), 105 (60), 76 (45); Anal. Calc for C42H31Cl2FN2O3
(700.17): C 71.90, H 4.45, N 3.99%. Found: C 72.04, H
4.38, N 4.04%.
1″‑Benzyl‑4′‑(pyridin‑3‑yl)‑5″‑(pyridin‑3‑ylmethylene)‑5′‑(p
‑tolyl)dispiro[indene‑2,2′‑pyrrolidine‑3′,3″‑piperidine]‑1,3,
4″‑trione (13 h)
White solid, 0.243 g (77%), mp 208–210 °C; IR (KBr) (ꢀ
max, cm−1): 3342 (NH), 1695 (CO), 1595 (C=C); 1H NMR
(500 MHz, DMSO-d6) ꢀH =2.15 (d, J=12.4 Hz, 1H, –CHN),
2.22 (s, 3H, Me), 2.90 (d, J = 15.2 Hz, 1H, –NCHPh),
3.08 (d, J = 15.2 Hz, 1H, –NCHPh), 3.31 (d, J = 12.4 Hz,
1H, –CHN), 3.60 (d, J = 12.6 Hz, 1H, –CHC=C), 3.73
(d, J = 12.6 Hz, 1H, –CHC=C), 3.85 (s, 1H, –NH), 4.34
(d, J = 11.4 Hz, 1H, –CHpy), 5.30 (d, J = 11.4 Hz, 1H,
1″‑Benzyl‑5′‑phenyl‑4′‑(thiophen‑2‑yl)‑5″‑(thiophen‑2
ylmethylene)dispiro[indene‑2,2′‑pyrrolidine‑3′,3″‑piperidin
e]‑1,3,4″‑trione (13 g)
White solid, Yield: 0.26 g (83%), mp 201–203 °C; IR
(KBr) (ꢀmax,cm−1): 3350 (NH), 1743 (CO), 1570 (C=C);
1H NMR (500 MHz, DMSO-d6) ꢀH =2.33 (d, J=12.5 Hz,
1H, –CHN), 2.79–2.83 (dd, J=2.7, 15.8 Hz, 1H, NCHPh),
3.16 (d, J = 15.8, 1H, NCHPh), 3.34 (d, J = 12.5 Hz, 1H,
–CHN), 3.57–3.60 (dd, J = 2.1, 12.6 Hz, 1H, –CHC=C),
3.69 (d, J = 12.6 Hz,1H, –CHC=C), 3.83 (s, 1H, –NH–),
4.65 (d, J=11.1 Hz, 1H, –CHthio), 5.09 (d, J=11.1 Hz,1H,
–CHNH), 6.83 (s, 1H, CH=), 7.07–8.43 (m, 21H, Ar); 13
C
NMR (125 MHz, DMSO-d6) ꢀC = 21.1, 53.17, 55.1, 56.3,
60.0, 62.6, 69.3, 78.7, 122.9, 123.4, 123.7, 123.8, 128.0,
128.5, 129.2, 130.1, 130.2, 131.6, 133.4, 134.5, 135.4,
136.0, 136.6, 136.9, 137.3, 137.8, 139.1, 139.8, 139.8,
Scheme 2 Synthesis of 1-ben-
zyl-3,5-bis[(E)-arylmethylidene]
tetrahydro-4(1H)-pyridinone
derivative 12a–d
Scheme 3 Synthesis of spirofused spiropyrrolidine 1,3-indanediones 13a–i
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Journal of the Iranian Chemical Society
Table 1 Synthesis of spirofused spiropyrrolidine 1,3-indanediones 13a–i
Entry
Dipolarophile
Benzylamine
Product
Yield (%)
O
O
H
N
H
O
N
H
O
H
1
73
H2N
N
Ph
6a
12a
O
13a
F
O
F
H
N
N
H
O
H
O
H
2
55
N
H2N
Ph
12a
6b
13b
O
O
H
N
H
O
H
N
N
N
O
H
3
84
N
N
H2N
Ph
N
6a
12b
13c
O
O
O
O
N
H
N
O
O
H
O
H
4
59
O
H
N
N
N
N
H2N
Ph
N
12b
6c
13d
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Journal of the Iranian Chemical Society
Table 1 (continued)
Entry
Dipolarophile
Benzylamine
Product
Yield (%)
O
H
N
O
N
H
H
O
H
O
5
73
Cl
Cl
Cl
N
Ph
H2N
Cl
6a
13e
12c
F
O
O
F
H
N
H
H
N
Cl
6
Cl
O
H
O
55
Cl
N
H2N
Ph
12c
Cl
6b
13f
O
O
H
N
S
S
H
H
N
O
H
O
7
83
S
N
H2N
S
Ph
6a
13g
12d
Me
O
O
Me
H
N
N
N
N
H
H
8
77
O
H
O
N
N
H2N
Ph
N
12b
6d
13h
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Journal of the Iranian Chemical Society
Table 1 (continued)
Entry
Dipolarophile
Benzylamine
Me
Product
O
Yield (%)
Me
H
O
N
H
N
H
S
S
9
68
O
H
O
S
N
H2N
S
Ph
6d
12d
13i
Scheme 4 Synthesis of spirofused spiropyrrolidine oxindole 15
1″‑Benzyl‑4′‑(thiophen‑2‑yl)‑5″‑(thiophen‑2‑ylmethylene)‑
5′‑(p‑tolyl)dispiro[indene‑2,2′‑pyrrolidine‑3′,3″‑piperidine]‑
1,3,4″‑trione (13i)
White solid, Yield 0.220 g (68%), mp 202–204 °C; IR
(KBr) (ꢀmax, cm−1): 3345 (NH), 1740 (CO), 1508 (C=C); 1H
NMR (500 MHz, DMSO-d6) ꢀH =2.10 (s, 3H, Me), 2.32 (d,
J=12.4 Hz, 1H, –CHN), 2.81 (d, J=15.3 Hz, 1H, –NCHPh),
3.15 (d, J = 15.3 Hz, 1H, –NCHPh), 3.34 (d, J = 12.4 Hz,
1H, –CHN), 3.58 (d, J = 12.4 Hz, 1H, –CHC=C), 3.69
(d, J = 12.4 Hz, 1H, –CHC=C), 3.82 (s, 1H, –NH-), 4.61
(d, J = 11.2 Hz, 1H, –CHthio), 5.05 (d, J = 11.2 Hz, 1H,
–CHNH), 6.86 (s, 1H, CH=), 6.94 (s, 1H, Ar), 7.11–7.87 (m,
18H, Ar); 13C NMR (125 MHz, DMSO-d6)ꢀC =21.2, 52.9,
53.3, 53.6, 64.4, 64.4, 69.0, 79.2, 122.9, 123.4, 125.6, 127.3,
128.1, 128.5, 128.7, 128.9, 129.1, 129.7, 130.0, 130.3,
133.8, 135.6, 135.8, 136.0, 136.5, 136.8, 136.9, 137.5,
138.2, 139.4, 140.1, 142.0, 197.5, 197.7, 198.7; IE-MS m/z
(%): 640 (M+, 1), 404 [25], 377 (77), 202 (94), 91 (100);
Fig. 1 ORTEP diagram of 15
143.1, 148.8, 150.1, 151.1, 151.3, 196.3, 197.8, 198.9;
IE-MS: m/z (%): 630 (M+,1), 416 [13], 366 (68), 276 (76),
91 (100); Anal. Calc for C41H34N4O3 (630.75): C 78.07, H
5.43, N 8.88%. Found; C 78.29, H 5.25, N 8.76%.
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Journal of the Iranian Chemical Society
Scheme 5 Synthesis of spirofused spiropyrrolidine oxindole derivative 15 via endo-transition state
Scheme 6 Synthesis of spirofused spiropyrrolidine 1,3-indanediones derivatives 13a–i via endo-transition states
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Journal of the Iranian Chemical Society
Anal. Calc for C39H32N2O3S2 (640.82): C 73.10, H 5.03, N
4.37, S 10.01%. Found: C 72.92, H 4.96, N 4.80, S 9.89%.
As shown in Scheme 4, the product 15 is formed with high
regio- and stereoselectivity with vicinal trans benzylic
protons confrmed by using monocrystal X-ray difraction
analysis (Fig. 1) [30]. The regioselectivity observed in
15 can be attributed to the regioselective endo-approach
of the dipole toward the termini of the dipolarophile 12e
(Scheme 5).
1″‑Benzyl‑5″‑((E)‑4‑methylbenzylidene)‑4′‑phenyl‑3′‑(p‑to
lyl)dispiro[indoline‑3,1′‑cyclopentane‑2′,3″‑piperidine]‑2,4
″‑dione [15]
Since the trans benzylic protons of 13a–i appear as
a doublet with large coupling constants between J = 11.1
to 11.4 Hz, the formation of spirofused spiropyrrolidine
1,3-indanediones 13a–i via the endo-transition states of the
dipole toward the termini of the dipolarophiles 12a–d with
vicinal trans benzylic protons is concluded (Scheme 6).
These cycloadditions are chemoselective since addition
occurs exclusively on one double bond of 12a–d, afording
the mono-spiropyrrolidine 1,3-indanedione derivatives, per-
haps due to the steric efect experienced on the in situ gen-
erated azomethine ylides by 13a–i on the second cycload-
dition to bis-spiropyrrolidine 1,3-indanediones. Moreover,
these cycloadditions also proceed stereoselectively since in
all cases only one diastereomer with four stereocenters is
obtained in satisfactory yields (55–84%).
White crystal, Yield 0.24 g (76%), mp 226–227 °C; IR
(KBr) (ꢀmax, cm−1): 3027 (NH), 1685 (CO), 1509 (C=C);
1H NMR (500 MHz, DMSO-d6), δH =1.82 (d, J=12.5 Hz,
1H, –CHN), 2.20 (s, 3H, Me), 2.24 (s, 3H, Me), 2.74 (dd,
14.8 Hz, 1H, –NCHPh), 3.04 (d, J=10.6 Hz, 1H, –CHC=C),
3.14 (d, J = 14.8 Hz, 1H, –NCHPh), 3.54 (m, 2H, NH,
–CH2C=C), 3.61 (d, J = 12.5 Hz, 1H, –CHN), 4.46 (d,
J = 10.3 Hz, 1H, –CHPhMe), 5.37 (dd, J = 6.0, 10.3 Hz,
1H, CHNH), 6.65 (d, J = 7.6 Hz, 1H, Ar), 6.80–6.90 (m,
3H, Ar), 6.92–7.27 (m, 13H, Ar), 7.48 (d, J =6.9 Hz, 2H,
Ar), 10.44 (s, 1H, –NHCO); 13C NMR (125 MHz, DMSO-
d6): δC =21.1, 21.3, 53.9, 57.3, 57.8, 62.4, 63.5, 65.1, 71.7,
109.1, 120.9, 127.3, 127.4, 127.6, 128.0, 128.4, 128.5,
128.7, 129.3, 129.4, 129.4, 129.6, 130.0, 130.4, 132.2,
132.6, 135.2, 136.1, 137.0, 137.4, 139.3, 142.8, 143.3,
180.2, 199.0; IE-MS m/z (%): 629 (1, M+), 393 [25], 365
[10], 207 [17], 115 [28], 133 (63), 91 (100); Anal. Calcd for
C43H39N3O2 (629.30): C 82.01, H 6.24, N 6.67%. Found: C
81.55, H 6.47, N 6.84%.
Conclusion
In conclusion, a number of spirofused spiropyrrolidine
1,3-indanediones were synthesized via a three-component
reaction of 1-benzyl-3,5-bis[(E)-arylmethylidene]tetrahy-
dro-4(1H)-pyridinones 12a–d with benzyl amines 6a–d
and ninhydrin [1]. These new structures broaden the hybrid
scafolds that are accessible through a one-pot reaction, and
many of them may represent interesting pharmacophores.
Results and discussion
Initially, 1-benzyl-3,5-bis[(E)-arylmethylidene]tetrahydro-
4(1H)-pyridinone derivatives 12a–d were prepared via
Knöevenagel condensation of 1-benzyl-4-piperidinone
10 with aromatic aldehydes 11a–d using the previously
reported procedure [21] (Scheme 2). In the next step, a
mixture of ninhydrin 1 and benzylamines 6a–d was stirred
at room temperature for 10 min. After the formation of the
corresponding imines as indicated by change in color from
yellow to light violet, derivatives 12a–d were added and
the deep violet solutions heated at refux for appropriate
times. Upon completion as indicated by TLC, the solids
were separated and washed with cold EtOH. Recrystalliza-
tion of solids from a mixture of acetone and EtOH fnally
aforded the desired products 13a–i in satisfactory yields
(Scheme 3, Table 1). All compounds were characterized
by elemental analysis, MS, IR, and 1H and 13C NMR spec-
troscopy. The stereochemistry of 13a–i was apparent on
the basis of 1H NMR spectra in which benzylic protons of
pyrrolidine rings appear as two doublets with J= 11.1 to
11.4 Hz, indicating a trans stereochemistry. Since no X-ray
crystallography could be obtained for 13a–i, isatin 14 was
used to study its reaction with 12e and benzylamine (6a).
Acknowledgements The authors acknowledge the University of Tehran
for fnancial support of this research.
References
1. B. Liang, S. Kalidindi, J.R. Porco Jr., C.R. Stephenson, Org. Lett.
12, 572 (2010)
2. S.L. Cui, X.F. Lin, Y.G. Wang, Org. Lett. 8, 4517 (2006)
3. B. Ganem, Acc. Chem. Res. 42, 463 (2009)
4. K. Kriis, K. Ausmees, T. Pehk, M. Lopp, T. Kanger, Org. Lett. 12,
2230 (2010)
5. J.D. Sunderhaus, S.F. Martin, Chem. Eur. J. 15, 1300 (2009)
6. L. Banf, R. Riva, Org. Reaction 65, 1 (2005)
7. D.J. Ramón, M. Yus, Angew. Chem. Int. Ed. 44, 1602 (2005)
8. A. Dömling, Chem. Rev. 106, 17 (2006)
9. R.R. Kumar, S. Perumal, Tetrahedron 63, 12220 (2007)
10. M.S. Singh, S. Chowdhury, S. Koley, Tetrahedron 72, 1603 (2016)
11. A.A. Raj, R. Raghunathan, Tetrahedron 57, 10293 (2001)
12. V. Jager, R. Muller, T. Liebold, M. Hein, M. Schwarz, M. Fengler,
L. Jaroskova, M. Patzel, P.Y. Le Roy, P. Bull. Soc. Chim. Belg.
103, 491 (1994)
1 3

Journal of the Iranian Chemical Society
13. I. Coldham, R. Hufton, Chem. Rev. 15, 2765 (2005)
14. N. Uchide, K. Ohyama, J. Antimicrob. Chemother. 52, 8 (2003)
15. M.J. Kornett, A.P. Thio, J. Med. Chem. 19, 892 (1976)
16. M.A. Abou-Gharbia, P.H. Doukas, Heterocycles 12, 637 (1979)
17. J. Kobayashi, M. Tsuda, K. Agemi, H. Shigemori, M. Ishibashi,
T. Sasaki, Y. Mikami, Tetrahedron 47, 6617 (1991)
18. D.M. James, H.B. Kunze, D.J.J. Faulkner, D. Nat, Prod. 54, 1137
(1991)
22. S. Ruhemann, J. Chem. Soc. 97, 1438 (1910)
23. R. Grigg, S. Thianpatanagul, J. Chem. Soc. Chem. Commun. 180
(1984)
24. H. Ardill, M.J.R. Dorrity, R. Grigg, Tetrahedron 46, 6433 (1990)
25. A.S. Filatov, S. Wang, O.V. Khoroshilova, S.V. Lozovskiy, A.G.
Larina, V.M. Boitsov, A.V. Stepakov, J. Org. Chem. 84, 7017
(2019)
26. M. Ghandi, A. Yari, S.J. Tabatabaei Rezaei, A. Taheri, Tetrahe-
dron Lett. 50, 4724 (2009)
19. E. Abignente, M. Biniecka-Picazio, M. Acta Pol. Pharm. 34, 241
(1977)
27. M. Ghandi, A. Taheri, A. Abbasi, Tetrahedron 66, 6744 (2010)
28. M. Ghandi, A. Taheri, A. Hasani Bozcheloei, A. Abbasi, R. Kia,
Tetrahedron 68, 3641 (2012)
20. J.R. Dimmock, J.A. Jha, G.A. Zello, G.R.K. Sharma, A. Shriv-
astav, P. Selvakumar, T.M. Allen, C.L. Santos, J. Balzarini, E.
De Clercq, E.K. Manavathu, J.P.J. Stables, Enzyme Inhib. Med.
Chem. 18, 325 (2003)
29. M. Ghandi, N. Zarezadeh, A. Abbasi, RSC Adv. 6, 67805 (2016)
30. Crystallographic data for 6a has been deposited in the Cambridge
Crystallographic Data Centre with the deposition numbers CCDC
1953641. http://www.ccdc.ca-m.ac.uk/conts/retrieving.html
21. Z.G. Han, S.J. Tu, B. Jiang, S. Yan, X.H. Zhang, S.S. Wu, W.J.
Hao, X.D. Cao, F. Shi, G. Zhang, N. Ma, Synthesis, 1639 (2009)
1 3