A facile regio- and stereoselective synthesis of novel dispirooxindolyl- [acridine-2′,3-pyrrolidine/thiapyrrolizidine]-1′-ones via 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetlet.2011.11.048

A facile regio- and stereoselective synthesis of novel dispirooxindolyl- [acridine-2′,3-pyrrolidine]-1′-ones and dispirooxindolyl-[acridine- 2′,3-thiapyrrolizidine]-1′-ones have been accomplished via 1,3-dipolar cycloaddition of azomethine ylides, generat

Full text of DOI:10.1016/j.tetlet.2011.11.048

Tetrahedron Letters 53 (2012) 349–353
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Tetrahedron Letters
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A facile regio- and stereoselective synthesis of novel
dispirooxindolyl-[acridine-20,3-pyrrolidine/thiapyrrolizidine]-10-ones
via 1,3-dipolar cycloaddition of azomethine ylides
Shanmugavel Uma Maheswari a, Subbu Perumal a, , Abdulrahman I. Almansour b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, Tamil Nadu, India
b Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
A facile regio- and stereoselective synthesis of novel dispirooxindolyl-[acridine-20,3-pyrrolidine]-10-ones
and dispirooxindolyl-[acridine-20,3-thiapyrrolizidine]-10-ones have been accomplished via 1,3-dipolar
cycloaddition of azomethine ylides, generated in situ from the reaction of sarcosine/1,3-thiazolane-4-car-
boxylic acid and substituted isatins, to a series of (E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones
in good yields.
Article history:
Received 6 October 2011
Revised 7 November 2011
Accepted 10 November 2011
Available online 18 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylide
1,3-Dipolar cycloaddition
(E)-2-[Arylmethylidene]-3,4-dihydro-
1(2H)-acridinones
Dispirooxindolyl-[acridine-20,3-
pyrrolidine]-10-ones
The 1,3-dipolar azomethine ylide cycloaddition is a powerful tool
for the construction of five-membered heterocycles and spiro-com-
pounds1a,b in a highly regio- and stereoselective manner.2 The
spiro-pyrrolidinyl-oxindole nucleus is often found in the molecular
framework of many natural products, viz horsfiline,3 coerulescine,4
and elacomine5 (Fig. 1). The spiro-pyrrolidinyl oxindoles possess a
myriad of biological activities such as inhibition of the mammalian
cell cycle at G2/M phase,6 inhibition ofmicrotubule assembly,7 mod-
ulation of the function of muscarinic serotonin receptors,8 antitu-
mor activity against human brain cancer cell lines, neuroblastoma
SKN-BE (2), and malignant glioma GAMG.9 Pyrrolothiazoles are
endowed with a wide range of biological activities, viz hepatopro-
tective,10 antibiotic,11 antidiabetic,12 and anticonvulsant.13
In addition, acridine and its derivatives play an important role in
medicinal chemistry. For example, tacrine (Fig. 1) is a well-known
first acridine drug, approved by the FDA, for the treatment of Alzhei-
mer’s disease.14 This is also useful for the treatment of central
anticholinergic syndrome,15,16 intractable pain from terminal
carcinoma,17 and myasthenia gravis.18 Velnacrine and suronacrine
(Fig. 1), structurally similar to tacrine, inhibit acetylcholinesterase
in vitro and are active in a model that may be predictive of AD but
have less acute toxicity in rats and mice.19 Amsacrine is one of the
first DNA-intercalating agents to be considered as a topoisomerase
II inhibitor.20 Acridine derivatives also display a wide range of phar-
macological activities such as antiviral,21 antimalarial,22 antihel-
mintic,23 and antitumor.24
The above-mentioned biological importance of spiro[pyrroli-
dine-3,30-oxindole] and acridine sub-structures in conjunction
with our interest in the synthesis of novel heterocycles employing
domino25 and 1,3-dipolar cycloaddition26 reactions, led us now to
report the synthesis of hybrid heterocycles comprising acridine
and spiro-pyrrolidinyl-oxindole sub-structures (Fig. 1). To the best
of our knowledge this is the first report on the synthesis of dispiro-
oxindolopyrrolidine–acridine heterocyclic hybrids.
In the present investigation, the required dipolarophiles,
(E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones 3a–j, were
prepared by the base-catalyzed condensation of 3,4-dihydroacri-
din-1(2H)-one27 1 with substituted benzaldehydes 2.28 The (E)-
2-[arylmethylidene]-3,4-dihydro-1(2H)-acridinones 3a–j readily
reacted with nonstabilized azomethine ylides, generated in situ by
the decarboxylative condensation of substituted isatins 4 (R = H or
Cl) with amino acid, sarcosine 5, to afford dispirooxindolyl-
[acridine-20,3-pyrrolidine]-10-ones 7 and 8 (Scheme 1). In order
to optimize the solvent for the reaction, we have investigated
the three-component reaction of (E)-2-[4-chlorobenzylidene]-3,
4-dihydro-1-(2H)-acridinone 3g (1 mmol), isatin 4 (1 mmol) and
sarcosine 5 (1 mmol) under heating to reflux in different solvents,
viz methanol, dioxane, dioxane/methanol (1:1 v/v) mixture, toluene,
and acetonitrile to furnish dispirooxindolyl-[acridine-20,3-pyrroli-
dine]-10-one 7g (Table 1). As can be seen from Table 1, the best
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.048

350
S. U. Maheswari et al. / Tetrahedron Letters 53 (2012) 349–353
R3
MeO
HN
NHSO2Me
NH R1
R2
N
R1 = R2 = R3 = H: Tacrine
N
R1 = OH, R2 = R3 = H: Velnacrine
R1 = OH, R2 = H, R3 = CH2Ph; Suronacrine
Amsacrine
H
N
OH
H
HN
N
O
OMe
O
O
N
NMe
(-)-Horsf iline
N
Me
Me
Elacomine
Coerulescine
NH
O
N
R1
R
N
R2
H
O
Ar
R1 = Me, R2 = H; R1 and R2 = CH2-S-CH2
Dispiroheterocycles of the present work
Figure 1. Biological relevance of the dispirooxindolopyrrolidine/thiapyrrolizidine–acridine hybrids to naturally occurring acridines and oxindolopyrrolidines.
NH
H
N
O
N
COOH
R
CH3
H3C
R
N
5
H
O
O
O
O
Ar
O
7 R = H; 8 R = Cl
ArCHO
Ar
O
2
NH
NH
4
KOH, aq.EtOH
N
3
N
1
O
Dioxane:MeOH (1:1)
N
S
N
reflux, 6-8 h
S
H
H
Ar
COOH
N
H
9 R = H
6
Scheme 1. Synthesis of dispirooxindolyl-[acridine-20,3-pyrrolidine/thiapyrrolizidine]-10-ones 7–9.
Table 1
substituted isatins 4 (1 mmol) and sarcosine 5 (1 mmol) in diox-
ane/methanol (1:1 v/v) for 6–8 h, till the reactions were completed
(TLC). After removing the solvent, the crude product was purified
by column chromatography to afford pure dispirooxindolyl-[acri-
dine-20,3-pyrrolidine]-10-ones 7 and 8 (Scheme 1) in 85–98%
yields29 (Table 2). Neither the starting materials nor any other
characterizable product could be obtained from this reaction. A ser-
ies of twenty dispirooxindolyl-[acridine-20,3-pyrrolidine]-10-ones 7
and 8 has been synthesized by this protocol.
Solvent-screen for the synthesis of 7g
Entry
Solvent
Reaction time (h)
Yield of 7ga,b (%)
1
2
3
4
5
CH3OH
7
6
6
8
8
68
81
98
53
—
1,4-Dioxane
1,4-Dioxane/CH3OH (1:1)
CH3CN
Toluene
a
Reaction performed under heating at reflux.
Isolated yield after purification by column chromatography.
b
The structure of dispirooxindolyl-[acridine-20,3-pyrrolidine]
-10-ones was elucidated using 1H, 13C, and 2D NMR spectroscopic
data as described for 7g (Fig. 2). In the 1H NMR spectrum of 7g,
one of the 30-CH2 and one of the 40-CH2 hydrogens appear as triplet
of doublets at 1.40 and 3.10 ppm (J = 13.8 and 4.8 Hz), respectively,
and the other two hydrogens appear as multiplets at 2.52–2.57 and
2.89–2.95 ppm, respectively. These 30-CH2 and 40-CH2 hydrogens
results were obtained by heating the reaction mixture to reflux in
dioxane/methanol mixture to yield 7g as a single regioisomer in
good yield (Table 1, entry 3). Consequently, all the subsequent reac-
tions were performed by heating an equimolar mixture of (E)-2-
[arylmethylidene]-3,4-dihydro-1-(2H)-acridinones 3a–j (1 mmol),

S. U. Maheswari et al. / Tetrahedron Letters 53 (2012) 349–353
351
Table 2
NH
Synthesis of dispirooxindolyl-[acridine-20,3-pyrrolidine]-10-ones 7 and 8
O
Entry Dipolarophile
3
Product Ar in 3, 7 and
8
R
Yielda
(%)
Mp (°C)
CH3
H
H
H
N
H
H
N
H
H
H
1
2
3
4
5
6
a
b
c
d
e
f
7a
7b
7c
7d
7e
7f
7g
7h
7i
4-MeC6H4
2-MeC6H4
4-PriC6H4
2-MeOC6H4
4-BrC6H4
2-BrC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
H
H
94
89
88
91
90
92
98
87
89
89
192–194
210–212
217–219
237–239
222–224
219–220
220–222
224–226
219–221
169–171
213–215
220–222
209–211
234–236
221–223
217–219
218–220
222–224
223–225
149–151
H
H
H
H
H
H
O
H
7
8
9
g
h
i
H
Cl
2,4-Cl2C6H3
4-FC6H4
2.52-2.57, m, 1H
10
11
12
13
14
15
16
17
18
19
20
j
7j
3-O2NC6H4
4-MeC6H4
2-MeC6H4
4-PriC6H4
2-MeOC6H4
4-BrC6H4
2-BrC6H4
4-ClC6H4
1.40, td, J = 13.8, 4.8 Hz, 1H
1"
a
b
c
d
e
f
g
h
i
8a
8b
8c
8d
8e
8f
8g
8h
8i
Cl 98
Cl 87
Cl 85
Cl 93
Cl 86
Cl 87
Cl 88
Cl 90
Cl 91
Cl 85
29.3
NH
2.89-2.95, m, 1H
2"
3.10, td, J = 13.8 Hz, 4.8 Hz, 1H
O
29.0
2.13, s, 3H
CH3
34.1
10'
N
5
5'
2
10a'
N
4a'
9a'
3'
1
6'
7'
H
4'
1'
3.52, t, J = 8.4 Hz
3.99, t, J = 8.4 Hz
57.5
3
4
H
8a'
2,4-Cl2C6H3
4-FC6H4
8'
H
9'
O
j
8j
3-O2NC6H4
a
Isolated yield after purification by column chromatography.
4.99, t, J = 8.4 Hz, 1H
46.9
Cl
Figure 2. Selected HMBCs and 1H and 13C NMR chemical shifts of 7g.
the quinoline ring appearing as a singlet at 8.84 ppm shows (i)
C,H-COSY correlation with a signal at 138.0 ppm due to C-90 and
(ii) HMBCs with C-80 at 128.9 ppm, C-10a0at 148.6 ppm, C-4a0 at
160.3 ppm and C-10 at 197.6 ppm. From the HMBC of H-90 with a
carbon signal at 128.9 ppm, the doublet at 7.91 ppm (J = 8.1 Hz),
can be assigned to H-80and the carbon signal at 128.9 ppm to
C-80. The H-70 and H-60, related by H,H-COSY correlation appear
show C,H-COSY correlations with carbon signals at 29.3 ppm and
29.0 ppm, respectively. Further, 30-CH2 hydrogens show a HMBC
with the carbon signal at 75.8 ppm due to C-2. The 5-CH2 hydro-
gens appear as triplets at 3.52 and 3.99 ppm (J = 8.4 Hz), and show
C,H-COSY correlation with C-5 at 57.5 ppm. Further, 5-CH2 show
HMBCs with C-2 at 75.8, C-3 at 60.8 and C-1000 at 137.3 ppm. The
triplet at 4.99 ppm (J = 8.4 Hz), related by a H,H-COSY correlation
with 5-CH2 hydrogens, due to H-4, shows HMBCs with C-2 at
75.8 ppm, C-3 at 60.8 ppm, C-1000 at 137.3 ppm, C-2000 at
131.5 ppm and carbonyl carbon C-10 at 197.6 ppm. The H-90 of
as
a multiplet at 7.50–7.53 ppm and a triplet at 7.71 ppm
(J = 8.1 Hz), respectively. The H-50 appearing as a doublet at
7.80 ppm (J = 8.1 Hz) shows C,H-COSY correlation with a carbon
signal at 126.9 ppm due to C-50. The NH hydrogen of the isatin ring
gives a singlet at 10.30 ppm. The presence of a molecular ion peak
Figure 3. ORTEP diagram of 7g.

352
S. U. Maheswari et al. / Tetrahedron Letters 53 (2012) 349–353
O
R
CH3
HN
N+
H
N
O
O
-
COOH
CH3
N+
R
HN
H3C
5
O
N
Ar
-
N
H
H
R
4
O
3
H
N
O
CH3
R
N
N
H
Ar
O
7 and 8
Scheme 2. Plausible mechanism for the regio- and stereoselective formations of dispirooxindolyl-[acridine-20,3-pyrrolidine]-10-ones.
Supplementary data
Table 3
Synthesis of dispirooxindolyl-[acridine-20,3-thiapyrrolizidine]-10-ones 9
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.048.
Entry
Compd
Ar
R
Yielda (%)
Mp (°C)
1
2
3
4
9a
9d
9g
9h
4-MeC6H4
2-MeOC6H4
4-ClC6H4
H
H
H
H
89
86
91
93
177–179
197–199
174–176
187–189
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funded through the research Grant RGP-VPP-026.

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Perumal, S. Tetrahedron 2007, 63, 2865–2874; (j) Karthikeyan, S. V.; Perumal, S.
Tetrahedron Lett. 2007, 48, 2261–2265.
thiapyrrolizidine]-10-ones (7–9):
dihydro-1-(2H)-acridinones (1 mmol), isatin/5-chloroisatin (1 mmol) and
A mixture of (E)-2-[arylmethylidene]-3,4-
3
sarcosine 5/1,3-thiazolane-4-carboxylic acid 6 (1 mmol) was heated to reflux
in dioxane/methanol (1:1 v/v) for 6–8 h. After completion of the reaction as
evident from TLC, the solvent was removed under reduced pressure and the
crude product was subjected to column chromatography using petroleum
ether-AcOEt (5:1 v/v) as eluent to obtain pure product 7–9. Characterization
data for
a representative compound 7g are given below. 1-Methyl-
2-spiro[2.300]oxindole-4-(4-chlorophenyl)-30,40-dihydro-1H-spiro[acridine-20,
3-pyrrolidine]-10-one (7g). Isolated as pale yellow solid. Yield: 98%, mp = 220–
222 °C; 1H NMR (300 MHz, DMSO-d6) dH: 1.40 (td, 1H, J = 13.8, 4.8 Hz), 2.13 (s,
3H, NCH3), 2.52–2.57 (m, 1H), 2.89–2.95 (m, 1H), 3.10 (td, 1H, J = 13.8, 4.8 Hz),
3.52 (t, 1H, J = 8.4 Hz), 3.99 (t, 1H, J = 8.4 Hz), 4.99 (t, 1H, J = 8.4 Hz), 6.48 (d, 2H,
J = 7.5 Hz, Ar-H), 6.77 (t, 1H, J = 7.5 Hz, Ar-H), 6.87 (d, 1H, J = 7.5 Hz, Ar-H), 7.28
(d, 2H, J = 7.8 Hz, Ar-H), 7.47 (d, 2H, J = 7.8 Hz, Ar-H), 7.50–7.53 (m, 1H, Ar-H),
7.71 (t, 1H, J = 8.1 Hz, Ar-H), 7.80 (d, 1H, J = 8.1 Hz, Ar-H), 7.91 (d, 1H, J = 8.1 Hz,
Ar-H), 8.84 (s, 1H, Ar-H), 10.30 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) dC:
29.0, 29.3, 34.1, 46.9, 57.5, 60.8, 75.8, 109.6, 121.5, 125.2, 126.1, 126.3, 126.4,
126.9, 127.8, 128.0, 128.9, 129.2, 131.7, 131.9, 132.4, 137.3, 138.0, 141.9, 148.6,
160.3, 176.9, 197.6; Mass m/z: 494.2 (M+); Anal. Calcd for C30H24ClN3O2: C,
72.94; H, 4.90; N, 8.51%. Found C, 72.83; H, 4.96; N, 8.60%.
26. (a) Ranjth Kumar, R.; Perumal, S.; Kagan, H. B.; Guillot, R. Tetrahedron 2006, 62,
12380–12391; (b) Ranjith Kumar, R.; Perumal, S. Tetrahedron 2007, 63, 7850–
7857; (c) Suresh Kumar, R.; Perumal, S.; Kagan, H. B.; Guillot, R. Tetrahedron:
Asymmetry 2007, 18, 170–180; (d) Ranjth Kumar, R.; Perumal, S. Tetrahedron
2007, 63, 12220–12231.
27. Sridharan, V.; Ribelles, P.; Ramos, T.; Menéndez, J. C. J. Org. Chem. 2009, 74,
5715–5718.
28. General procedure for synthesis of (E)-2-[arylmethylidene]-3,4-dihydro-1(2H)-
acridinones 3: A solution of KOH (1 mmol) in 1 ml of water was added to a
mixture of 3,4-dihydroacridin-1(2H)-one (1 mmol) and the appropriate
aldehydes (1 mmol) in 5 ml of ethanol and stirred at room temperature for
10–20 min. After completion of the reaction (TLC), the mixture was poured into
ice-water (30 mL) and the resulting solid 3 was filtered off and washed with
water. Characterization data for a representative compound 3d are given
below.
30. Crystallographic data (excluding structure factors) for compound 7g in this
Letter have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 827431. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:deposit@ccdc.cam.ac.uk].