One-pot, catalyst-free synthesis of spirooxindole and 4 h-pyran derivatives

Article abstract of DOI:10.1080/00397911.2013.837488

The synthesis of biologically valuable spirooxindoles and 4H-pyrans is described under catalyst-free conditions through sequential Knoevenagel-Michael- cyclization reactions from isatin or aromatic aldehyde, malononitrile, and 1,3-dicarbonyl compounds. Th

Full text of DOI:10.1080/00397911.2013.837488

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One-Pot, Catalyst-Free Synthesis of
Spirooxindole and 4H-Pyran Derivatives
Thanasekaran Ponpandian a b & Shanmugam Muthusubramanian a
a Department of Organic Chemistry , School of Chemistry, Madurai
Kamaraj University , Madurai , India
b Department of Medicinal Chemistry , Orchid Chemicals and
Pharmaceuticals Ltd. , Chennai , India
Published online: 20 Feb 2014.
To cite this article: Thanasekaran Ponpandian & Shanmugam Muthusubramanian (2014) One-Pot,
Catalyst-Free Synthesis of Spirooxindole and 4H-Pyran Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:6, 868-874, DOI:
10.1080/00397911.2013.837488
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Synthetic Communications1, 44: 868–874, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.837488
ONE-POT, CATALYST-FREE SYNTHESIS OF
SPIROOXINDOLE AND 4H-PYRAN DERIVATIVES
Thanasekaran Ponpandian1,2 and
Shanmugam Muthusubramanian1
1Department of Organic Chemistry, School of Chemistry,
Madurai Kamaraj University, Madurai, India
2Department of Medicinal Chemistry, Orchid Chemicals and
Pharmaceuticals Ltd., Chennai, India
GRAPHICAL ABSTRACT
Abstract The synthesis of biologically valuable spirooxindoles and 4H-pyrans is described
under catalyst-free conditions through sequential Knoevenagel–Michael–cyclization reactions
from isatin or aromatic aldehyde, malononitrile, and 1,3-dicarbonyl compounds. The reaction
conditions are very simple, providing excellent yield.
[Supplementary materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords Catalyst-free; isatin; malononitrile; 4H-pyrans; spirooxindoles
INTRODUCTION
Spirooxindole[1] and 4H-pyrans[2] are structural units of natural products
and also display a wide range of biological activities such as anti-cancer, anti-HIV,
antiviral, antiancaphylactia, antifungal, and antibacterial activities. A sequential
Knoevenagel–Michael–cyclization reaction was one of the more convenient proto-
cols for the construction of these skeletons from readily available starting materials
such as isatin or aromatic aldehyde, malononitrile, and 1,3-dicarbonyl compounds.
This class of reaction has been carried out in the presence of quaternary ammonium
salt, base, Lewis acid, or ionic liquids such as InCl3,[3a] 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU),[3b] triethylbenzylammonium chloride,[3c] piperidine,[3d] NH4Cl,[3e]
Received June 21, 2013.
Address correspondence to Shanmugam Muthusubramanian, Department of Organic Chemistry,
School of Chemistry, Madurai Kamaraj University, Madurai 625021, India. E-mail: muthumanian2001@
yahoo.com
868

SPIROOXINDOLE AND 4H-PYRAN DERIVATIVES
869
dimethylaminopyridine (DMAP),[3f] tetrabutylammonium bromide (TBAB),[3g]
hexadecyltrimethylammonium bromide,[3h] alum,[3i] S-proline,[3j]b-CD,[3k] ethylene-
diammonium diacetate (EDDA),[3l] hexadecyldimethylbenzyl ammonium bromide,[3m]
K3PO4,[3n] hexamethylenetetramine,[3o] KF-alumina,[3p] and nano-ZnO[3q] and ionic
liquids such as [BMIm]BF4,[3r] tetramethylguanidinium triflate,[3s] and [DMDBSI] ꢀ
2HSO4.[3t] The role of catalyst in this reaction was to catalyze the Knoevenagel as well
[4a]
as Michael addition reactions. Recently Elinson et al.
and Khaksar et al.[4b]
reported the noncatalytic thermal synthesis of 4H-pyrans in isopropyl alcohol (IPA)
or water and 2,2,2-trifluoroethanol under reflux condition respectively. Each of the
protocols has its own merits, with at least one drawback such as poor yield, harsh
reaction condition, long reaction time, and high catalyst loading. With this literature
background, we planned to develop an improved, catalyst-free, and easy method to
access the spirooxindoles and 4H-pyrans, and the results are presented here.
DISCUSSION
For optimization of the conditions, the reaction of 4-fluorobenzaldehyde,
malononitrile, and dimedone was considered as the model. Here all the starting
materials were mixed together, and the reaction was performed in different solvents
at room temperature. Initially water, the polar protic environmentally friendly
solvent, was tried and the expected product 4a was obtained in 75% after 24 h
(Table 1, entry 1) but ethanol yielded 72% of 4a after 15 h (Table 1, entry 2).
Previously this class of reaction was performed with different catalysts or without
Table 1. Optimization of reaction conditions
Entry
Solvent
Water
EtOH
Time (h)
Yield (%)a
1
2
24
15
24
24
24
24
24
24
24
6
75
72
3
Cyclohexane
Toluene
THF
N=R
N=R
Trace
Trace
Trace
15
4
5
6
DCM
7
Acetone
CH3CN
Dioxane
DMA
8
9
18
65
10
11
12
DMF
DMSO
6
68
98
1
aIsolated yield.

870
T. PONPANDIAN AND S. MUTHUSUBRAMANIAN
any catalyst in polar protic solvents such as water, ethanol, and isopropanol with
limited success. The nonpolar solvents (cyclohexane and toluene) and borderline
polar-aprotic solvents (tetrahydrofuran and methylene dichloride) were totally
ineffective in this sequential reaction (Table 1, entries 3 to 6), whereas polar aprotic
solvents (DMF and DMA) gave moderate yields of 4a (Table 1, entries 10 and 11).
Dioxane, acetonitrile, and acetone were not successful (Table 1).
The highly polar aprotic solvent dimethylsulfoxide (DMSO) worked well in
this reaction, giving quantitative yield (98%) of 4H-pyran 4a in a short reaction time
(Table 1, entry 12) and hence was identified as the solvent of choice. The mild basic
character of the oxygen in DMSO facilitates the reaction efficiently and also the
product was isolated in a pure form by simple filtration. DMSO is a versatile and
powerful solvent for organic reactions involving displacement, elimination, conden-
sation, and polymerization reactions, and it can facilitate a reaction without a catalyst.[5]
Recently, Xue et al.[5a] have reported the uncatalyzed Knoevenagel condensation of
isatin and rhodanines in DMSO, and Dash et al.[5b] have reported the aldol reaction
of thiazolidinedione in DMSO medium without the use of any catalyst.
The substrate scope was then explored with different aromatic aldehydes
and 1,3-dicarbonyl components, and the results are presented in Table 2. The
reaction has gone smoothly in the presence of strong electron-releasing (OCH3)
and electron-withdrawing (NO2) groups in the phenyl ring (Table 2, entries 2 to
5). The reaction went well even with a free carboxylic acid group in the phenyl
ring, requiring no protection (Table 2, entry 6). Heteroaromatic aldehydes also
participated well in this reaction (Table 2, entries 7 and 8). When cyclohexan-1,3-dione
and 4-hydroxycoumarin were employed instead of dimedone, the reaction took
more time for completion with poor yield. When the reaction was carried out
at 70ꢁC, the reaction was completed in 3–10h in these cases (Table 2, entries 9 to 14).
The plausible mechanism of this uncatalyzed sequential reaction is given
in Scheme 1. The mild basic nature of oxygen of DMSO may facilitate the Knoevenagel
condensation and the Knoevenagel product can then undergo Michael addition
with 1,3-dicarbonyl compound. The subsequent cyclization leads to the 4H-pyran
skeleton 4.
The established protocol was extended to isatin, and the reaction of isatin,
malononitrile, and dimedone or cyclohexan-1,3-dione was carried out in DMSO
at 70 ꢁC for 1 h. The desired products 6a and 6b were obtained in 85% and
74% respectively (Scheme 2). The reaction of isatin, malononitrile, and 4-hydroxy-
coumarin yielded the products 7a and 7b in good yield, but required more reaction
time compared to that for 6.
EXPERIMENTAL
Typical Procedure for the Synthesis of 4H-Pyrans (4) as Exemplified
for 2-Amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-4H-chromene-3-carbonitrile (4a)
A mixture of 4-fluoro benzaldehyde (0.5 g, 4.0 mmol), malononitrile (0.29 g,
4.4 mmol), and dimedone (0.56 g, 4.0 mmol) in DMSO (5 mL) was stirred at room
temperature for 1 h. The resulting mixture was poured into ice and stirred for

SPIROOXINDOLE AND 4H-PYRAN DERIVATIVES
Table 2. Catalyst-free synthesis of 4H-pyran skeleton
871
Time
(h)
Yield
(%)a
Mp (ꢁC)
observed
Mp (ꢁC)
reported
Entry
Ar
3
Product
1
2
Phenyl
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3c
3c
1.5
1.5
1
4b
4c
4d
4e
4f
96
98
228–230
238–240
177–179
195–197
217–219
238–240
211–213
206–208
225–227
259–261
254–256
241–243
226–228[3p]
237–239[3m]
178–180[3m]
194–196[3m]
218–220[3m]
—
4-Chlorophenyl
4-Nitrophenyl
4-Methoxyphenyl
4-Methylphenyl
3-Carboxyphenyl
2-Thienyl
3
90
85
4
5
5
2
86
92
6
1
4g
4h
4i
7
2
88
210–212[3n]
—
8
1-Acetyl-indol-3-yl
4-Chlorophenyl
4-Chlorophenyl
4-Methylphenyl
4-Hydroxy-3-
methoxyphenyl
Phenyl
3
87
9
10
3
4j
72b
88b
78b
62b
224–226[3m]
260–262[3b]
253–255[3b]
—
10
11
12
4k
4l
6
10
4m
13
14
3c
3c
10
10
4n
4o
73b
69b
257–259
229–231
256–258[3b]
228–229[3o]
2-Thienyl
aIsolated yield.
bThe reaction was carried out at 70 ꢁC.
Scheme 1. Mechanism for the formation of 4H-pyran skeleton.

872
T. PONPANDIAN AND S. MUTHUSUBRAMANIAN
Scheme 2. Synthesis of spirooxindole skeleton.
15 min, and the solid obtained was filtered and washed with water and diethyl ether
to afford pure product (1.21 g, 98%) as a white powder. Mp 188–190 ꢁC; IR nmax
(KBr) 3356, 3179, 2190, 1674, 1637, 1604, 1507, 1464, 1410, 1367 cmꢂ1; dH
(400 MHz, CDCl3) 1.03 (s, 3H), 1.11 (s, 3H), 2.22 (d, J ¼ 6.6 Hz, 2H), 2.45 (s, 2H),
4.40 (s, 1H), 4.56 (s, 2H), 6.97 (t, J ¼ 8.6 Hz, 2H), 7.20 (dd, J ¼ 8.6 Hz, 2.8 Hz,
2H); dC (100 MHz, DMSO-d6) 26.8, 28.3, 31.8, 34.9, 50.0, 58.1, 112.6, 115.0,
119.6, 129.0, 140.9, 158.5, 159.7, 162.1, 162.5, 195.7. Anal. calcd. for C18H17FN2O2:
C, 69.22; H, 5.49; N, 8.97. Found: C, 69.28; H, 5.51; N, 8.99%. ESI-m=z calcd. for
[C18H17FN2O2þH]þ 313.1; found 313.1.
Typical Procedure for the Synthesis of Spirooxindoles (6 and 7)
as Exemplified for 2-Amino-7,7-dimethyl-2’,5-dioxo-5,6,7,8-
tetrahydrospiro[chromene-4,3’-indoline]-3-carbonitrile (6a)
A mixture of isatin (0.6 g, 4.0 mmol), malononitrile (0.29 g, 4.4 mmol),
and dimedone (0.56 g, 4.0 mmol) in DMSO (5 mL) was stirred at 70 ꢁC for 1 h.
The resulting mixture was poured into ice and stirred for 15 min; the solid obtained
was filtered and washed with water and diethyl ether to afford pure product (1.16 g,
85%) as a pale yellow solid. Mp 267–269 ꢁC (lit.[31] 268–270 ꢁC); IR nmax (KBr) 3378,
3315, 3143, 2192, 1722, 1683, 1657, 1621, 1605, 1472, 1349 cmꢂ1; dH (400 MHz,
DMSO-d6) 1.00 (s, 3H), 1.03 (s, 3H), 2.11 (q, J ¼ 16.1 Hz, 2H), 2.54–2.61 (m, 2H),
6.78 (d, J ¼ 7.6 Hz, 1H), 6.89 (t, J ¼ 7.4 Hz, 1H), 6.97 (d, J ¼ 7.2 Hz, 1H), 7.14 (t,
J¼ 7.6 Hz, 1H), 7.22 (s, 2H), 10.39 (s, 1H); dC (100 MHz, DMSO-d6) 27.4, 28.0, 32.3,
47.2, 50.4, 57.9, 109.6, 111.2, 117.7, 122.1, 123.4, 128.5, 134.8, 142.4, 159.1, 164.5,
178.4, 195.2. Anal. calcd. for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C,
68.11; H, 5.12; N, 12.55%. ESI-m=z calcd. for [C19H17N3O3- H]þ 334.1; found 334.1.
SUPPORTING INFORMATION
1
Full experimental details, analytical data, and copies of H and 13C spectra
can be found via the Supplementary Content section of this article’s Web page.

SPIROOXINDOLE AND 4H-PYRAN DERIVATIVES
873
ACKNOWLEDGMENTS
The authors thank the Department of Science and Technology, New Delhi, for
assistance under the IRHPA Program for the NMR facility at Madurai Kamaraj
University and thank Orchid Chemicals and Pharmaceuticals Ltd. for providing
facilities.
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