Oxalic acid dihydrate: Proline as a new recyclable designer solvent: A sustainable, green avenue for the synthesis of spirooxindole

Article abstract of DOI:10.1007/s11164-015-2093-3

The quest to develop an environmentally friendly, sustainable protocol for immensely bioactive spirooxindole derivatives has encouraged to explore oxalic acid dihydrate: proline low transition temperature mixture as a new designer solvent for the said syn

Full text of DOI:10.1007/s11164-015-2093-3

Res Chem Intermed
DOI 10.1007/s11164-015-2093-3
Oxalic acid dihydrate: proline as a new recyclable
designer solvent: a sustainable, green avenue
for the synthesis of spirooxindole
Dattatray R. Chandam1 Abhijeet G. Mulik1
•
•
Dayanand R. Patil1 Madhukar B. Deshmukh1,2
•
Received: 14 March 2015 / Accepted: 6 May 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The quest to develop an environmentally friendly, sustainable protocol for
immensely bioactive spirooxindole derivatives has encouraged to explore oxalic acid
dihydrate: proline low transition temperature mixture as a new designer solvent for the
said synthesis at room temperature. It has been successfully applied for the three
component reaction of isatin, malononitrile or ethyl cyanoacetate and 1,3–dicarbonyl
compounds for the first time. Moderate to good yield of the products, shorter reaction
time, energy efficiency, chromatography-free purification process, recyclability and high
atom economy are the captivating feature of this protocol which will find applications in
multi-component, diversity-oriented synthesis.
Graphical Abstract
&
Madhukar B. Deshmukh
shubhlaxmi111@gmail.com
1
2
Hetrocyclic Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416004, India
Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur 416004,
India
123

D. R. Chandam et al.
Keywords Isatin Á Multi-component reactions Á Low transition temperature
mixture Á Group-assistant-purification process Á Spiro fused heterocycles
Introduction
In the development of environmentally friendly synthetic routes for drug discovery
processes, multi-component reactions (MCRs) have been recognized as a powerful
tool during last ten years. These reactions comprises the formation of several bonds
in a single operation with remarkable advantages such as operational simplicity,
reduction of tedious workup, extraction and purification processes, a high degree of
atom economy and a shorter reaction time [1–4]. Furthermore, the quest to develop
an ecologically sustainable protocol for immensely bioactive molecules has
provoked the scientific community to adopt a ‘‘green’’ chemistry principle. In this
esteem, to meet the fundamental scientific challenges of protecting human health
and environment, significant attention has been paid to MCRs for their use in eco-
compatible reactions promoting a benign solvent rather than a toxic organic solvent.
In recent years, low transition temperature mixtures (LTTMs) or deep eutectic
solvents (DESs) have been found to be powerful, greener and cleaner alternatives to
conventional molecular solvents. Since inception [5], they have been considered as
designer solvents, as their properties are solely dependent on the natures of the
hydrogen bond donor and hydrogen bond acceptors. In comparison with ionic
liquids, LTTMs can be prepared with 100 % atom economy from easily accessible
chemicals. They are found to be non-toxic to the environment, biodegradable and
inexpensive. As LTTMs consist mainly of ionic species, they have a strong ability to
dissolve CO2 [6]. Recently, they have been successfully applied as extraction media
for proteins and potential lubricants [7, 8]. Various organic transformations like
acid-catalyzed reactions, base-catalyzed reactions, Suzuki coupling and Heck
coupling have been reported using a DES or LTTM as a catalyst [9–13].
Additionally, numerous MCRs have been investigated using a DES or LTTM as a
solvent [14, 15]. The use of LTTMs in MCRs has opened a new green avenue for
synthetic organic chemistry. For this reason, MCRs in LTTMs are of having
outstanding value in organic synthesis and green chemistry.
Among N-heterocycle skeletons, the indole moiety, being a ‘‘privileged
scaffold’’, is an important active feature and structural unit of variety of natural
products [16]. Furthermore, an enhancement in biological activity was observed in
spirooxindole derivatives due to the presence of a sterically constrained spiro
structure at the C3 position [17–20]. For example, some cytostatic alkaloids, like
spirotryprostatins and pteropodines, are effective inhibitors of microtubule activity
and modulators of muscarinic serotonin receptor functions (Fig. 1). Spirooxindole
compounds with substituted, fused 4H chromenes at the C3 position have immense
importance because of their diuretic, anticoagulant, anticancer and spasmolitic
activities [21–23].
A variety of protocols [24–39] have been reported for the synthesis of spiro [4H-
pyran-3,3-oxindole] derivatives. Most of the reported methods are associated with
123

Oxalic acid dihydrate: proline as a new recyclable designer…
O
CH3
O
N
N
H
H
H
N
O
H
HH
N
N
O
O
CH3
CH3
CH3
CH3
Me O
O
O
O
N
H
O
OCH3
N
H
N
H
Me O
Pteropodine
Spirotryprostatin B
Spirotryprostatin A
Fig. 1 Bioactive molecules of spirooxindole
the use of either carcinogenic organic solvents, high temperatures, expensive and
non-commercially available catalysts, or are lacking catalyst reusability. Therefore,
there is still need for versatile, simple and environmentally friendly sustainable
protocols. Considering the above subjects and our continuing efforts to develop new
environmentally benign synthetic methodologies [40–44], herein, we explored the
role of oxalic acid dihydrate: proline LTTM as a reaction-promoting medium for the
first time for the synthesis of diverse spirooxindole derivatives at room temperature
(Scheme 1).
Experimental
General
All chemicals and solvents were reagent grade. Analytical thin-layer chromatog-
raphy (TLC) was performed using percolated silica gel 60-F254 plates. Infrared (IR)
spectra on potassium bromide (KBr) disks were recorded on a Shimadzu IR-470 FT-
IR spectrophotometer. Routine nuclear magnetic resonance (NMR) spectra were
taken in DMSO d6 (dimethyl sulfoxide-d6) using a Bruker 300 and a 400-MHz
spectrophotometer with tetramethylsilane (TMS) as an internal standard. Elemental
analysis was done using an Euro elemental analyzer.
Typical procedure for preparation of an LTTM
The LTTM was synthesized according to the method reported in the literature [45]. The
mixtureofoxalicaciddihydrate(12.6 g,100 mmol)andproline(11.5 g,100 mmol)ata
ratio of 1:1, when heated slowly at 80 °C for 1 h, resultedin the formation of a yellowish
viscous liquid (i.e., LTTM) with 100 % atom economy (Scheme 2).
Typical procedure for an LTTM promoted reaction
A mixture of dimedone (0.140 g, 1 mmol), isatin (0.147 g, 1 mmol) and malononitrile
(0.066 g, 1 mmol) was stirred in round bottom flask containing 5 mL of oxalic acid
dihydrate:proline LTTM at room temperature for an appropriate time. After completion
of the reaction, as indicated by TLC, 10 mL of water was added to the reaction mixture
123

D. R. Chandam et al.
Z
X
X
O
O
NH2
O
O
R2
R2
LTTM
RT
CN
R
X
Z
X
O
O
+
+
N
N
X
3
O
R1
R1
4
2
1
Scheme 1 Synthesis of spirooxindole derivatives in an oxalic acid dihydrate: proline LTTM at room
temperature
H
OH
O
OH
O
O
O
HO
O
O
º
Heated slowly to 80 C
+
N
H
OH
2H2O
N
HO
O
2H2O
LTTM
H
oxalic acid
dihydrate
proline
Scheme 2 Preparation of an oxalic acid dihydrate: proline LTTM
and the insoluble crude product was filtered off. The aqueous layer was evaporated
under vacuum to recover the LTTM. The crude product was washed with distilled water
(5 mL) and recrystallized from ethanol (10 mL).
Recyclability of an oxalic acid dihydrate: proline LTTM
Recyclability ofthe LTTM was studied using the reaction of 1 mmol of isatin,
1 mmol of dimedone, 1 mmol of malononitrile and the oxalic acid dihydrate:
proline LTTM under optimized conditions. After completion of the reaction, as
indicated by TLC, 10 mL of water was added to the reaction mixture and the crude
product was separated by filtration. The LTTM was recovered by evaporating the
water at 80 °C under vacuum. The recycled LTTM was reused for the next batch
1
and recycled again. No observable differences were found between the H NMR
1
spectra of fresh and recovered LTTM after four successive runs. Fresh LTTM: H
NMR (300 MHz, DMSO d6): dH (ppm) 1.84–1.99 (m, 3H), 2.17–2.23 (m, 1H),
3.16–3.24 (m, 2H), 4.11–4.16 (t, 1H), 7.60 (bs, 9H).
1
Recovered LTTM: H NMR (300 MHz, DMSO d6): dH (ppm) 1.83–1.96 (m,
3H), 2.16–2.21 (m, 1H), 3.16–3.22 (m, 2H), 4.10–4.15 (t, 1H), 7.22 (bs, 9H).
Selected spectral data
2-amino-7,7-dimethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,30-indoline]-
3-carbonitrile (4a)
Colorless Powder, M.P. 269–271 °C, IR (KBr) (Vmax/cm-1): 3399, 3322, 3196,
1
2202, 1706, 1672. H NMR (300 MHz, DMSO d6): dH (ppm) 1.01–1.04 (d, 6H,
123

Oxalic acid dihydrate: proline as a new recyclable designer…
2CH3), 2.12–2.05 (dd, 2H, CH2), 2.50–2.56 (d, 2H, CH2), 6.78–6.80 (d, 1H, Ar-H),
6.86–6.91 (t, 1H, Ar-H), 6.96–6.98 (t, 1H, Ar-H), 7.11–7.14 (1H, m, Ar-H), 7.17 (s,
2H, NH2), 10.35 (s, 1H, NH). 13C NMR (75 MHz, DMSO d6): d (ppm) 27.52,
28.04, 32.37, 47.32, 50.52, 58.13, 109.71, 111.29, 117.72, 122.14, 123.45, 128.61,
134.87, 142.54, 159.25, 164.58, 178.47, 195.29 Anal. Calcd for C19H17N3O3: C,
68.05; H, 5.11; N, 14.31 %. Found: C, 68.09; H, 5.08; N, 14.28 %.
2-Amino-5-oxo-7,7-dimethyl-spiro[(4H)-5,6,7,8-tetrahydrochromene-4,30-(30H)-10-
methyl-indol]-(10H)-20-one-3-carbonitrile (4e)
Colorless Powder, M.P. 255–258 °C, IR (KBr) (Vmax/cm-1): 3472, 3315, 2189,
1715, 1654.1H NMR (400 MHz, DMSO d6): dH (ppm) 0.99 (s, 3H, CH3), 1.05 (s,
3H, CH3), 2.14–2.02 (2H, AB system, JHH = 16.4 Hz), 2.43 (dd, 2H, CH2), 3.18
2
(s, 3H, N-CH3), 6.38 (s, 2H, NH2), 6.81–6.79 (1H, d, Ar), 6.95–6.94 (2H, d, Ar),
7.21–7.17 (1H, m, Ar). 13C NMR (100 MHz, DMSO d6): d (ppm) 26.66, 27.63,
28.41, 32.21, 46.85, 50.56, 108.17, 111.54, 117.20, 122.77, 122.95, 128.75, 133.38,
143.70, 159.17, 164.09, 176.95, 194.95. Anal. Calcd for C20H19N3O3: C, 68.75; H,
5.48; N, 12.03 %. Found: C, 68.69; H, 5.53; N, 12.08 %.
2-Amino-5-oxo-7,7-dimethyl-spiro[(4H)-5,6,7,8-tetrahydrochromene-4,30-(30H)-10-
phenyl-indol]-(10H)-20-one-3-carbonitrile (4f)
Colorless Powder, M.P. [ 300 °C, IR (KBr) (Vmax/cm-1): 3595, 3376, 3294,
2192, 1682, 1602.1H NMR (300 MHz, DMSO d6): dH (ppm) 1.03 (s, 3H, CH3), 1.05
(s, 3H, CH3), 2.26–2.12 (2H, AB system, JHH = 16.2 Hz), 2.62 (s, 2H, CH2),
2
6.67–6.65 (2H, d, NH2), 7.06–7.01 (2H, t, Ar), 7.22–7.14 (2H, m, Ar), 7.40–7.34
(2H, m, Ar), 7.50–7.45 (1H, m, Ar), 7.63–7.58 (2H, m, Ar). 13C NMR (100 MHz,
DMSO d6): d (ppm) 27.53, 28.10, 32.50, 47.14, 50.35, 52.74, 109.04, 111.36,
117.62, 123.52, 123.87, 127.10, 128.56, 128.94, 130.12, 133.72, 135.27, 143.77,
159.32, 164.94, 176.59, 194.64. Anal. Calcd for C25H21N3O3: C, 72.98; H, 5.14; N,
10.21 %. Found: C, 73.03; H, 5.11; N, 10.18 %.
Ethyl-2-amino-5-oxo-spiro[(4H)-5,6,7,8-tetrahydrochromene-4,30-(30H)-50-nitro-
indol]-(10H)-20-one-3-carboxylate (4j)
Colorless powder, M.P. 277–279 °C, IR (KBr) (Vmax/cm-1): 3290, 3187, 2959,
1
1732, 1686, 1644. H NMR (300 MHz, DMSO d6): dH (ppm) 0.845–0.798 (t, 3H,
CH3), 0.97 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.11 (s, 2H, CH2), 2.65–2.50 (2H, AB
2
system, JHH = 17.4 Hz), 3.77–3.72 (q, 2H, CH2), 6.885–6.91 (d, 2H, NH2), 7.75
(1H, s, Ar), 8.10–7.98 (m, 3H, Ar), 13C NMR (100 MHz, DMSO d6): d (ppm) 26.66,
27.63, 28.41, 32.21, 46.85, 50.56, 108.17, 111.54, 117.20, 122.77, 122.95, 128.75,
133.38, 143.70, 159.17, 164.09, 176.95, 194.95. Anal. Calcd for C21H21N3O7: C,
59.01 %; H, 4.95 %; N, 9.83 %. Found: C, 58.95 %; H, 4.93 %,; N, 9.88 %.
123

D. R. Chandam et al.
7-Amino-2,20,4-trioxo-1,10,2,20,3,4-hexahydrospiro[indole-30,5-pyrano[2,3-d]
pyrimidine]-6-carbonitrile (4k)
Colorless powder, M.P. 274–276 °C, IR (KBr) (Vmax/cm-1): 3306, 3145, 2204,
1714, 1393.1H NMR (300 MHz, DMSO d6):dH (ppm) 6.80–6.78 (1H, d, Ar),
6.94–6.91 (1H, dd, Ar), 7.18–7.11 (1H, m, Ar), 7.32 (s, NH2). 10.44 (s, NH), 11.08
(s, NH), 13C NMR (75 MHz, DMSO d6): dc (ppm) 47.15, 58.49, 87.31, 109.73,
117.29, 122.22, 124.17, 128.86, 133.95, 142.61, 149.66, 153.79, 158.72, 161.83,
178.05. Anal. Calcd for C15H9N5O4: C, 55.73 %; H, 2.81 %; N, 21.66 %. Found: C,
55.69 %; H, 2.85 %; N, 21.60 %.
7-Amino-2,20,4-trioxo-1,10,2,20,3,4-hexahydrospiro[50nitroindole-30,5-pyrano[2,3-
d]pyrimidine]-6-carbonitrile (4n)
Colorless powder, M.P. [ 300 °C, IR (KBr) (Vmax/cm-1): 3444, 3299, 3182, 2200,
1750, 1698 1H NMR (300 MHz, DMSO d6): dH (ppm) 7.00–7.02 (1H, d, Ar), 7.55
(2H, s, NH2), 8.14–8.18 (1H, dd, Ar), 8.24–8.25 (1H, d, Ar), 11.18 (1H, s, NH),
11.22 (1H, s, NH), 12.40 (1H, s, NH), 13C NMR (75 MHz, DMSO d6): dc (ppm)
56.70, 86.28, 109.88, 117.19, 120.45, 126.35, 135.09, 143.05, 149.10, 149.73,
154.36, 159.12, 162.11, 178.83. Anal. Calcd for C15H8N6O6: C, 48.92 %; H,
2.19 %; N, 22.82 %. Found: C, 48.85 %; H, 2.24 %; N, 22.80 %.
7-Amino-2,20,4-trioxo-1,10,2,20,3,4-hexahydrospiro[50iodoindole-30,5-pyrano[2,3-d]
pyrimidine]-6-carbonitrile (4o)
Reddish powder, M.P. 276–278 °C (dec.), IR (KBr) (Vmax/cm-1): 3291, 3146,
2198, 1689, 1643 1H NMR (300 MHz, DMSO d6): dH (ppm) 6.62–6.65 (1H, d, Ar),
7.46–7.51 (2H, m, Ar), 7.55 (2H, s, NH2), 10.62 (1H, s, NH), 11.17 (1H, s, NH),
12.33 (1H, s, NH),. 13C NMR (75 MHz, DMSO d6): dc (ppm) 47.09, 57.47, 85.22,
86.69, 112.29, 117.34, 132.60, 136.55, 137.48, 142.30, 149.70, 154.01, 158.84,
161.99, 177.72. Anal. Calcd for C15H8IN5O4: C, 40.11 %; H, 1.80 %; N, 15.59 %.
Found: C, 40.05 %; H, 1.78 %; N, 15.66 %.
70-Amino-10,30-dimethyl-2,20,40-trioxo-1,10,2,20,30,40-hexahydrospiro
[50bromoindole-3,50-pyrano[2,3-d]pyrimidine]-60-carbonitrile (4r)
Colorless powder, M.P. [ 300 °C, IR (KBr) (Vmax/cm-1): 3375, 3305, 3202, 2197,
1
1683, 1653. H NMR (300 MHz, DMSO d6): dH (ppm) 3.05 (3H, s, N-CH3), 3.38
(3H, s, N-CH3), 6.79–6.77 (1H, d, Ar), 7.39–7.36 (2H, d, J = 10.8 Hz), 7.61–7.52
(2H, bs, NH2), 10.61 (s, NH). 13C NMR (75 MHz, DMSO d6): dc (ppm) 28.10,
29.80, 48.08, 57.67, 87.04, 117.63, 113.94, 117.09, 127.19, 131.64, 136.54, 141.98,
150.14, 152.72, 158.65, 159.98, 177.63. Anal. Calcd for C17H12N5O4: C, 47.46 %;
H, 2.81 %; N, 16.28 %. Found: C, 47.50 %; H, 2.78 %; N, 16.22 %.
123

Oxalic acid dihydrate: proline as a new recyclable designer…
70-Amino-10,30-dimethyl-2,20,40-trioxo-1,10,2,20,30,40-hexahydrospiro[50iodoindole-
3,50-pyrano[2,3-d]pyrimidine]-60-carbonitrile (4s)
Colorless powder, M.P. = 265–267 °C (dec.), IR (KBr) (Vmax/cm-1): 3369, 3301,
2196, 1705, 1679 1H NMR (300 MHz, DMSO d6): dH (ppm) 3.37 (6H, s, 2 N-CH3),
6.64–6.67 (1H, d, Ar), 7.49–7.51 (2H, d, Ar), 7.61 (2H, s, NH2), 10.64 (1H, s, NH).
13C NMR (75 MHz, DMSO d6): dc (ppm) 28.13, 29.81, 47.83, 57.43, 85.22, 86.94,
112.34, 117.20, 132.54, 136.70, 137.53, 142.28, 150.16, 152.72, 158.65, 160.02,
177.69. Anal. Calcd for C17H12IN5O4: C, 42.79 %; H, 2.53 %; N, 14.68 %. Found:
C, 42.84 %; H, 2.50 %; N, 14.71 %.
70-Amino-5-chloro-2,40-dioxo-20-thioxo-10,20,30,40-tetrahydrospiro[indoline-3,50-
pyrano [2,3-d] pyrimidine]-60-carbonitrile (4u)
Colorless powder, M.P. 224–226 °C, IR (KBr) (Vmax/cm-1): 3359, 3282, 3148,
2197, 1686, 1575. 1H NMR (300 MHz, DMSO d6): dH (ppm) 6.83–6.80 (1H, d, Ar),
7.21–7.24 (1H, d, Ar), 7.40 (1H, s, Ar), 7.53 (2H, s, NH2), 10.71 (1H, s, NH), 12.55
(1H, s, NH). 13C NMR (75 MHz, DMSO d6): dc (ppm) 57.32, 91.48, 111.13, 117.14,
124.85, 126.37, 128.93, 135.47, 141.53, 153.46, 158.69, 159.68, 174.47, 177.51.
Anal. Calcd for C15H11N5O3SCl: C, 48.20 %; H, 2.16 %; N, 18.74 %; S, 8.58 %.
Found: C, 48.25 %; H, 2.18 %; N, 18.70 %; S, 8.55 %.
70-Amino-1-methyl-2,40-dioxo-20-thioxo-10,20,30,40-tetrahydrospiro[indoline-3,50-
pyrano[2,3-d]pyrimidine]-60-carbonitrile (4x)
Colorless powder, M.P. [ 300 °C, IR (KBr) (Vmax/cm-1): 3344, 3175, 2848, 2206,
1682, 1647, 1593. 1H NMR (300 MHz, DMSO d6): dH (ppm) 3.14 (3H, s, N-CH3),
6.98–7.03 (2H, t, Ar), 7.24–7.28 (2H, t, Ar J = 10.8 Hz), 7.315 (1H, s, NH), 7.46
(2H, s, NH2), 12.50 (1H, s, NH). 13C NMR (75 MHz, DMSO d6): dc (ppm) 26.94,
56.65, 91.96, 108.55, 110.96, 123.11, 125.95, 129.31, 132.83, 138.16, 144.02,
158.70, 160.01, 161.27, 174.41, 176.16. Anal. Calcd for C16H11N5O3S: C, 54.38 %;
H, 3.14 %; N, 19.82 %; S, 9.07 %. Found: C, 54.32 %; H, 3.11 %; N, 19.87 %; S,
9.11 %.
70-Amino-5-iodo-2,40-dioxo-20-thioxo-10,20,30,40-tetrahydrospiro[indoline-3,50-
pyrano[2,3-d] pyrimidine]-60-carbonitrile (4y)
Colorless powder, M.P. = 250–253 °C (dec.), IR (KBr) (Vmax/cm-1): 3275, 3156,
2194, 1681, 1615, 1570. 1H NMR (300 MHz, DMSO d6): dH (ppm) 6.63–6.66 (1H,
d, Ar), 7.49–7.52 (3H, m, 2Ar and 1NH), 7.63 (2H, s, NH2), 10.67 (1H, s, NH),
12.54 (1H, s, NH). 13C NMR (75 MHz, DMSO d6): dc (ppm) 46.95, 57.23, 85.33,
112.31, 132.89, 135.96, 137.65, 142.33, 153.37, 158.69, 159.71, 174.32, 177.27.
Anal. Calcd for C15H8IN5O3S: C, 38.73 %; H, 1.73 %; N, 15.05 %; S, 6.89 %.
Found: C, 38.78 %; H, 1.69 %; N, 15.01 %; S, 6.95 %.
123

D. R. Chandam et al.
Result and discussion
In view of the important applications of bioactive spirooxindole derivatives, our
current focus has been targeted on the facile synthesis of these moieties at room
temperature. As a part of the endeavor, the reaction of isatin (1 mmol),
malononitrile (1 mmol) and dimedone (1 mmol) was selected as a template
reaction. The model reaction was carried out in different DESs or LTTMs at room
temperature (Table 1, entries 1–8). In the absence of solvent, the reaction afforded
traces of the product (Table 1, entry 1). A comparison of efficiency of the LTTM
revealed that oxalic acid dihydrate: proline LTTM (Table 1, entry 6) as a superior
solvent.
With these interesting results in our hand, we then explored the scope of the
present method with various isatins, malononitrile or ethyl cyanoacetate, and
various 1,3-dicarbonyl compounds; results are depicted in Table 2. As shown in
Table 2, it was observed that this protocol works well with a wide array of
substrates. A series of 5-substituted and N-substituted isatins and various dicarbonyl
compounds were used in the reaction. Although the reaction of isatin and dimedone
with malononitrile or ethyl cyanoacetate proceeded smoothly, the reaction time with
ethyl cyanoacetate was longer than that with malononitrile (Table 2, entry 7–10),
which is possibly due to lower reactivity of ethyl cyanoacetate.
Table 1 Screening of various LTTMs and optimum conditions for the synthesis of spirooxindolea
derivatives in different conditions
O
3
O
O
NH2
CN
CN
CN
reaction conditions
rt
O
O
+
+
N
H
O
O
N
H
4a
1
2
Entry
Solvent
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
a
No solvent
Choline chloride: urea
250
125
85
Traces
40
Choline chloride: oxalic acid
Dimethyl urea: citric acid
Choline chloride: SnCl2
Oxalic acid dihydrate: proline
Malic acid: proline
40
170
150
30
30
35
94
50
70
Lactic acid: proline
45
65
Reaction condition: all three reactants in equimolar ratio, solvent, RT
Isolated yield
b
123

Oxalic acid dihydrate: proline as a new recyclable designer…
Table 2 Synthesis of spirooxindole derivativesa (5a–5j) with varying reactants over LTTMs at room
temperature
Z
X
X
O
O
NH2
O
O
R2
R2
LTTM
RT
CN
R
X
Z
X
O
+
O
+
N
N
X
3
O
R1
R1
4
2
1
O
N
O
O
O
O
O
O
I
O
O2N
O
Br
Cl
O
O
O
O
O
N
N
H
N
H
N
H
N
H
N
H
Ph
1g
1c
1f
1a
1b
1d
1e
O
O
O
O
CN
COOEt
HN
CN
CN
N
HN
S
N
H
O
O
N
O
O
O
N
H
O
3d
3c
2b
3a
3b
2a
Entry
Isatin
Alkyl
malonate
1,3-dicarbonyl
compound
Product
Time
(min)
Yieldb
(%)
Atom
economyd
1
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
3d
3d
4a
4b
4c
4d
4e
4f
30
35
35
40
32
30
55
58
62
65
55
56
60
70
65
60
60
59
55
60
62
65
70
60
94
89
89
87
91
90
86
84
85
83
90
87
88
82c
89c
86
85
86
88c
84
82
83
78
80c
89.13
85.09
85.29
83.06
86.53
86.22
82.13
80.52
81.80
79.64
85.25
82.23
84.22
78.17
85.56
81.80
81.21
82.54
84.80
79.76
78.22
79.61
74.50
76.11
2
3
4
5
6
7
1a
1b
1c
1d
1a
1b
1c
1d
1g
1a
1b
1c
1g
1a
1b
1c
1d
1e
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
123

D. R. Chandam et al.
Table 2 continued
Entry
Isatin
Alkyl
malonate
1,3-dicarbonyl
compound
Product
Time
(min)
Yieldb
(%)
Atom
economyd
25
1g
2a
3d
4y
60
81c
77.98
a
Reaction condition: All three reactants in equimolar ratio, oxalic acid dihydrate: proline RT
b
c
d
Isolated yield
Repared for first time
Atom economy = molecular weight of desired product/sum of molecular weight of all
reactants 9 100 %
O
N
H
H
H
O-
H
O
O
N
N
OH
OH
O
O
OH
OH
O
OH
HOOC
CN
O
O
O-
O
O
H
H
O
NC
O
O
H
CH-
CN
NC
H
N
NC
O
CN
OH
OH
O
O
O
O
H
N
O
H
OH
O
O
O
O
H
O
O
OH
H
H
CN
CN
CN
O
NH2
O
NH
N
O
O
Where
=
O
N
H
Scheme 3 Plausible mechanism for spirooxindole synthesis showing electrophilic activation of isatin
through hydrogen bonding
The selectivity of an LTTM is due to the hydrogen bonding nature of the LTTM
enhancing the electrophilicity of carbonyl groups which substantially promotes the
reaction. Though the role of an LTTM is yet to be confirmed, we explore the
probable mechanism of LTTM promoted one-pot synthesis of spirooxindole
involving initial formation of a Knoevenagel adduct with subsequent Michael
addition and cyclization via hydrogen bonding, as depicted in Scheme 3.
Next, recyclability is an essential aspect in view of green chemistry. The
possibility of recyclability of LTTM was examined by using the reaction of isatin,
malononitrile and dimedone as model substrates under optimized conditions. After
123

Oxalic acid dihydrate: proline as a new recyclable designer…
Table 3 Recyclability of the LTTM
Run
Fresh
94
I
II
III
87
IV
80
LTTM
92
90
Fig. 2 Recyclability of the
LTTM
Recyclability of LTTM
94
95
92
90
Yield
90
85
80
75
70
87
80
IV
Fresh
I
II
III
Run
Atom Economy
90
85
80
75
70
65
60
55
50
45
40
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v
Product
Fig. 3 Percent atom economy of product (4a–4v)
completion of the reaction, water (10 mL) was added to the reaction mixture and
crude product was separated by filtration. Finally, the LTTM was recovered by
evaporating the water at 80 °C under vacuum and was reused for the next batch and
recycled again. It was found that the LTTM could be used for four successive runs
without a noticeable decrease in its activity (Table 3, Fig. 2). In addition, a group-
assistant-purification (GAP) chemistry process [46] was used for purification of
crude product. All the products were obtained as pure by just washing the solid crude
products with ethanol, avoiding traditional chromatography and recrystallization
purification processes. The products were characterized by spectroscopic analysis
(1HNMR, 13CNMR, CHNS) and confirmed by comparison of the spectroscopic data
123

D. R. Chandam et al.
Table 4 Comparison of efficiency of oxalic acid dihydrate: proline with several catalysts in the literature
for the synthesis of spirooxindole (4a)
Entry
Reaction condition
Time (min)
Yield (%)
Reference
1
2
3
4
5
6
7
8
Nano-MgO/H2O/80 °C
L-proline/H2O/80 °C
SBNPTT/H2O/reflux
120
15
93
[26]
92
[30]
20
97
[31]
PEG-400/50 °C
TEBA/H2O/60 °C
InCl3/MW or reflux
60
92
[35]
180
3 or 90
20
90
[36]
93 or 75
75
[37]
Magnetic catalyst/H2O/30 °C
Oxalic acid dihydrate: proline LTTM/RT
[38]
30
94
Present work
and melting points with authentic literature data. Moreover, the sustainability and
greenness of the protocol was proven by its atom economy. Higher atom economy
values were found to support the greenness of the methodology (Fig. 3).
The proficiency of this protocol has been compared with some of the previously
reported methods and results are compiled in Table 4. It is clear from Table 4 that
oxalic acid dihydrate: proline is an environmentally benign and efficient reaction
promoting medium for the synthesis of a series of spirooxindole derivatives.
Conclusion
An efficient and simple method for the synthesis of spirooxindole derivatives was
developed via one-pot, three component reaction of isatin, malononitrile or ethyl
cyanoacetate and 1,3-dicarbonyl compounds. Most of the reported methods involve
an expensive catalyst which requires tedious preparation, involve harmful organic
solvents and lack recyclability. The present method offers several advantages, such
as simple LTTM preparation with 100 % atom efficiency, good product yield, shorter
reaction times, LTTM recyclability enabling avoidance of hazardous organic
solvents, and a GAP chemistry procedure. Owing to the advantages of this protocol
over other methods, we expect that it will find extensive application in combinatorial
chemistry as well as multi-component green synthesis as it involves green, three
component, LTTM prompted reaction that afford different types of spirooxindole
fused heterocycles.
Acknowledgments We are thankful to Department of Chemistry, Shivaji University, Kolhapur for
providing spectral analysis. We are grateful to the UGC New Delhi [F.No.41-211/2012(SR)] for financial
support.
References
1. J. Zhu, H. Bienayme, Multi-component Reactions (Wiley-VCH, Weinheim Germany, 2005)
2. R.A. Sheldon, Pure Appl. Chem. 72, 1233–1246 (2000)
3. B.M. Trost, Science 254, 1471–1477 (1991)
123

Oxalic acid dihydrate: proline as a new recyclable designer…
4. M.S. Singh, S. Chowdhury, RSC Adv. 2, 4547–4592 (2012)
5. A.P. Abbott, G. Capper, D.L. Davies, R.K. Rasheed, V. Tambyrajah, Chem. Commun. 70–71 (2003)
6. X. Li, M. Hou, B. Han, X. Wang, L. Zou, J. Chem. Eng. Data 53, 548–550 (2008)
7. Q. Zeng, Y. Wang, Y. Huang, X. Ding, J. Chen, K. Xu, Analyst 139, 2565 (2014)
8. A.P. Abbott, E.I. Ahmed, R.C. Harris, K.S. Ryder, Green Chem. 16, 4156 (2014)
9. N. Azizi, S. Dezfooli, M.M. Hashemi, J. Mol. Liq. 194, 62–67 (2014)
10. D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, D.R. Patil, S.A. Sankpal, M.B. Deshmukh, J.
Mol. Liq. 207, 14–20 (2015)
11. S.B. Phadtare, G.S. Shankarling, Green Chem. 12, 458–462 (2010)
12. G. Imperato, S. Hoger, D. Lenoir, B. Konig, Green Chem. 8, 1051–1055 (2006)
13. F. Ilgen, B. Konig, Green Chem. 11, 848–854 (2009)
14. S. Gore, S. Baskaran, B. Konig, Green Chem. 13, 1009–1013 (2011)
15. Z.-H. Zhang, X.-N. Zhang, L.-P. Mo, Y.-X. Li, F.P. Ma, Green Chem. 14, 1502–1506 (2012)
16. W.J. Houlihan, W.A. Remers, R.K. Brown, Indoles, Part I (Wiley, New York, 1992)
17. T.H. Kang, K. Matsumoto, Y. Murakami, H. Takayama, M. Kitajima, N. Aimi, H. Watanabe, Eur.
J. Pharmacol. 444, 39–45 (2002)
18. J. Ma, S.M. Hecht, Chem. Commun. 1190–1191 (2004)
19. M.M. Khafagy, A.H. El-Wahas, F.A. Eid, A.M. El, Farmaco 57, 715–722 (2002)
20. J. Skommer, D. Wlodkowic, M.M. Matto, P. Eray, J. Leuk. Res. 30, 322–331 (2006)
21. W.P. Smith, L.S. Sollis, D.P. Howes, C.P. Cherry, D.I. Starkey, N.K. Cobley, J. Med. Chem. 41,
787–797 (1998)
22. L. Bonsignore, G. Loy, D. Secci, A. Calignano, Eur. J. Med. Chem. 28, 517 (1993)
23. L. Andreani, E. Lapi, Bol. Chim. Farm. 99, 583 (1960)
24. M. Seyed, T. Mahmood, F. Maryam, C. R. Chimie 17, 1160–1164 (2014)
25. D.S. Raghuvanshi, K.N. Singh, J. Heterocycl. Chem. 47, 1323 (2010)
26. B. Karmakar, A. Nayak, J. Banerji, Tetrahedron Lett. 53, 5004–5007 (2012)
27. S.P. Satasia, P.N. Kalaria, J.R. Avalani, D.K. Raval, Tetrahedron 70, 5763–5767 (2014)
28. Y. Li, H. Chen, C. Shi, D. Shi, S. Ji, J. Comb. Chem. 12, 231 (2010)
29. K. Niknam, P. Abolpour, Monatsh. Chem. 4, 683–690 (2015)
30. G.S. Hari, Y.R. Lee, Synthesis 3, 453 (2010)
31. S.J. Chai, Y.F. Lai, J.C. Zu, H. Zheng, Q. Zhu, P.F. Zhang, Adv. Synth. Catal. 353, 371 (2011)
32. R.M. Kurosh, Y.M. Leila, Tetrahedron 67, 5693 (2011)
33. M. Dabiri, M. Bahramnejad, M. Baghbanzadeh, Tetrahedron 65, 9443–9447 (2009)
34. S. Gao, C.H. Tsai, C. Tseng, C. Yao, Tetrahedron 64, 9143 (2008)
35. H.M. Meshram, D.A. Kumar, B.R.V. Prasad, P.V. Goud, Helv. Chim. Acta 93, 648 (2010)
36. S.L. Zhu, S.J. Ji, Y. Zhang, Tetrahedron 63, 9365 (2007)
37. G. Shanthi, G. Subbulakshmi, P.T. Perumal, Tetrahedron 63, 2057 (2007)
38. L. Jalili-Baleh, M. Narges, K. Mehdi, L. Mamani, A. Foroumadi, A. Shafiee, Helv. Chim. Acta 96,
1601 (2013)
39. Y.L. Gu, Green Chem. 14, 2091–2128 (2012)
40. D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, D.R. Patil, M.B. Deshmukh, Res. Chem.
Intermed. 41, 761–771 (2015)
41. A.G. Mulik, D.R. Chandam, P.P. Patil, S.D. Jagdale, D.R. Patil, M.B. Deshmukh, J. Mol. Liq. 179,
104–109 (2013)
42. D.R. Patil, D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, M.B. Deshmukh, Res. Chem.
Intermed (2014). doi:10.1007/s11164-014-1782-7
43. D.R. Patil, D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, R. Kant, V. Gupta, M.B. Deshmukh,
Catal. Lett. 144, 949–958 (2014)
44. A.A. Patravale, A.H. Gore, D.R. Patil, G.B. Kolekar, M.B. Deshmukh, P.V. Anbhule, Ind. Eng.
Chem. Res. 53, 16568–16578 (2014)
45. M. Francisco, M.C. Kroon, Angew. Chem. Int. Ed. 52, 3074–3085 (2013)
46. P. Kaur, S. Pindi, W. Wever, T. Rajale, G. Li, Chem. Commun. 46, 4330–4332 (2010)
123