Oxalic acid dihydrate and proline based low transition temperature mixture: An efficient synthesis of spiro [diindenopyridine-indoline] triones derivatives

Article abstract of DOI:10.1016/j.molliq.2016.02.101

The new facile approach has been developed for the synthesis of spiro [diindenopyridine-indoline] triones under the umbrella of green chemistry. The developed protocol is endowed with the use of low transition temperature mixture as a green reaction medium, operational simplicity, easy workup procedures, good to excellent product yields, and non-chromatographic purification procedure. Since indenone fused motifs have a broad spectrum of biological activities, this protocol is expected to find application in the combinatorial synthesis of biologically active compounds.

Full text of DOI:10.1016/j.molliq.2016.02.101

Journal of Molecular Liquids 219 (2016) 573–578
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Oxalic acid dihydrate and proline based low transition temperature
mixture: An efficient synthesis of spiro [diindenopyridine-indoline]
triones derivatives
Dattatray R. Chandam a, Abhijeet G. Mulik a, Dayanand R. Patil a, Ajinkya P. Patravale a,
Digambar R. Kumbhar b, Madhukar B. Deshmukh a,b
a
Hetrocyclic Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416004, India
Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur 416004, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The new facile approach has been developed for the synthesis of spiro [diindenopyridine-indoline] triones under
the umbrella of green chemistry. The developed protocol is endowed with the use of low transition temperature
mixture as a green reaction medium, operational simplicity, easy workup procedures, good to excellent product
yields, and non-chromatographic purification procedure. Since indenone fused motifs have a broad spectrum of
biological activities, this protocol is expected to find application in the combinatorial synthesis of biologically ac-
tive compounds.
Received 18 October 2015
Received in revised form 22 January 2016
Accepted 27 February 2016
Available online xxxx
Keywords:
Isatin
© 2016 Elsevier B.V. All rights reserved.
Indenone fused heterocycles
Spiro compounds
Low transition temperature mixture
1. Introduction
upon the nature and ratio of the counterparts, they can be considered
as designer solvent. They radially dissolve CO2 as well as worked as
In the advancement of green chemistry, during the last few years,
considerable efforts have been made to design new protocols with less
environmental hazards, higher atom economy [1]. In this esteem, mul-
ticomponent reactions have been used as a powerful, highly atom effi-
cient tool to construct complex molecules starting from small
molecules [2]. Multicomponent reactions (MCRs) comprise facile, fast,
efficient synthesis of complex and bioactive molecules with reduction
in number of step as well as waste [3,4]. Such protocols due to their eas-
iness, efficacy along with high selectivity are found to be valuable asset
in drug designing and discovery process [5]. Moreover, replacement of
hazardous organic solvent with green or sustainable media is of great
importance in the context of green chemistry [6]. In the recent years,
low transition temperature mixtures (LTTMs) or deep eutectic solvent
(DES) have been emerged as the powerful alternatives to conventional
molecular solvent, ionic liquids. After inception by Abbott [7], Kroon
et al. extended their work with introduction of new LTTMs based on di-
verse varieties of hydrogen bond donor and acceptor. The ease of prep-
aration with 100% atom economy, nontoxic and biodegradable in
nature, and its recyclability are the significant advantages of LTTMs
over ionic liquids. As their physicochemical properties solely depend
extraction media for proteins, potential lubricants [8]. LTTMs or
DESs have been emerged as green reaction media for various organic
transformations [9–13].
Indole and its derivatives are omnipresent in the plants of both ma-
rine and terrestrial origin. Heterocycles containing indole motif is an im-
portant target in synthetic and medicinal chemistry since this fragment
is key moiety in various natural products as well as drug molecules [14].
Furthermore formation of spirooxindole ring system by the sharing of
indole-3-carbon atom greatly enhances the biological activity.
Spirooxindole ring system containing natural products like
rhynchophylline, isorhynchophylline exhibit a broad range of biological
activities [15,16] while spirotryprostatin A and B have been identified as
novel inhibitors of microtubule assembly [17] (Fig. 1).
Indenone fused heterocycles are recognized as an important biolog-
ical and medicinal frameworks (Fig. 1). Onychnine represents 4-
azafluorenone group of alkaloids having indenopyridine skeleton. In ad-
dition to this, indenopyridines display numerous biological activities
such as phosphodiesterase inhibition [18], adenosine A2a receptor an-
tagonistic [19], anti-inflammatory [20], coronary dilating calcium-
modulating activities [21]as well as they have been employed for the
treatment of hyperlipoproteinemia [22], neurodegenerative diseases
[23]. Indenopyrazoles act as ascyclin-dependent kinase inhibitors [24]
while indenopyridazines act as selective monoamine oxidase B (MAO-
B) inhibitors [25].
E-mail address: shubhlaxmi111@gmail.com (M.B. Deshmukh).
http://dx.doi.org/10.1016/j.molliq.2016.02.101
0167-7322/© 2016 Elsevier B.V. All rights reserved.

574
D.R. Chandam et al. / Journal of Molecular Liquids 219 (2016) 573–578
Fig. 1. Representative natural products having spirooxindole ring system and bioactive indenone fused heterocyclic compounds.
The literature survey reveals that there are few reports on the syn-
in the ratio of 1:1 at 80 °C for 1 h which afforded yellowish viscous liquid
(LTTM) with 100% atom economy (Scheme 2).
thesis of indenone-fused heterocycles such as spiro[diindeno[1,2-
b:2′,1′-e]pyridine-11,3′-indoline]-trione from isatin, 1,3-indanedione
and aromatic amine using PTSA [26,27], PEG-SO3H and [NMP]H2PO4
[28] as catalyst under different condition. However, most of the report-
ed methods are allied with the use of expensive catalyst, toxic solvent,
and tedious preparation of catalyst. Therefore, there is a need to develop
new eco-friendly methodology for bioactive indenone-fused
heterocycles.
To our best of knowledge, there is no report on low transition tem-
perature mixture prompted synthesis of indenone-fused heterocycles.
Combining the greenness of low transition temperature mixture with
multicomponent reaction and in continuation of our research work to
develop new environmentally benign synthetic methodologies along
with the biological screening of synthesized derivatives [29–31], we
wish to report the synthesis of spiro[diindeno [1,2-b:2′,1′-e]pyridine-
11,3′-indoline]-trione derivatives using oxalic acid: proline LTTM
(Scheme 1).
2.3. Typical procedure for the synthesis of Spiro [diindenopyridine-indoline]
triones (4a)
Isatin (0.147 g, 1 mmol), 1,3-indanedione (0.292 g, 2 mmol) and an-
iline (0.093 g, 1 mmol) were mixed in oxalic acid: proline LTTM (5 mL)
as solvent and the resultant mixture was heated at 80 °C for appropriate
time. After the completion of the reaction indicated by TLC, mixture was
stirred at room temperature and 5 mL distilled water was added. The in-
soluble crude product was filtered, washed with distilled water and re-
crystallized from ethanol and acetonitrile to obtain pure product.
2.4. Recyclability of oxalic acid dihydrate: proline LTTM
The recyclability of LTTM was studied using the reaction of Isatin
(0.147 g, 1 mmol), 1,3-indanedione (0.292 g, 2 mmol) and aniline
(0.093 g, 1 mmol) in oxalic acid: proline LTTM under optimized condi-
tions. After completion of the reaction, water (5 mL) was added to the
reaction mixture and crude product was separated by filtration. Finally,
LTTM was recovered by evaporating the water at 80 °C under vacuum
and was reused for the next batch and recycled again.
2. Experimental
2.1. General
All chemicals and solvents were reagent grade and used as pur-
chased without any further purification. Percolated silica gel 60-F254
plates were used to perform analytical thin-layer chromatography. IR
spectra were recorded on a Jasco FT-IR-LE-4600 spectrophotometer.
The routine nuclear magnetic resonance spectra were taken in DMSO
d6 using a Bruker 300 MHz spectrophotometer with TMS as an internal
standard. Elemental analysis was done by using EURO elemental
analyzer.
2.5. Spectral data
1. 5-(4-chlorophenyl)-5H-spiro[diindeno[1,2-b:2′,1′-e]pyridin-11,3′-
indoline]-2′,10,12-trione(4c).
Red powder, M.P. N 300 °C, IR (KBr): 3372, 3048, 2913, 1688,
1601 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.56–5.58 (d,
2H, Ar-H), 6.85–6.92 (m, 2H, Ar-H), 7.16–7.23 (m, 2H, Ar-H), 7.27–
7.29 (d, 4H, Ar-H), 7.41–7.43 (d, 2H, Ar-H), 7.88–7.92 (d, 2H, Ar-H),
8.03–8.06 (d, 1H, Ar-H), 8.23–8.26 (d, 1H, Ar-H), 10.66 (s, 1H, NH),
Anal. Calcd for C32H17N2O3Cl: C (74.93%), H (3.34%), N (5.46%),
Found: C (74.98%), H (3.30%), N (5.40%). Due to the very low solubil-
ity of 4c, we were unable to obtain 13C NMR data.
2.2. Preparation of LTTM
The LTTM has been synthesized according to reported method in lit-
erature [32]. The preparation of LTTM involves the heating of mixture of
proline (11.5 g, 100 mmol) and oxalic acid dihydrate (12.6 g, 100 mmol)
Scheme 1. Oxalic acid dihydrate: proline (LTTM) promoted synthesis of spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-trione.

D.R. Chandam et al. / Journal of Molecular Liquids 219 (2016) 573–578
575
Scheme 2. Preparation of oxalic acid dihydrate: proline LTTM.
2. 5′-Bromo-5-(4-chlorophenyl)-5H-spiro[diindeno[1,2-b:2′,1′-
e]pyridin-11,3′-indoline]-2′,10,12-trione (4 g).
C33H19N2O4Cl: C (73.00%), H (3.53%), N (5.16%), Found: C (73.04%),
H (3.50%), N (5.12%).
Red powder, M.P. N 300 °C, IR (KBr): 3367, 3055, 2918, 1682,
1599 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.55–5.58 (d,
2H, Ar-H), 6.83–6.86 (d, 1H, Ar-H), 7.22–7.43 (m, 8H, Ar-H), 7.80–
7.93 (m, 2H, Ar-H), 8.04–8.06 (d, 1H, Ar-H), 8.29–8.31 (d, 1H, Ar-
H), 10.82 (s, 1H, NH), 13C NMR (75 MHz, DMSO d6): δC (ppm) 46.2,
111.4, 111.4, 113.9, 121.7, 121.9, 122.1, 127.9, 130.9, 131.2, 131.8,
132.2, 132.6, 133.1, 136.4, 136.8, 137.1, 142.0, 156.5, 177.6, 190.0.
HRMS: calcd for C32H16BrClN2O3: 591.8; found: 592.0 Anal. Calcd
for C32H16BrClN2O3: C (64.94%), H (2.72%), N (4.73%), Found: C
(64.98%), H (2.70%), N (4.76%).
5. 5′-Chloro-5-(4-chlorophenyl)-5H-spiro[diindeno[1,2-b:2′,1′-
e]pyridin-11,3′-indoline]-2′,10,12-trione (4 k).
Red powder, M.P. N 300 °C, IR (KBr): 3379, 3282, 3236, 1691, 1619,
1581 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.55–5.58 (d,
2H, Ar-H), 6.87–6.90 (d, 2H, Ar-H), 7.29–7.61 (m, 8H, Ar-H), 7.85–
7.93 (d, 2H, Ar-H), 8.04–8.06 (d, 1H, Ar-H), 8.28–8.30 (d, 1H, Ar-H),
10.81 (s, 1H, NH), 13C NMR (100 MHz, DMSO d6): δC (ppm) 45.8,
110.4, 110.9, 121.1, 121.4, 121.6, 124.7, 125.7, 128.4, 130.3, 130.4,
130.6, 131.7, 132.1, 132.21, 132.5, 132.6, 136.0, 136.3, 136.6, 141.1,
156.0, 177.3, 189.5 HRMS: calcd for C32H16N2O3Cl2: 547.3; found:
547.1 Anal. Calcd for C32H16N2O3Cl2: C (70.21%), H (2.95%), N
(5.12%), Found: C (70.18%), H (2.90%), N (5.15%).
3. 5′-Chloro-5-phenyl-5H-spiro[diindeno[1,2-b:2′,1′-e]pyridin-11,3′-
indoline]-2′,10,12-trione (4i).
Red powder, M.P. N 300 °C, IR (KBr): 3329, 3052, 1731, 1682,
1580 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.44–5.47 (d,
2H, Ar-H), 6.88–6.90 (m, 1H, Ar-H), 7.10–7.16 (m, 2H, Ar-H), 7.24–
7.29 (m, 4H, Ar-H), 7.42 (s, 1H, Ar-H), 7.59–7.61 (d, 1H, Ar-H),
7.79–7.83 (t, 2H, Ar-H, J = 12 Hz), 7.87–7.96 (d, 3H, Ar-H), 10.81
(s, 1H, NH), 13C NMR (75 MHz, DMSO d6): δC (ppm) 46.4, 110.0,
110.9, 111.2, 120.7, 121.7, 121.9, 122.0, 125.2, 126.1, 126.2, 128.9,
130.2, 130.6, 130.7, 130.9, 131.2, 132.1, 132.1, 132.7, 132.8, 132.9,
133.1, 136.5, 136.6, 138.2, 141.6, 156.6, 177.9, 190.0. HRMS: calcd
for C32H17N2O3Cl: 512.9; found: 512.1 Anal. Calcd for
C32H17N2O3Cl: C (74.93%), H (3.34%), N (5.46%), Found: C (74.90%),
H (3.38%), N (5.42%).
6. 5′-Chloro-5-(4-nitrophenyl)-5H-spiro[diindeno[1,2-b:2′,1′-
e]pyridin-11,3′-indoline]-2′,10,12-trione (4 l).
Red powder, M.P. N 300 °C, IR (KBr): 3276, 3055, 1696, 1580,
1516 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.57–5.59 (d,
2H, Ar-H), 7.10–7.13 (d, 1H, Ar-H), 7.21–7.25 (m, 2H, Ar-H), 7.30–
7.32 (d, 4H, Ar-H), 7.85–7.94 (m, 2H, Ar-H), 8.05–8.07 (d, 1H, Ar-
H), 8.20–8.23 (d, 1H, Ar-H), 8.33–8.36 (d, 1H, Ar-H), 8.48 (s, 1H,
Ar-H), 11.44 (s, 1H, NH), Due to the very low solubility of 4 l, we
were unable to obtain 13C NMR data. HRMS: calcd for
C32H16N3O5Cl: 557.9; found: 558.1 Anal. Calcd for C32H16N3O5Cl: C
(68.89%), H (2.89%), N (7.53%), Found: C (68.85%), H (2.93%), N
(7.50%).
4. 5′-Chloro-5-(4-methoxyphenyl)-5H-spiro[diindeno[1,2-b:2′,1′-
e]pyridin-11,3′-indoline]-2′,10,12-trione (4j).
7. 5-(4-Chlorophenyl)-5′-nitro-5H-spiro[diindeno[1,2-b:2′,1′-
e]pyridin-11,3′-indoline] -2′,10,12-trione (4o).
Red powder, M.P. N 300 °C, IR (KBr): 3347, 3065, 1729, 1707,
1676 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 3.95 (s, 3H,
,
Table 2
OCH3), 5.57–5.60 (d, 2H, Ar-H), 6.89–6.92 (d, 1H, Ar-H), 7.14–
7.31(m, 9H, Ar-H), 7.55–7.56(d, 1H, Ar-H), 7.78–7.81 (d, 1H, Ar-H),
8.06–8.08 (d, 1H, Ar-H), 10.84 (s, 1H, NH), 13C NMR (75 MHz,
DMSO d6): δC (ppm) 18.8, 46.4, 56.2, 109.9, 111.0, 115.6, 115.7,
120.7, 121.8, 122.0, 122.1, 124.6, 125.0, 126.2, 126.3, 128.9, 130.6,
130.9, 131.1, 131.3, 131.6, 132.6, 132.7, 133.0, 136.4, 136.5, 136.6,
141.0, 141.4, 146.3, 148.5, 156.6, 157.2, 161.5, 178.2, 190.2, HRMS:
calcd for C33H19N2O4Cl: 542.9; found: 540.5 Anal. Calcd for
Synthesis of Spiro [diindenopyridine-indoline] trionesa.
Entry
X
Y
Product Time
(min) (%)
Yieldb Atom economyd E-factore
1
2
3
4
5
6
7
8
H
H
4a
20 94
84.4
84.0
81.4
79.7
86.8
85.2
83.4
82.5
84.1
81.8
81.9
80.2
80.6
81.9
80.1
75.8
0.18
0.19
0.23
0.26
0.15
0.17
0.20
0.21
0.19
0.22
0.22
0.24
0.24
0.22
0.24
0.32
H
H
H
OCH3 4b
17
93
Cl
NO2
H
4c
4d
4e
18
25
18
15
17
25
20
15
18
25
25
20
22
35
90c
88
Br
Br
Br
Br
Cl
Cl
Cl
Cl
NO2
92
OCH3 4f
90
Cl
NO2
H
4g
4h
4i
88c
87
Table 1
Screening of the solvents to optimize the reaction conditiona.
9
93c
90c
90c
88c
89
10
11
12
13
14
15
16
OCH3 4j
Entry
Solvent
Time (min)
Yieldb (%)
Cl
NO2
H
4k
4l
4m
1
2
3
4
5
7
8
9
No solvent
Water
Glycerol
Polyethylene glycol
2,2,2-trifluroethanol
Oxalic acid dihydrate: proline
Choline chloride: urea
Choline chloride: oxalic acid
Guanidine hydrochloride: urea
180
150
80
45
60
20
65
35
90
N10
20
50
55
70
94
60
70
60
NO2 OCH3 4n
NO2 Cl
NO2 NO2
90
4o
4p
88c
83
a
Reaction condition: isatin (1 mmol), 1,3-indanedione (2 mmol) and aniline (1 mmol),
LTTM (5 mL)/80 °C.
b
Isolated yields.
Products prepared for first time.
Atom economy = (weight of desired product/sum of molecular weight of all reac-
c
10
d
a
Reaction condition: isatin (1 mmol), 1,3-indanedione (2 mmol) and aniline (1 mmol)
heated at 80 °C in 5 mL of respective solvent.
tant) × 100.
e
E-factor = [mass of waste]/mass of product.
b
Yields refer to pure isolated products.

576
D.R. Chandam et al. / Journal of Molecular Liquids 219 (2016) 573–578
Scheme 3. Plausible mechanism of formation of spiro [diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-trione.
Red powder, M.P. N 300 °C, IR (KBr): 3294, 3048, 1702, 1621,
LTTM. The plausible mechanism of formation of product is shown in
Scheme 3. The hydrogen bonding effect of LTTM initiated the addition
of 1,3-indanedione on isatin to yield intermediate 5. Intermediate 5 fur-
ther reacted with aromatic amine followed by cyclisation to afford
product.
Furthermore, all the pure products can be simply obtained by wash-
ing the solid crude products with ethanol that avoids traditional chro-
matography and recrystallization purification. Another advantage of
this protocol is the recyclability of low transition temperature mixture
from reaction mixtures which is extremely important from economic
and environmental point of view. After completion of the reaction,
water was added to reaction mixtures and the mixture was filtered to
isolate the product. The aqueous layer was evaporated to recover
LTTM. The recovered LTTM was reused directly with fresh substrates
under identical conditions without further purification. Even after four
successive run, catalytic activity of oxalic acid dihydrate: proline (1:1)
LTTM remains undamaged (Table 3, Fig. 2).
The proficiency of this protocol has been compared with some of the
previously reported catalysts in Table 4. As presented in Table 4, results
indicate that oxalic acid dihydrate: proline (1:1) LTTM can act as suit-
able, eco-safe reaction promoting medium. In addition to this, green-
ness of the protocol can be easily proven by percent atom economy
and E-factor. It is clearly seen from the calculated percent atom econo-
my and E-factor values of each derivatives synthesized (Figs. 3, 4),
that protocol is highly atom economic with minimum waste expulsion
indicating maximum conversion of raw materials into product.
1580 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 5.54–5.57 (d,
2H, Ar-H), 6.87–6.90 (d, 1H, Ar-H), 7.11–7.17 (m, 2H, Ar-H), 7.24–
7.30 (m, 5H, Ar-H), 7.65–7.66 (d, 1H, Ar-H), 8.33 (s, 1H, Ar-H),
8.57–8.65 (d, 3H, Ar-H), 10.83 (s, 1H, NH), Due to the very low solu-
bility of 4o, we were unable to obtain 13C NMR data. Anal. Calcd for
C32H16N3O5Cl: C (68.89%), H (2.89%), N (7.53%), Found: C (68.94%),
H (2.90%), N (7.56%).
3. Results and discussion
At the outset, the reaction of isatin (1 mmol), 1, 3-indanedione
(2 mmol) and aniline (1 mmol) was investigated as a model reaction
using different conditions. Under catalyst and solvent free condition,
very poor yield was observed (Table 1, entry). Keeping in mind the im-
portance of green chemistry, we targeted our investigation to find out
eco-friendly protocol. Further, to optimize the reaction condition, vari-
ous solvents like water, glycerol, polyethylene glycol, 2,2,2-
trifluoroethanol and different LTTMs have been employed. The results
summarized in Table 1 indicate that excellent yield of desired product
in shorter reaction time was obtained in oxalic acid: proline LTTM
(Table 1, entry 7).
With this promising result in our hand, further to delineate the gen-
erality and scope of present protocol, we extended this reaction over
wide array of substrate. Isatin and aromatic amines with electron releas-
ing as well as electron withdrawing substituents has been used to study
effect of substituents over yield and time of completion of reaction. In
most of the cases, reaction proceeded smoothly to afford high yield in
shorter reaction time as indicated in Table 2. In case of electron with-
drawing substituent on isatin and aromatic amine, low yield was ob-
tained with more reaction time (Table 2, entry 16).
The role of low transition temperature mixture as a catalyst or reac-
tion promoting medium is still not clear. The electrophilic activation of
carbonyl group takes place through the hydrogen bonding nature of
Table 3
Recyclability of LTTM.
Run
Fresh
94
I
II
III
IV
Yield
92
91
89
86
Fig. 2. Recyclability of LTTM.

D.R. Chandam et al. / Journal of Molecular Liquids 219 (2016) 573–578
577
Table 4
Comparison of efficiency of Oxalic acid dihydrate: proline LTTM over reported catalyst.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.molliq.2016.02.101.
Sr. No Reaction Condition
Time (min) Yield (%) Reference
1
2
3
4
5
PTSA/Grinding
3–4
60
85
82
94
92
94
25
26
27
27
A
PTSA/CH3CN/Reflux
PEG-OSO3H/80 °C
[NMP]H2PO4/80 °C
10
15
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