Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole and chromone based bis(indolyl)alkanes: Green, chromatography free protocol

Article abstract of DOI:10.1016/j.molliq.2015.02.036

The new green approach has been used for the reaction of indole with various carbonyl compounds. The attractive features of this protocol are the use of green reaction medium, good to excellent product yields, operational simplicity, easy workup procedures and the use of group assistance purification process avoiding chromatographic purification. This protocol is expected to find application in the combinatorial synthesis of biologically active compounds, since indole and chromone motifs have a broad spectrum of biological activities.

Full text of DOI:10.1016/j.molliq.2015.02.036

MOLLIQ-04688; No of Pages 7
Journal of Molecular Liquids xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
1Q1 Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for
synthesis of 3,3-diaryloxindole and chromone based bis(indolyl)alkanes:
2
3Q2 Green, chromatography free protocol
4Q3 Dattatray Chandam a, Abhijeet Mulik a, Prasad Patil b, Suryabala Jagdale a, Dayanand Patil a,
⁎
5
Sandeep Sankpal a, Madhukar Deshmukh a,
a
6Q4
7
Heterocyclic Laboratory, Department of Chemistry, Shivaji University, Kolhapur 416004, India
Department of Agrochemicals and Pest Management, Shivaji University, Kolhapur 416004, India
b
OOF
8
a r t i c l e i n f o
a b s t r a c t
9
Article history:
The new green approach has been used for the reaction of indole with various carbonyl compounds. The attrac- 20
tive features of this protocol are the use of green reaction medium, good to excellent product yields, operational 21
simplicity, easy workup procedures and the use of group assistance purification process avoiding chromato- 22
graphic purification. This protocol is expected to find application in the combinatorial synthesis of biologically 23
10
11
12
13
Received 12 November 2014
Received in revised form 31 January 2015
Accepted 25 February 2015
Available online xxxx
active compounds, since indole and chromone motifs have a broad spectrum of biological activities.
© 2015 Published by Elsevier B.V.
24
25
14
Keywords:
15
16
17
18
19
Isatin
Indole
3-Formyl chromone
Low transition temperature mixture (LTTM)
Group assistance purification (GAP)
29
67
28
30
1. Introduction
derivatives, 3-formylchromone is a highly reactive and well-studied 51
compound. The reaction of a 3-formylchromone with indole leads to a 52
new class of biologically active molecules which are used as building 53
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
Indole and its derivatives are quite pervasive in the plants of both
marine and terrestrial origin [1]. Among them, bis(indolyl)alkanes and
3,3-diaryloxindole constitute an important class of bioactive metabo-
lites. Particularly, bis(indolyl)methanes are the most active cruciferous
ingredients, showing a wide array of biological activities [2–5]. Fur-
thermore, 3,3-diaryloxindole moiety is an integral common structural
motif of many natural products, clinical drugs and biologically active
compounds and is known to possess anti-convulsant, antibacterial,
anti-inflammatory, antiprotozoal and mechanism-specific antiprolifer-
ative properties [6,7]. For instance, 3-arylidineindoline-2-one ana-
logues with an oxyindole scaffold exhibited potential HDAC inhibition
activity and diaryl oxyindole showed micromolar activity against lung
cancer cell while diindolyl oxindoles showed anticancer potency
against human cancer cells (Fig. 1a, b, c). Moreover, chromones widely
distributed in nature show useful properties. The broad range of bio-
logical application [8] such as tyrosine and protein kinase C inhibi-
tion and antifungal, antiviral, anti-tubulin and antihypertensive
activities of chromone derivatives have attracted the attention of
many researchers. They are also active against benzodiazepine recep-
tors and on lipoxygenases and cyclooxygenases. Among chromone
blocks in synthetic organic and medicinal chemistry.
54
A brief review on the literature reveals that the synthesis of 3,3- 55
diaryloxindole skeleton can be achieved by coupling of indoles and car- 56
bonyl compounds in silica-sulfuric acid [9], ionic liquids [10], ceric am- 57
monium nitrate [11], dodecylsulfonic acid [12], nano-SiO2/TiO2 [13], 58
KAl(SO4)2 [14], FeCl3 [15], I2 [16], β-cyclo-dextrin [17] and PTSA [18] 59
while that of chromone based bis(indolyl)alkanes (BIAs) can be 60
achieved by few methods [19]. However, most of the methods are 6Q15
flawed by aspects such as unsatisfactory yield, prolonged reaction 62
time, inconvenient availability of reagent, toxic solvents and expensive 63
catalysts, hence, there is a need to develop eco-safe methodology for 64
the synthesis of oxindoles.
65
In the context of green chemistry, the development of greener and 66
cleaner synthetic methodology is mainly based on the replacement of 67
hazardous and harmful solvents with “green” or “sustainable” media 68
[20]. At the beginning of this century, new generations of solvents 69
named low transition temperature mixtures (LTTMs) or deep eutectic 70
solvents (DESs) were introduced. LTTM or DES has many advantages 71
than IL such as 100% atom economic preparation, nontoxic to the envi- 72
ronment, possess biodegradable properties, or are obtained from biode- 73
gradable resources, and are readily available and inexpensive. M. C. 74
Kroon et al. [21] extended the work of Abbott and published a series 75
UNCORRECTED PR
⁎
Corresponding author.
E-mail address: shubhlaxmi111@gmail.com (M. Deshmukh).
http://dx.doi.org/10.1016/j.molliq.2015.02.036
0167-7322/© 2015 Published by Elsevier B.V.
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

2
D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
H
N
R
R
HN
R1
HN
R
O
a
O
R
O
N
X
N
X
R1
R2
R1
c
b
Fig. 1. Biological active compounds of indole and isatin.
76
77
78
79
80
81
82
83
84
85
86
87
88
of new low melting mixtures based on diverse varieties of hydrogen
bond donors and acceptors. Their physico-chemical properties solely
depend upon the nature and ratio of the counterparts. Since inception,
a few numbers of organic transformations have been reported using
LTTM or DES as environmentally friendly solvents [22].
A literature survey reveals that there is no report available on
the low transition temperature mixture assisted synthesis of 3, 3-
diaryloxindole and 3-formyl chromone based bis(indolyl)alkanes.
Considering the above subject and in connection with our research
work to develop new environmental benign synthetic methodolo-
gies [23], herein we report synthesis of 3,3-diaryloxindole along
with bis(indolyl)alkanes (chromone based) (Scheme 1) using oxalic
acid: proline LTTM.
then heated slowly and maintained at 80 °C for 1 h resulting in the for- 103
mation of yellowish viscous liquid (LTTM) with 100% atom economy. 104
2.3. Typical procedure for the synthesis of 3,3-di(indolyl)indolin-2-one 105
(3a)
106
Indole (0.234 g, 2 mmol) and isatin (0.147 g, 1 mmol) were mixed in 107
oxalic acid: proline (5 ml) as solvent and the resultant mixture was 108
stirred at room temperature for appropriate time. After the completion 109
of the reaction indicated by TLC, 5 ml distilled water was added. The 110
insoluble crude product was filtered, washed with distilled water and 111
recrystallized from ethanol.
112
2.4. Typical procedure for the synthesis of 3-[Bis(1H-indol-3-yl)methyl]-4- 113
chromenone (5a) 114
89
90
2. Experimental
2.1. General
Indole (0.234 g, 2 mmol) and 3-formyl chromone (0.174 g, 1 mmol) 115
were mixed in oxalic acid: proline (5 ml) as solvent and the resultant 116
mixture was stirred at room temperature for appropriate time. After 117
the completion of the reaction indicated by TLC, 5 ml distilled water 118
was added. The insoluble crude product was filtered, washed with dis- 119
91
92
93
94
95
96
97
98
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 on KBr disks were recorded on a Schimadzu IR-470 FT-IR spec-
trophotometer. 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 a
EURO elemental analyzer.
tilled water and recrystallized from ethanol.
120
2.5. Recyclability of oxalic acid dihydrate: proline LTTM
121
The recyclability of low transition temperature mixture (LTTM) was 122
studied using the reaction of 1 mmol of isatin (or 1 mmol of 3-formyl 123
chromone) and 2 mmol of indole in LTTM under optimized conditions. 124
After completion of the reaction, water (5 ml) was added to the reaction 125
mixture and crude product was separated by filtration. The low transi- 126
tion temperature mixture (LTTM) was recovered by evaporating the 127
water at 80 °C under vacuum. The recycled LTTM was reused for the 128
99
2.2. Preparation of LTTM
100
The LTTM has been synthesized according to reported method in lit-
101 erature [21]. It is prepared by mixing of oxalic acid dehydrate (12.6 g,
102 100 mmol) and proline (11.5 g, 100 mmol) in the ratio of 1:1 and
next batch and recycled again.
129
H
OH
O
OH
O
Heated slowly to 800C
O
HO
O
O
+
O
N
H
OH
2H2O
N
HO
O
2H2O
H
oxalic acid
dihydrate
proline
LTTM
O
O
O
R1
O
CHO
HN
R1
R1
O
R1
O
R1
R1
R1
2
N
H
O
R2
2
4
N
R
LTTM/ RT
LTTM/ RT
N
R
N
R
N
R
N
R
1
R
2R2
R2
R2
5 (a - f)
3 (a - l)
Scheme 1. Oxalic acid dihydrate: proline (LTTM) assisted synthesis of 3,3-diaryloxindole and chromone based bis(indolyl)alkanes.
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
3
t1:1
t1:2
Table 1
2.6. Selected spectral data
130
131
Screening of the solvents to optimize the reaction condition.
1. 5-Chloro-3,3-di(1H-indol-3-yl)indolin-2-one (3b).
White solid, M.P. 295–296 °C, IR (KBr): 3449, 1691, 1617, 1476, 132
1458, 1103 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 6.77– 133
,
6.82 (t, 2H, Ar-H, J = 13.8 Hz), 6.87 (s, 2H, Ar-H), 6.95–7.03 (m, 134
3H, Ar-H), 7.15–7.17 (d, 1H, Ar-H, J = 5.4 Hz), 7.21–7.25 (m, 3H, 135
Ar-H), 7.32–7.35 (d, 2H, Ar-H, J = 7.8 Hz), 10.62–10.66 (brs, 1H, 136
NH), 10.85–10.90 (brs, 2H, 2NH), 13C NMR (75 MHz, DMSO d6): d 137
(ppm) 53.3, 111.3, 112.0, 114.0, 117.7, 121.0, 121.4, 124.7, 125.1, 138
125.9, 126.1, 127.9, 136.9, 137.4, 140.6, 178.9, Anal. Calcd 139
for C24H16N3OCl: C (72.45%), H (4.05%), N (10.56%), Found: C 140
t1:3
t1:4
Entry
Solvent
Time (min)
Yielda
t1:5
1
2
3
4
5
6
7
8
No solvent
Water
Ethylene glycol
Polyethylene glycol
2,2,2-Trifluoroethanol
Oxalic acid dihydrate: glycine
Oxalic acid dihydrate: proline
Guanidine hydrochloride: urea
240
200
175
135
60
30
15
40
Trace
Trace
Trace
20
80
78
t1:6
t1:7
t1:8
(72.42%), H (4.08%), N (10.58%).
141
t1:9
2. 3,3-Bis(5-methoxy-1H-indol-3-yl)indolin-2-one (3f).
142
t1:10
t1:11
t1:12
93
60
White solid, M.P. 290–292 °C, IR (KBr): 3392, 1684, 1618, 1579, 143
1474, 1103 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 3.41 144
,
a
(s, 3H, OCH3), 3.53 (s, 3H, OCH3), 6.70–6.73 (d, 3H, Ar-H, J = 145
7.2 Hz), 6.88–7.03 (m, 4H, Ar-H), 7.22–7.29 (m, 5H, Ar-H), 10.62 146
(s, 1H, NH), 10.81 (s, 2H, 2NH), 13C NMR (75 MHz, DMSO d6): d 147
t1:13
Yields refer to pure isolated products.
OOF
Yieldc (%)
t2:1
t2:2
Table 2
Synthesis of 3,3-diaryloxindole using oxalic acid dihydrate: proline (LTTM)a.
t2:3
t2:4
Entry
1
Indole
Isatin
Productb
Time (min)
15
Atom economyd
88
93
3a
t2:5
t2:6
2
3
15
16
88
89
84
85
3b
3c
t2:7
t2:8
4
5
18
14
80
90
77
86
3d
3e
t2:9
6
7
15
17
88
84
84
81
3f
t2:10
3g
t2:11
t2:12
8
9
18
17
82
85
79
82
3h
3i
t2:13
t2:14
10
11
15
UNCORRECTED PR
84
86
81
82
3j
15
3k
t2:15
12
25
80
76
3l
a
t2:16
t2:17
t2:18
t2:19
Reaction conditions: isatin (1 mmol), indole (2 mmol), LTTM (5 ml)/room temperature.
All the products are known and identified by comparison of physical constants, NMR with authentic samples, Ref. [9–18].
Isolated yields.
b
c
d
Atom economy = (weight of desired product / sum of molecular weight of all reactant) × 100.
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

4
D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
53.0, 55.6, 103.8, 109.9, 110.9, 112.5, 114.1, 121.9, 125.4, 125.6,
6. 3-[Bis(1H-indol-3-yl)methyl]-4-chromenone (5a).
Off white solid, M.P. 233–235 °C, IR (KBr): 3461, 1628, 1600, 1572, 181
1418, 1144 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 6.05 182
180
126.6, 128.3, 132.6, 135.0, 141.9, 152.9, 179.2, Anal. Calcd for
C26H21N3O3: C (73.74%), H (5.00%), N (9.92%), Found: C (73.72%),
H (4.98%), N (9.95%).
,
(s, 1H, CH), 6.88–6.93 (t, 2H, Ar-H, J = 15 Hz), 6.98 (s, 2H, Ar-H), 183
7.03–7.08 (t, 2H, Ar-H, J = 15 Hz), 7.35–7.37 (d, 4H, Ar-H, J = 184
8.1 Hz), 7.48–7.50 (t, 1H, Ar-H, J = 7.5 Hz), 7.58–7.60 (d, 1H, 185
Ar-H, J = 8.4 Hz), 7.75–7.80 (t, 1H, Ar-H, J = 15.3 Hz), 7.91 (s, 1H, 186
Ar-H), 8.08–8.11 (d, 1H, Ar-H, J = 7.8 Hz), 10.87 (s, 2H, 2NH), 187
Anal. Calcd for C26H18N2O2: C (79.98%), H (4.65%), N (7.17%), 188
3. 3,3-Bis(5-cyano-1H-indol-3-yl)indolin-2-one (3g).
White solid, M.P. 272–274 °C, IR (KBr): 3500, 2229, 1669, 1619,
1422, 1101 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 6.97–
,
7.04 (m, 4H, Ar-H), 7.19–7.31 (m, 4H, Ar-H), 7.49–7.52 (d, 2H,
Ar-H, J = 8.4 Hz), 7.61 (s, 2H, Ar-H), 10.71 (s, 1H, NH), 10.51 (s,
2H, 2NH), 13C NMR (75 MHz, DMSO d6): d (ppm) 52.5, 101.2,
110.5, 113.5, 115.5, 120.9, 122.3, 124.1, 125.6, 126.3, 127.2, 128.7,
133.5, 139.2, 141.5, 178.7, Anal. Calcd for C26H15N5O: C (75.53%),
H (3.66%), N (16.94%), Found: C (75.50%), H (3.68%), N (16.95%).
4. 3,3-Bis(5-nitro-1H-indol-3-yl)indolin-2-one (3h).
Found: C (79.90%), H (4.60%), N (7.23%).
7. 3-[(5-Cyano-1H-indol-3-yl)(4-oxo-3-chromenyl)methyl](1H- 190
indole-5-carbonitrile) (5b) (new product). 191
White solid, M.P. N300 °C, IR (KBr): 3445, 2217, 1625, 1601, 192
1430, 1142 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 193
189
,
Yellow solid, M.P. N300 °C, IR (KBr): 3279, 1670, 1622, 1517, 1469,
1131 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 6.96–6.98 (d,
1H, Ar-H, J = 7.5 Hz), 7.03–7.10 (m, 3H, Ar-H), 7.18–7.24 (t, 2H, Ar-
H, J = 18 Hz), 7.47–7.49 (d, 2H, Ar-H, J = 6.3 Hz), 7.89–7.92 (d, 2H,
Ar-H, J = 8.4 Hz), 8.25 (s, 2H, Ar-H), 10.82 (s, 1H, NH), 11.63 (s, 2H,
2NH), 13C NMR (75 MHz, DMSO d6): d (ppm) 52.5, 110.5, 112.4,
116.9, 117.2, 118.0, 122.2, 125.1, 128.2, 128.7, 133.3, 140.6, 140.8,
141.6, 178.5, Anal. Calcd for C24H15N5O4: C (63.58%), H (3.33%), N
(15.45%), Found: C (63.60%), H (3.30%), N (15.42%).
6.10 (s, 1H, CH), 7.29 (s, 2H, Ar-H), 7.40–7.62 (m, 6H, Ar-H), 194
7.77–7.82 (t, 1H, Ar-H, J = 15.3 Hz), 7.94 (s, 2H, Ar-H), 7.98 (s, 195
1H, Ar-H), 8.06–8.09 (d, 1H, Ar-H, J = 7.8 Hz), 11.52 (s, 2H, 196
2NH), 13C NMR (75 MHz, DMSO d6): d (ppm) 29.5, 101.0, 197
113.3, 116.9, 118.8, 121.2, 123.9, 124.3, 124.9, 125.7, 126.3, 198
126.5, 127.3, 134.4, 138.8, 155.2, 156.3, 176.1, Anal. Calcd for 199
C28H16N4O2: C (76.35%), H (3.66%), N (12.72%), Found: C 200
(76.40%), H (3.60%), N (12.75%).
201
8. 3-[Bis(2-methyl-1H-indol-3-yl)methyl]-4-chromenone (5c).
202
5. 3,3-Bis(3-methyl-1H-indol-3-yl)indolin-2-one (3l).
Off white solid, M.P. N300 °C, IR (KBr): 3406, 1630, 1571, 1398, 203
White solid, M.P. N300 °C, IR (KBr): 3419, 1726, 1615, 1384, 1314,
1246, 1146 cm−1 1H NMR (300 MHz, DMSO d6): δH (ppm) 204
,
1174 cm−1
,
1H NMR (300 MHz, DMSO d6): δH (ppm) 1.92 (s, 6H,
2.50 (s, 6H, 2CH3), 5.92 (s, 1H, CH), 6.71–6.76 (t, 2H, Ar-H, J = 205
14.7 Hz), 6.88–6.93 (t, 2H, Ar-H, J = 15 Hz), 7.06–7.09 (d, 2H, 206
Ar-H, J = 8.1 Hz), 7.21–7.24 (d, 2H, Ar-H, J = 8.1 Hz), 7.45– 207
7.50 (t, 1H, Ar-H, J = 15 Hz), 7.61–7.63 (d, 1H, Ar-H, J = 208
8.4 Hz), 7.70 (s, 1H, Ar-H), 7.77–7.82 (t, 1H, Ar-H, J = 14.1 Hz), 209
8.02–8.05 (d, 1H, Ar-H, J = 7.8 Hz), 10.78 (s, 2H, 2NH), 13C 210
NMR (75 MHz, DMSO d6): d (ppm) 12.5, 30.5, 109.8, 110.9, 211
2CH3), 6.96–6.98 (d, 6H, Ar-H, J = 3.3Hz), 7.30–7.39 (m, 6H,
Ar-H), 10.31 (s, 2H, 2NH), 10.70 (s, 1H, NH), 13C NMR (75 MHz,
DMSO d6): d (ppm) 9.2, 55.0, 107.9, 110.3, 111.7, 118.1, 118.6,
121.3, 122.4, 126.0, 128.9, 129.5, 131.4, 132.1, 135.7, 142.0, 176.4,
Anal. Calcd for C26H21N3O: C (79.77%), H (5.41%), N (10.73%),
Found: C (79.75%), H (5.40%), N (10.76%).
t3:1
t3:2
Table 3
Synthesis of chromone based bis(indolyl)alkanes using oxalic acid dihydrate: proline (LTTM)a.
t3:3
t3:4
Entry
1
Indole
Product
Time (min)
14
Yieldb (%)
92d
Atom economyc
88
5a
t3:5
t3:6
2
3
15
14
86e
88d
83
84
5b
5c
t3:7
4
12
90d
86
5d
t3:8
t3:9
5
6
18
20
82e
81e
79
78
5e
5f
a
t3:10
t3:11
t3:12
t3:13
t3:14
Reaction conditions: 3-formyl chromone (1 mmol), indole (2 mmol), LTTM (5 ml)/room temperature.
Isolated yields.
Atom economy = (weight of desired product / sum of molecular weight of all reactant) × 100.
Known products identified by comparison of physical constants, NMR with authentic samples, Ref. [19].
Products prepared for the first time.
b
c
d
e
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
5
H
H
N
N
OH
OH
O
O
OH
OH
O
O
O
O
N
H
O-
H
N+
H
O
H
COOH
OH
H
O
O
O
O
H
N
N+
H
H
O-
HN
N
H
N+
H
N
H
N
H
Scheme 2. A plausible mechanism for synthesis of 3,3-diaryloxindole and bis(indolyl)alkanes (chromone based).
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
118.3, 118.6, 118.8, 120.1, 123.4, 125.6, 125.7, 126.7, 128.6,
132.7, 134.4, 135.5, 154.8, 156.2, 176.3, Anal. Calcd for
C28H22N2O2: C (80.36%), H (5.30%), N (6.69%), Found: C
(80.40%), H (5.20%), N (6.75%).
even after prolonged stirring (Table 1, entry 1). Since, in the presence 247
OOF
of high temperature and strong acidic medium, polymerization of 248
indole occurs which results in poor or low yield of product, the key 249
focus of our investigation was to find out efficient and elegant room 250
temperature protocol. Then, to optimize the reaction conditions, differ- 251
ent solvents like water, ethylene glycol, polyethylene glycol, 2,2,2- 252
trifluoroethanol and some LTTMs were screened to test their efficacy. 253
In case of guanidine hydrochloride: urea, reaction was carried out at 254
70 °C. The excellent yield of desired product with high purity and 255
shorter reaction time at room temperature was obtained in oxalic acid 256
9. 3-[Bis(5-nitro-1H-indol-3-yl)methyl]-4-chromenone (5e) (new
product).
Light green solid, M.P. N300 °C, IR (KBr): 3328, 1636, 1577, 1510,
1469, 1165 cm−1, 1H NMR (300 MHz, DMSO d6): δH (ppm) 6.26
(s, 1H, CH), 7.37 (s, 2H, Ar-H), 7.46–7.62 (m, 4H, Ar-H), 7.77–
7.82 (t, 1H, Ar-H, J = 15.6 Hz), 7.97–8.02 (m, 3H, Ar-H), 8.08–
8.11 (t, 1H, Ar-H, J = 8.1 Hz), 8.40 (s, 2H, Ar-H), 11.72 (s, 2H,
2NH), 13C NMR (75 MHz, DMSO d6): d (ppm) 29.4, 112.6,
116.2, 117.1, 118.6, 118.8, 123.8, 125.7, 125.8, 126.0, 126.4,
128.5, 134.5, 140.3, 140.8, 155.4, 156.3, 176.1, Anal. Calcd for
C26H16N4O6: C (65.00%), H (3.36%), N (11.66%), Found: C
(65.10%), H (3.30%), N (11.70%).
dihydrate: proline LTTM (Table 1, entry 7).
257
We then investigated with a wide array of substrates the generality 258
and versatility of this protocol. The reaction of substituted isatin with 2Q569
various indoles (except 3-methyl indole Table 2, entry 12) underwent 260
smoothly affording excellent yield at room temperature as summarized 261
in Table 2. 3-Methyl indole gave low yield at room temperature but at 262
70 °C, it afforded excellent yield. In general, the nature of substituents 263
on isatin and indole showed negligible effect in reaction time and yield. 264
Encouraged by the above results, we next planned to extend 265
the application of LTTM for the synthesis of chromone based 266
bis(indolyl)alkanes. Gratifyingly, it was found that trial reaction of 267
3-formyl chromone (1 mmol) and indole (2 mmol) afforded excellent 268
yield of product (Table 3, entry 1). In order to study the effect of various 269
substituents of indole over the yields and reaction time, different 270
derivatives were synthesized and the results are summarized in Table 3 271
(entries 2 to 6). The reaction of 3-methyl indole with 3-formyl chromone 272
was carried out at 70 °C as low yield obtained at room temperature 273
228 10. 3-[Bis(3-methyl-1H-indol-2-yl)methyl]-4-chromenone (5f)
229
230
231
232
233
234
235
236
237
238
239
240
241
(new product).
Off white solid, M.P. 258–260 °C, IR (KBr): 3418, 1620, 1601,
1394, 1353, 1144 cm−1 1H NMR (300 MHz, DMSO d6): δH
,
(ppm) 2.04 (s, 6H, 2CH3), 6.10 (s, 1H, CH), 6.98–67.05 (m, 4H,
Ar-H), 7.26–7.29 (d, 2H, Ar-H, J = 7.8 Hz), 7.41–7.43 (d, 2H,
Ar-H, J = 7.5 Hz), 7.48–7.54 (t, 1H, Ar-H, J = 15.3 Hz), 7.66–
7.69 (d, 1H, Ar-H, J = 8.4 Hz), 7.80–7.85 (t, 1H, Ar-H, J =
15.6 Hz), 7.97 (s, 2H, Ar-H), 8.08–8.10 (d, 1H, Ar-H, J =
7.2 Hz), 10.59 (s, 2H, 2NH), 13C NMR (75 MHz, DMSO d6): d
(ppm) 8.6, 32.2, 106.9, 111.5, 118.2, 118.7, 118.8, 121.0, 123.8,
124.0, 125.6, 125.9, 129.2, 133.2, 134.6, 135.8, 156.0, 156.4,
176.0, Anal. Calcd for C28H22N2O2: C (80.36%), H (5.30%), N
(6.69%), Found: C (80.30%), H (5.35%), N (6.65%).
(Table 3, entry 6).
274
The role of the LTTM as a catalyst or reaction promoting medium is 275
still not clear. The hydrogen bonding nature of LTTM activates carbonyl 276
group electrophilically. The reaction of carbonyl group with hydrogen of 277
242 3. Result and discussion
92
1
00
93
90
UNCORRECTED PR
88
90
89
243
At the outset, the reaction of isatin (1 mmol) and indole (2 mmol)
90
80
70
60
50
83
85
244 was carried out as model reaction to optimize the reaction condition.
245 The results have been shown in Table 1. In solvent free and catalyst
246 free conditions, model reaction yielded trace amount of product 3a
77
80
Yield of 3a
Yield of 5a
t4:1
t4:2
Table 4
Recyclability of LTTM.
Fresh
F
irst
Second
T
hird
Fourth
t4:3
Run
Fresh
First
Second
Third
Fourth
R
un
t4:4
t4:5
Yield of 3a
Yield of 5a
93
92
90
90
89
88
85
83
80
77
Fig. 2. Recyclability of LTTM.
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

6
D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
t5:1
t5:2
Table 5
4. Conclusion
304
Comparison of the results of present protocol with reported methods.
In summary, an extremely efficient and green process has been 305
developed for the synthesis of 3,3-diaryloxindole and chromone 306
based bis(indolyl)alkane derivatives in oxalic acid dehydrate: pro- 307
line (LTTM). The current method has the advantages of avoiding the 308
use of toxic solvents, versatility of substrate, short reaction time, high 309
yield, ease of product isolation and purification, low costs and simplicity 310
in process and handling. These advantages of LTTM make it a useful and 311
t5:3
Entry Catalyst
Condition
Time Yield Ref.
(min)
t5:4
t5:5
t5:6
t5:7
t5:8
t5:9
t5:10
t5:11
For synthesis of 3,3-di(indolyl)indolin-2-one
1
2
3
4
5
6
7
CAN
Ultrasonic/ethanol
RT/dichloromethane
50 °C/solvent free
RT/dichloromethane
RT/acetonitrile
180
120
30
95
94
85
92
93
98
93
[11]
[9]
Silica sulphuric acid
Nano-TiO2/SiO2
PTSA
FeCl3
[13]
[18]
[15]
[16a]
A
20
15
attractive process for the said synthesis.
312
I2
RT/isopropanol
15
15
Oxalic acid dihydrate:
proline
Acknowledgment
313
t5:12
t5:13
For synthesis of 3-[Bis(1H-indol-3-yl)methyl]-4-chromenone
t5:14
t5:15
t5:16
t5:17
8
9
10
11
TPPMS/CBr4
No catalyst
No catalyst
Oxalic acid dihydrate:
proline
RT/acetonitrile
240
72
54
54
92
[19a]
[19b]
[19c]
A
We are thankful to the Department of Chemistry, Shivaji University, 314
85–90 °C/solvent-free 300
85–90 °C/solvent-free 300
14
Kolhapur for spectral analysis.
315
Appendix A. Supplementary data
316
t5:18
A: this work.
Supplementary data to this article can be found online at http://dx. 317
doi.org/10.1016/j.molliq.2015.02.036.
318
278 indole results in the formation of azafulvenium salt which further reacts
279 with another indole molecule to form corresponding products as shown
280 in Scheme 2.
References
319
320
[1] (a) R.J. Sundberg, The Chemistry of Indoles, Academic Press, New York, 1996.;
(b) A. Casapullo, G. Bifulco, I. Bruno, R. Riccio, New bisindole alkaloids of the 321
topsentin and hamacanthin classes from the Mediterranean Marine Sponge 322
281
Moreover, this synthesis was confirmed to follow the GAP chemistry
282 (group-assistant-purification chemistry) process [24], since all the pure
283 products can be simply obtained by washing the solid crude products
284 with ethanol avoiding traditional chromatography and recrystallization
285 purification. In addition, the convenient recycling of low transition tem-
286 perature mixture from reaction mixtures which is extremely important
287 from economic and environmental point of view also represents signif-
288 icant advantages of this procedure. Water was added to reaction mix-
289 tures after the reaction was completed and the mixture was filtered to
290 isolate the product. The water was evaporated and recovered LTTM
291 was used directly with fresh substrates under identical conditions with-
292 out further purification. Recyclability study indicated that oxalic acid
293 dihydrate: proline (1:1) remains in high catalytic activity even after
294 four successive runs (Table 4, Fig. 2).
Rhaphisia lacazei, J. Nat. Prod. 63 (2000) 447–451.
[2] S. Safe, S. Papineni, S. Chintharlapalli, Cancer chemotherapy with indole-3-carbinol, 324
bis(3′-indolyl)methane and synthetic analogs, Cancer Lett. 269 (2008) 326–338. 325
[3] (a) C. Bonnesen, I.M. Eggleston, J.D. Hayes, Dietary indoles and isothiocyanates that 326
are generated from cruciferous vegetables can both stimulate apoptosis and 327
confer protection against DNA damage in human colon cell lines, Cancer Res. 328
323
61 (2001) 6120–6130;
329
(b) Y. Gong, G.L. Firestone, L.F. Bjeldanes, 3,3′-Diindolylmethane is a novel topo- 330
isomerase IIα catalytic inhibitor that induces S-phase retardation and mitotic 331
delay in human hepatoma HepG2 cells, Mol. Pharmacol. 69 (2006) 1320–1327. 332
[4] (a) R. Bell, S. Carmeli, N. Sar, N. Sar, Vibrindole A, a metabolite of the marine bacte- 333
rium, Vibrio parahaemolyticus, isolated from the toxic mucus of the boxfish 334
Ostracion cubicus, J. Nat. Prod. 57 (1994) 1587–1590;
335
(b) M. Kobayashi, S. Aoki, K. Gato, K. Matsunami, M. Kurosu, I. Kitagawa, Marine nat- 336
ural products. XXXIV. Trisindoline, a new antibiotic indole trimer, produced by a 337
bacterium of Vibrio sp. separated from the marine sponge Hyrtios altum, Chem. 338
Pharm. Bull. 42 (1994) 2449–2451;
339
295
The applicability and efficiency of this protocol have been compared
(c) G. Sivaprasad, P.T. Perumal, V.R. Prabavathy, N. Mathivanan, Synthesis and anti- 340
microbial activity of pyrazolylbisindoles—promising anti-fungal compounds, 341
296 with some of the previously reported catalysts in Table 5. As shown in
297 Table 5, the LTTM can act as a suitable solvent catalyst system with
298 respect to reaction times and yields of the products. The proficiency
299 and greenness of the protocol can be easily proven by percent atom
300 economy. From the calculated percent atom economy values of each
3Q017 derivative synthesized (Fig. 3), it is clearly seen that this protocol is
302 highly atom economic due to maximum conversion of raw materials
303 into product resulting in the minimum waste generation.
Bioorg. Med. Chem. Lett. 16 (2006) 6302–6305.
[5] (a) K. Sujatha, P.T. Perumal, D. Muralidharan, M. Rajendran, Indian J. Chem. Sect. B 343
48 (2009) 267–272; 344
342
(b) C. Praveen, D. Muralidharan, P.T. Perumal, Synthesis, antimicrobial and antioxi- 345
dant evaluation of quinolines and bis(indolyl)methanes, Bioorg. Med. Chem. 346
Lett. 20 (2010) 7292–7296.
347
[6] (a) K.C. Joshi, V.N. Pathak, S.K. Jain, Studies of potential organo-fluorine antibacteri- 3Q498
al agents. Part 5: synthesis and antibacterial activity of some new fluorine- 349
containing indole-2,3-dione derivatives, Pharmazie 35 (1980) 677;
350
(b) H. Pajouhesh, R. Parsons, F.D. Popp, Potential anticonvulsants VI: condensation 351
of isatins with cyclohexanone and other cyclic ketones, J. Pharm. Sci. 72 352
(1983) 318.
[7] F.D. Pope, Potential anticonvulsants. IX. Some isatin hydrazones and related com- 354
pounds, J. Heterocycl. Chem. 21 (1984) 1641–1645. 355
353
[8] D.A. Horton, G.T. Bourne, M.L. Smythe, The combinatorial synthesis of bicyclic 356
privileged structures or privileged substructures, Chem. Rev. 103 (2003) 893–930. 357
[9] J. Azizian, A.A. Mohammadi, N. Karimi, M.R. Mohammadizadeh, A.R. Karimi, Silica 358
sulfuric acid a novel and heterogeneous catalyst for the synthesis of some new 359
A
tom Economy
88
88
9
8
8
7
7
6
6
5
5
0
5
0
5
0
5
0
5
0
86
86
85
84
8
4
84
83
82
82
81
81
oxindole derivatives, Catal. Commun. 7 (2006) 752–755.
360
79
79
7
8
77
[10] (a) K. Rad-Moghadam, M. Sharifi-Kiasaraie, H. Taheri-Amlashi, Synthesis of 361
symmetrical and unsymmetrical 3,3-di(indolyl)indolin-2-ones under con- 362
76
trolled catalysis of ionic liquids, Tetrahedron 66 (2010) 2316–2321;
363
(b) N.O. Karimi, H. Hooesina, S. Majid, Z. Minaa, Z. Masoumeh, N. Tavakoli, On 364
water: Brønsted acidic ionic liquid [(CH2)4SO3HMIM][HSO4] catalysed synthesis 365
of oxindoles derivatives, Chin. J. Chem. 29 (2011) 321–323.
366
[11] S.J. Ji, S.Y. Wang, Facile synthesis of 3,3-di(heteroaryl)indolin-2-one derivatives 367
catalyzed by ceric ammonium nitrate (CAN) under ultrasound irradiation, Tetrahe- 368
dron 62 (2006) 1527–1535.
369
[12] H. Parasa, D.S. Saikat, K. Dilip, Efficient synthesis of bis- and tris-indolylalkanes 370
catalyzed by a Brønsted acid–surfactant catalyst in water, Synth. Commun. 38 371
3a 3b 3c 3d 3e 3
f 3g 3h 3i 3j 3k 3l 5a 5b 5c 5d 5e 5f
(2008) 2870–2880.
372
Products
[13] M. Haghighi, K. Nikoofar, Nano TiO2/SiO2: an efficient and reusable catalyst for 373
the synthesis of oxindole derivatives, J. Saudi Chem. Soc. (2014)http://dx.doi.org/ 374
Fig. 3. Atom economy of products.
10.1016/j.jscs.2014.09.002.
375
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036

D. Chandam et al. / Journal of Molecular Liquids xxx (2015) xxx–xxx
7
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
[14] J. Azizian, A.A. Mohammadi, A.R. Karimi, M.R. Mohammadizadeh, KAl(SO4)2.12H2O
as a recyclable Lewis acid catalyst for synthesis of some new oxindoles in aqueous
media, J. Chem. Res. Synop. 6 (2004) 424–426.
[15] A. Kamal, Y.V.V. Srikanth, N.A. Khan, T.B. Shaik, M. Ashraf, Synthesis of 3,3-diindolyl
oxyindoles efficiently catalysed by FeCl3 and their in vitro evaluation for anticancer
activity, Bioorg. Med. Chem. Lett. 20 (2010) 5229–5231.
[16] (a) P. Paira, A. Hazra, S. Kumar, R. Paira, K.B. Sahu, S. Naskar, P. Saha, S. Mondal, A.
Maity, S. Banerjee, N.B. Mondal, Efficient synthesis of 3,3-diheteroaromatic
oxindole analogues and their in vitro evaluation for spermicidal potential,
Bioorg. Med. Chem. Lett. 19 (2009) 4786–4789;
(c) T.L. Greaves, C.J. Drummond, Protic Ionic Liquids: Properties and Applications, 412
Chem. Rev. 108 (2008) 206–237. 413
[21] M. Francisco, A. van den Bruinhorst, M.C. Kroon, Low-transition-temperature 414
mixtures (LTTMs): a new generation of designer solvents, Angew. Chem. Int. Ed. 415
52 (2013) 3074–3085.
416
[22] (a) N. Azizi, S. Dezfooli, M. Khajeh, M.M. Hashemi, Efficient deep eutectic solvents 417
catalyzed synthesis of pyran and benzopyran derivatives, J. Mol. Liq. 186 (2013) 418
76–80;
(b) N. Azizi, E. Batebi, Highly efficient deep eutectic solvent catalyzed ring opening 420
of epoxides, Catal. Sci. Technol. 2 (2012) 2445–2448; 421
419
(b) B.V.S. Reddy, N. Rajeswari, M. Sarangapani, Y. Prashanthi, R.J. Ganji, A.
Addlagatta, Iodine-catalyzed condensation of isatin with indoles: a facile syn-
thesis of di(indolyl)indolin-2-ones and evaluation of their cytotoxicity, Bioorg.
Med. Chem. Lett. 22 (2012) 2460–2463.
(c) S.B. Phadtare, G.S. Shankarling, Halogenation reactions in biodegradable solvent: 422
efficient bromination of substituted 1-aminoanthra-9, 10-quinone in deep 423
eutectic solvent (choline chloride/:/urea), Green Chem. 12 (2010) 458–462;
(d) N. Azizi, S. Dezfooli, M.M. Hashemi, Greener synthesis of spirooxindole in deep 425
eutectic solvent, J. Mol. Liq. 194 (2014) 62–67; 426
424
[17] N. Subhendu, S. Pritam, P. Rupankar, P. Priyankar, H. Abhijit, S.B. Krishnendu, B. Sukdeb,
M.B. Nirup, Aqueous phase supramoleculer synthesis of 3,2- and 3,3-dihetero-aromatic
oxindoles catalysed by β-cyclodextrin, J. Chem. Res. 3 (2009) 174–177.
[18] J. Yu, T. Shen, Y. Lin, Y. Zhou, Q. Song, Rapid and efficient synthesis of 3,3-Di(1H-
indol-3-yl)indolin-2-ones and 2,2-Di(1H-indol-3-yl)-2H-acenaphthen-1-ones cata-
lyzed by p-TSA, Synth. Commun. 44 (2014) 2029–2036.
[19] (a) C. Huo, C. Sun, C. Wang, X. Jia, W. Chang, Triphenylphosphine-m-sulfonate/
carbon tetrabromide as an efficient and easily recoverable catalyst system for
Friedel–Crafts alkylation of indoles with carbonyl compounds or acetals, ACS
Sustainable Chem. Eng. 1 (2013) 549–553;
(b) V.Y. Sosnovskikh, R.A. Irgashev, A.A. Levchenko, Uncatalyzed addition of indoles
and N-methylpyrrole to 3-formylchromones: synthesis and some reactions of
(chromon-3-yl)bis(indol-3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-
2-ylmethylene)chroman-4-ones, Tetrahedron 64 (2008) 6607–6614;
(c) V.Y. Sosnovskikh, R.A. Irgashev, Uncatalyzed addition of indoles and N-
methylpyrrole to 3-formylchromones: synthesis of (chromon-3-yl)bis(indol-
3-yl)methanes and E-2-hydroxy-3-(1-methylpyrrol-2-ylmethylene)chroman-
4-ones under solvent-free conditions, Tetrahedron Lett. 48 (2007) 7436–7439.
[20] (a) J. Ranke, S. Stolte, R. Stormann, J. Arning, B. Jastorff, Design of sustainable chem-
ical products, the example of ionic liquids, Chem. Rev. 107 (2007) 2183–2206;
(b) N.V. Plechkova, K.R. Seddon, Applications of ionic liquids in the chemical indus-
try, Chem. Soc. Rev. 37 (2008) 123–150;
(e) H.R. Lobo, B.S. Singh, G.S. Shankarling, Lipase and deep eutectic mixture cata- 427
lyzed efficient synthesis of thiazoles in water at room temperature, Catal. Lett. 428
142 (2012) 1369–1375.
429
[23] (a) A. Mulik, D. Chandam, P. Patil, D. Patil, S. Jagdale, M. Deshmukh, Proficient syn- 430
thesis of quinoxaline and phthalazinetrione derivatives using [C8dabco]Br ionic 431
liquid as catalyst in aqueous media, J. Mol. Liq. 179 (2013) 104–109;
432
(b) . D. Patil, D. Chandam, A. Mulik, P. Patil, S. Jagadale, R. Kant, V. Gupta, M. 433
Deshmukh, Novel Brønsted acidic ionic liquid ([CMIM][CF3COO]) prompted mul- 434
ticomponent hantzsch reaction for the eco-friendly synthesis of acridinediones: 435
an efficient and recyclable catalyst, Catal. Lett. 144 (2014) 949–958;
436
(c) D.R. Chandam, A.G. Mulik, P.P. Patil, S.D. Jagdale, D.R. Patil, M.B. Deshmukh, 4Q3170
(−)-Camphor-10-sulfonic acid catalyzed atom efficient and green synthesis 438
of triazolo[1,2-a]indazole-triones and spiro triazolo[1,2-a]indazole-tetraones, 439
OOF
Res. Chem. Intermed. (2015)http://dx.doi.org/10.1007/s11164-013-1226-9 440
(article in press).
441
[24] (a) P. Kaur, S. Pindi, W. Wever, T. Rajale, G. Li, Asymmetric catalytic Strecker reac- 442
tion of N-phosphonyl imines with Et2AlCN using amino alcohols and BINOLs as 443
catalysts, Chem. Commun. 46 (2010) 4330–4332;
444
(b) P. Kaur, S. Pindi, W. Wever, T. Rajale, G. Li, Asymmetric catalytic N-phosphonyl 445
imine chemistry: the use of primary free amino acids and Et2AlCN for asym- 446
metric catalytic strecker reaction, J. Org. Chem. 75 (2010) 5144–5150.
447
448
UNCORRECTED PR
Please cite this article as: D. Chandam, et al., Oxalic acid dihydrate: Proline (LTTM) as a new generation solvent for synthesis of 3,3-diaryloxindole
and chromone based bis(indolyl)alkanes: Green, chromatogra..., J. Mol. Liq. (2015), http://dx.doi.org/10.1016/j.molliq.2015.02.036