Catalyst-free glycerol-mediated green synthesis of 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-diones

Article abstract of DOI:10.1080/00397911.2017.1359844

The development of new catalyst-free green and efficient protocol to access 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-diones, potential privileged scaffolds for drug discovery, is disclosed. Key feature of this methodology is the dual use of glycerol—a recyclable, bioorganic compound, as a solvent cum promoter. Other highlights include use of inexpensive reagents, mild reaction conditions, operational simplicity, short reaction time, no need for chromatographic purification, and high yields.

Full text of DOI:10.1080/00397911.2017.1359844

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Catalyst free glycerol mediated green synthesis
of 5′-thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-
ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-
diones
Jyoti Tiwari, Mohammad Saquib, Swastika Singh, Fatima Tufail, Jaya Singh &
Jagdamba Singh
To cite this article: Jyoti Tiwari, Mohammad Saquib, Swastika Singh, Fatima Tufail, Jaya
Singh & Jagdamba Singh (2017): Catalyst free glycerol mediated green synthesis of 5′-
thioxospiro[indoline-3,3′-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3′-[1,2,4]triazolidine]-2,5′-diones,
Synthetic Communications, DOI: 10.1080/00397911.2017.1359844
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Date: 31 July 2017, At: 09:10

Catalyst free glycerol mediated green synthesis of 5'-
thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-
ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones
Jyoti Tiwari
Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, India
Mohammad Saquib
Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, India
Swastika Singh
Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, India
Fatima Tufail
Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, India
Jaya Singh
Department of Chemistry, LRPG College, Sahibabad, Ghaziabad, India
Jagdamba Singh
1

Environmentally Benign Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, India
Address correspondence to Jagdamba Singh, Environmentally Benign Synthesis Lab,
Department of Chemistry, University of Allahabad, Allahabad-211002, India. Tele: +91
9415218507. E-mail: dr.jdsau@gmail.com
Supplemental data (Full experimental detail, 1H, D2O shake, 13C NMR, DEPT IR and MS data as
well as 1H, D2O shake, 13C NMR, DEPT spectral sheets of representative compounds) for this
article can be access on the publisher’s website.
ABSTRACT
The development of a new catalyst free green and efficient protocol to access 5'-
thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-
diones, potential privileged scaffolds for drug discovery, is disclosed. Key feature of this
methodology is the dual use of glycerol - a recyclable, bioorganic compound, as a solvent cum
promoter. Other highlights include use of inexpensive reagents, mild reaction conditions,
operational simplicity, short reaction time, no need for chromatographic purification and high
yields.
GRAPHICAL ABSTRACT
2

KEYWORDS: Spirooxindoles, catalyst free, glycerol, thioxospiro[indoline-3,3'-
[1,2,4]triazolidin]-2-ones, spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones
Introduction
Spirooxindolemotifconstitutes the core structures of a variety of alkaloids and natural
products.[1–3] It is also present as key structural element in a number of medicinally relevant
synthetic molecules.[4–7] Likewise 1,2,4-triazole is an important three nitrogen containing
heterocyclic nucleus exhibiting diverse biological activities.[8–12] Amongst 1,2,4triazoles, 1,2,4-
triazole-3-thiones/triazole-3-ones form an important subclass, which have recently been
recognized as promising scaffolds for medicinal chemistry.[13] Triazole-3-thione and triazole-3-
one motifs are found in many biologically relevant natural products and synthetic molecules and
have been explored for a variety of biological activities.[14–18] Recently molecular hybridization
has been recognized as a promising new tool for the design of new chemical entities by the
combination of two bioactive compounds and/or pharmacophoric units.[19–21]
In this context, the integration of the spirooxindole and triazole-3-thione/one motif unto
one platform to obtain 5'-thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-
[1,2,4]triazolidine]-2,5'-diones hybrid scaffolds may prove to be highly beneficial from the
medicinal point of view.
However, surprisingly only three methods for the synthesis of 5'-thioxospiro[indoline-
3,3'-[1,2,4]triazolidin]-2-ones and just one method for the synthesis of spiro[indoline-3,3'-
[1,2,4]triazolidine]-2,5'-dioneshave been documented so far. Though the reported methods are
useful they do suffer from drawbacks like use of high reaction temperature and exotic catalysts.
Consequently the development of more efficient and greener methods for the synthesis of
3

5'-thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-
2,5'-dionesis a highly sought after synthetic goal.[22]
With the present emphasis on use of eco-friendly techniques in organic synthesis,
researchers are increasingly directing their efforts towards elimination of toxic organic
solvents and catalysts which are the cause for maximum pollution generated by the
,
24]
chemical processes.[23 In this context glycerol - a biomass derived solvent is garnering
special interest as a prototypical alternative green solvent due to its unique
physicochemical properties such as low toxicity, high polarity, high boiling point and
reusability [25]
Consequently, in continuation of our ongoing research on the development
.
of green synthesis of biologically important heterocycles,[26] we herein report the
development of a new glycerol promoted, efficient and green synthesis of 5'-
thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-
diones from isatins and thiosemicarbazide/semicarbazide.
Results and Discussion
In our initial effort to find a new eco-friendly method for the synthesis of 5'-
thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-
diones, we conducted a model reaction using isatin (1a, 1mmol), and thiosemicarbazide (2a, 1
mmol) without using any solvent or catalyst at room temperature (RT). Although hydrazone
formation was observed after 3 hours of stirring but no cyclization was observed even after 9
hours of additional stirring (Table 1, entry 1). When the experiment was repeated at 80 °C
formation of the final product was observed although the yield was very low (37%) (Table 1,
entry 2). The reaction was now conducted using water as a solvent. No cyclized product was
4

observed at RT, however at elevated temperature desired product formation was observed in
65% yield (Table 1, entries 3 and 4). However when ethanol was used as a solvent in place of
water, formation of the desired 5'-thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones 3a was
observed in 62% at RT. Refluxing led to a good increase in yield (81%) and reduction in reaction
time. (Table 1, entry 5 and 6). We also tried the reaction in other solvents and solvent
combinations like methanol, THF, acetonitrile and glycerol: water but without any success. In
our efforts to improve the yield of the reaction we used glycerol as the solvent. A remarkable
enhancement in yield (76%) was observed even at RT (Table 1, entry 12). We repeated the
experiment at higher temperature at 60 °C in the hope of improving the yield. As per our
expectations there was a further increase in yield (95 %) and a big reduction in reaction time (1.5
h) (Table 1, entry 13). A further increase in reaction temperature however, led to a slight
decrease in yield (Table 1, entry 14). In order to study the effect of temperature on reaction yield
and time we also conducted the reaction at a more ambient temperature (40 °C). Surprisingly no
loss of yield was observed in this case although the reaction was relatively slower (Table 1,
entry 15). We also tried PEG-400 and glycerol/water mixtures as solvents but better yields were
not observed. From the above set of experiments we choose the experiment at entry 15, Table 1
(95% yield, 1.6 h) as a model reaction, because although in entry 13 the reaction was slightly
faster, higher temperature (60 °C), have been used which is not desirable.
Once optimum reaction conditions had been identified, the scope and efficiency of the
developed synthetic strategy was explored using variously substituted isatins, semicarbazides
and thiosemicarbazides (Table 2). It was observed that when an electron withdrawing group was
present on the isatin, the reaction proceeded faster and the product was formed in higher yields,
while the presence of an electron donating group slowed down the reaction and led to reduction
5

in yield of the product (Table 2).Likewise use of thiosemicarbazide led to much higher yields
and faster reaction rates as compared to semicarbazide (Table 2).
We have proposed a tentative mechanistic pathway for the synthesis of 5'-
thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-
diones as shown below in Scheme 1.[22a] Initially, the reaction involves the glycerol mediated
formation the hydrazone I followed by cyclization through the attack of the nitrogen lone pair on
the carbon of imino bond of hydrazone resulting in the formation of 5'-thioxospiro[indoline-3,3'-
[1,2,4]triazolidin]-2-ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones.
In order to further highlight the green credentials of the developed protocol we also
studied the recyclability and reusability of glycerol (Figure 1). On quenching the reaction with
hot water (10 ml), glycerol got dissolved, while the product which remained insoluble in water
was separated by simple filtration. The filtrate containing glycerol was extracted with methyl t-
butyl ether to remove any organic impurities and the aqueous layer was evaporated in vacuo to
give pure glycerol which was used for the next cycle. It was observed that the products were
obtained in excellent to good yield even after reusing the glycerol four times, which highlights
the use of glycerol as a recyclable, green and economical promoting media.
Experimental Section
All chemicals were reagent grade and purchased from Aldrich, Alfa Aesar, Merck,
Spectrochem and Qualigens and were used without further purification. The reactions
were monitored using pre-coated TLC plates of silica gel G/UV-254 of 0.25 mm
thickness (Merck 60 F-254). NMR spectra were recorded on a BrukerAvance-II 400FT
spectrometer at 400 MHz (1H) and 100 MHz (13C) in DMSO using TMS as an internal
6

reference. Mass Spectra (ESIMS) were obtained on Micromassquadro II spectrometer.
Elemental analysis were carried out in a Thermo Scientific (FLASH 2000) CHN
Elemental Analyser. Melting points were determined by open glass capillary method and
are uncorrected. Chemical shifts (δ) and coupling constants (J) are expressed in ppm and
Hz, respectively. Multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet.
General method for synthesis of 5'-thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-
ones/spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones
To a round bottom flask containing 5 ml glycerol was added respective isatin (1 mmol)
and respective thiosemicarbazide/semicarbazide (1 mmol) under stirring. The temperature of the
reaction was set at 40oC and the resulting mixture was stirred till completion and progress of
reaction was monitored with TLC (Hexane/EtOAc 2:1). The reaction was quenched with hot
water whence glycerol got dissolved in water and the resulting insoluble solid precipitate was
filtered and dried to obtain the crude product which was as good as pure (1H NMR).The aqueous
phase containing glycerol was extracted with methyl t-butyl ether (4 × 25 mL) to remove any
trace of organic compounds and then evaporated in vacuo to give pure glycerol which was used
for the next cycle.
5'-Thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-one(3a)22b
1
Yellow solid; Mp: 251-253°C; IR (KBr): 3428, 3343, 1716, 1089 cm-1; H NMR
(DMSO-d6) (δ, ppm): 6.91 (1H, d, J = 7.8Hz ); 7.05-7.09 (1H, m); 7.32-7.36 (1H, m ); 7.64 (1H,
13
d, J = 7.3 Hz ); 8.66 (1H, s); 9.02 (1H, s); 11.23(1H, s); 12.48 (1H, s); C NMR (DMSO-d6) (δ,
ppm): 111.0, 119.9, 120.9, 122.3, 131.2, 132.0, 142.2, 162.6, 178.6; MS (ESI): m/z 220; found
7

221 [M+H]+, Anal. Calcd. for C9H8N4OS: C, 49.08; H, 3.66; N, 25.44; found: C, 49.06; H, 3.63;
N, 25.46 %.
Conclusion
In summary, we have developed a simple and efficient, glycerol promoted green protocol
for the synthesis of5'-Thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/ Spiro[indoline-3,3'-
[1,2,4]triazolidine]-2,5'-dioneshybrid motifs, which are potentially important privileged
scaffolds. To the best of our knowledge this is the first catalyst free synthesis of 5'-
Thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-ones/Spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-
diones and only the second overall synthesis of 5'-Thioxospiro[indoline-3,3'-[1,2,4]triazolidin]-2-
ones/Spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones. Use of mild reaction conditions,
enabling use of a wide range of substrates, operational simplicity, short reaction times, easy
workup procedure, no chromatographic purification, high atom economy and high yields make
this method a preferred method for the synthesis of diverse5'-Thioxospiro[indoline-3,3'-
[1,2,4]triazolidin]-2-ones/Spiro[indoline-3,3'-[1,2,4]triazolidine]-2,5'-diones
Acknowledgements
The authors are thankful to SAIF, PU, Chandigarh for spectral data. The authors also
acknowledge the financial support from UGC, New Delhi in form of a major research project
(Project No. 42-263/2013 (SR) and fellowships for Swastika Singh and Fatima Tufail.
Mohammad Saquib thanks UGC, New Delhi for Dr. D.S. Kothari Postdoctoral Fellowship
(Award No. F.4-2/2006 (BSR)/13-1030/2013(BSR) while Jyoti Tiwari thanks CSIR, New Delhi
for SRF.
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10

Table 1. Optimization of reaction conditions for the synthesis of 3a
Entry
Solvent
None
Temp.
RT
Time
12 h
12 h
Yield of 3a (%)b
No reaction
37
1
2
None
80 C
RT
3
4
Water
Water
12 h
4 h
No reaction
Reflux
RT
65
62
81
78
53
59
61
71
76
95
91
95
76
5
Ethanol
10 h
6 h
6
Ethanol
Reflux
Reflux
Reflux
Reflux
RT
7
Methanol
THF
6 h
8
12 h
4 h
9
CH3CN
10
11
12
13
14
15
16
Ethanol: Water /1:1
Ethanol: Water /1:1
Glycerol
8 h
Reflux
RT
5 h
5 h
Glycerol
60 °C
80 °C
40 °C
60 °C
1.3 h
1.2 h
1.6 h
6 h
Glycerol
Glycerol
PEG-400
17
Glycerol: Water / 4:1
40 °C
11
2 h
80

18
Glycerol: Water /1:1
40 °C
2 h
76
aAll reactions were carried out with 1a (1 mmol), 2a (1mmol), in 5 mL of solvent under air.b Isolated yields.
12

Table 2. Substrate scopea,b,c
Entry
R1/R2/R3
Product
Time(h)
Yield (%)
1
2
5-F/H/H
5-Cl/H/H
3b
3c
3d
3e
3f
1.3
1.5
2
96
92
92
88
96
84
88
88
94
80
92
90
90
95
84
3
5-Br/H/H
4
5-I/H/H
2.5
1.3
3
5
5-NO2/H/H
3,5-CH3/H/H
H/CH3/H
6
3g
3h
3i
7
2
8
5-OCH3/H/CH3
5-NO2/H/CH3
5-CH3/H/CH3
5-Cl/H/H
2
9
3j
1.5
2.5
2
10
11
12
13
14
15
3k
5b
5c
5d
5e
5f
5-Br/H/H
2
5-I/H/H
2.5
1.5
3
5-NO2/H/H
3,5-CH3/H/H
13

aAll reactions were carried out with 1(1 mmol), 2 and 4 (1mmol), in 5 mL of solvent under air; b Yields reported are isolated
yields. cAll synthesized compounds are known in literature;[22] See Table S1 in Supplementary Information for literature
references to characterization data of individual compounds.
14

Figure 1. Recyclability of glycerol.
15

Scheme 1. Plausible mechanism.
16