Facile synthesis of ninhydrin and isatin based hydrazones in water using PEG-OSO3H as a highly efficient and homogeneous polymeric acid-surfactant combined catalyst

Article abstract of DOI:10.1016/j.tetlet.2013.05.105

The synthesis of a series of biologically important ninhydrin and isatin based hydrazones has been carried out by refluxing easily synthesized novel N′-(chloro-aryl-methylene)-tert-butylcarbazates with ninhydrin and isatins in the presence of PEG-OSO₃H as catalyst in water medium. The dual characteristic of PEG-OSO₃H as a Br?nsted acid as well as a phase-transfer catalyst is successfully exploited in this synthesis. Reduced reaction time, operational simplicity, excellent yields of the products with high purity, and more importantly, easy recoverability, and reusability of the homogeneous polymeric catalyst make the reaction an attractive, economic, and sustainable green synthetic methodology.

Full text of DOI:10.1016/j.tetlet.2013.05.105

Accepted Manuscript
Facile synthesis of ninhydrin and isatin based hydrazones in water using PEG-
OSO H as a highly efficient and homogeneous polymeric acid-surfactant com‐
3
bined catalyst
Kamalesh Debnath, Sudipta Pathak, Animesh Pramanik
PII:
S0040-4039(13)00884-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.105
TETL 43005
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Debnath, K., Pathak, S., Pramanik, A., Facile synthesis of ninhydrin and isatin based
hydrazones in water using PEG-OSO H as a highly efficient and homogeneous polymeric acid-surfactant combined
3
catalyst, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.105
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Facile synthesis of ninhydrin and isatin based hydrazones in water using
PEG-OSO3H as a highly efficient and homogeneous polymeric acid-
surfactant combined catalyst
Kamalesh Debnath, Sudipta Pathak and Animesh Pramanik*
Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India;
Fax: +91-33-2351-9755; Tel: +91-33-2484-1647.
E-mail: animesh_in2001@yahoo.co.in
Abstract: The synthesis of a series of biologically important ninhydrin and isatin based
hydrazones has been carried out by refluxing easily synthesized novel N′-(chloro-aryl-
methylene)-tert-butylcarbazates with ninhydrin and isatins in presence of PEG-OSO3H as
catalyst in water medium. The dual characteristic of PEG-OSO3H as a Brønsted acid as well
as a phase-transfer catalyst is successfully exploited in these synthesis. Reduced reaction
time, operational simplicity, excellent yields of the products with high purity, and more
importantly, easy recoverability and reusability of the homogeneous polymeric catalyst make
the reaction an attractive, economic and sustainable green synthetic methodology.
Keywords: Hydrazone derivatives, Ninhydrin, Isatin, N′-(chloro-aryl-methylene)-tert-
butylcarbazates, PEG-OSO3H, Water medium.
___________________________________________________________________________
Hydrazones possess various important bioactivities such as antimicrobial,1
anticonvulsant,2 analgesic,3 anti-inflammatory,4 antiplatelet,5 and antitumoral6 activities. The
hydrazone derivatives of isatin are also used as plasticizers and antioxidants,7 β-secretase-1
(BACE 1) inhibitors,8 commercial herbicides and acetohydroxyacid synthase inhibitor.9 Not
only that, ninhydrin and isatin based hydrazones also have large applications to act as
1

potential ligands in several metal bound complex formation.10,11a,b In the literature, only one
hydrazone derivative of ninhydrin10 and that of many isatin derivatives are reported.8,9,11
Generally, these biologically active hydrazone derivatives are synthesized by refluxing or
stirring several arylhydrazides with isatins or ninhydrin in various mediums like AcOH,
methanol, ethanol, ethanol-AcOH mixed solvent etc.8,11a-h or in solid state.11i Commercially,
limited numbers of arylhydrazides that are available are quite costly.12 In laboratory,
arylhydrazides are generally prepared, converting the aromatic acids into acid chloride by the
treatment with hazardous thionyl chloride, followed by the reflux with hydrated hydrazine
hydride,13 or by refluxing the mixture of aromatic esters with excess hydrazine hydride.9,14 In
both cases, refluxing with hydrazine hydride requires a long period of time, which is followed
then by 24 h cooling.9,13,14 In this context, an eco-friendly green synthetic methodology within
short reaction period should be devised to synthesize these biologically important hydrazone
derivatives.
Nowadays, green chemistry has attained the status of a major scientific discipline.15
The development of simple and efficient chemical processes or methodologies within the
frame of green chemistry16 for the synthesis of biologically important compounds in water
medium is in demand. Although water is a safe, very cheap, most abundant, and
environmentally benevolent solvent, organic synthesis in water medium is quite challenging
for several reasons: sluggish reaction rate due to solubility problems, deactivation of reagents
in water etc.17 These problems can be minimized or overcome by developing a synthetic
methodology in presence of surfactant combined catalyst. In this context, chlorosulphonic
acid-modified PEG-6000 (PEG-OSO3H)18 is an interesting example of mild, non-volatile and
non-corrosive Brønsted acid-phase transfer homogeneous polymeric catalyst19b,c with an
intriguing solubility profile e.g. it is soluble in many polar solvents including water and
methanol and insoluble in non-polar solvents such as hexanes, diethyl ether etc. The use of
2

this catalyst is highly expedient in organic synthesis because of simplified working
procedures, easy separation of products without discharging any harmful waste and
reusability of catalyst.19 As an acid catalyst, it can activate the substrate molecules and as a
surfactant, it increases the concentration of organic reactants to form micelle particles in
water.20 Considering the highly advantageous uses of PEG-OSO3H as acid-surfactant
combined catalyst, and in continuation of our research work with novel N′-(chloro-aryl-
methylene)-tert-butylcarbazates,21 herein, we wish to report a new, economic, mild, rapid,
and highly efficient green procedure to synthesize biologically important hydrazones of
ninhydrin and isatins from N′-(chloro-aryl-methylene)-tert-butylcarbazates in presence of
inexpensive, reusable, bio-degradable and environmentally benign PEG-OSO3H in water
medium (Scheme 1).
In our present work, we have synthesized several hydrazone derivatives of ninhydrin
5 and isatins 6 (Scheme 1), in which ninhydrin and several isatin derivatives were condensed
with differently substituted arylhydrazides, generated in situ from N′-(chloro-aryl-
methylene)-tert-butylcarbazates 4 through acid catalyzed reaction. Initially a series of carbo-
tert-butoxyhydrazones 3 were prepared by the condensation of aromatic aldehydes 1 with
tert-butylcarbazate 2. Subsequently, the compounds 3 were treated with N-chlorosuccinamide
in dry DMF medium to get N′-(chloro-aryl-methylene)-tert-butylcarbazates 4 in very high
yields.21,22 Then a mixture of ninhydrin and N′-(chloro-aryl-methylene)-tert-butylcarbazates 4
was refluxed in presence of PEG-OSO3H (20 mol %) in water medium for 30 min. The
yellow solid products 5 were precipitated out from the reaction mixture while cooling. In a
similar way, isatin and N′-(chloro-aryl-methylene)-tert-butylcarbazates 4 were refluxed in
presence of PEG-OSO3H (20 mol %) in water medium for 15 min to get the reddish yellow
products 6 on cooling the reaction mixture.22 In all cases, the final products were confirmed
3

1
by IR, H NMR, 13C NMR spectroscopy, X-ray diffraction study (Fig. 1)23 and also by
comparing the melting points of 6 with the reported values.
H
O
H
Ar
N
N
O
H2N
+
O
NH
Ar
H
O
1
O
2
3
Dry DMF,
Stirring at rt
NCS
O
O
R1
O
O
Ar
O
OH
OH
Cl
O
O
N
NH
N
O
R1
R2
Ar
N
N
N
Ar
O
O
NH
H
PEG
20 mol %
H2O, Reflux
PEG
20 mol %
OSO3H
OSO3H
N
H2O, Reflux
15 min
O
5
R2
30 min
4
6
Scheme 1. Formation of N’-(1,3-dioxo-indan-2-ylidene)-arylhydrazides 5 and N’-(2-oxo-
1,2-dihydro-indol-3-ylidene)-arylhydrazides 6.
C13
C2
C1
O1
C12
C14
C6
C3
C7
C11
C15
C4
C10
C5
C16
N2
C8
C9
N1
O3
O2
.
Figure 1. ORTEP diagram of compound 5a (Ar=Ph) with atom numbering scheme. Thermal
ellipsoids are shown at the 50% probability. (CCDC No. 919629)
4

O
Cl
O
Ph
O
NH
N
Ph
O
Catalyst
N
O
+
NH
Solvent
Reflux
O
N
H
N
H
4a
6a
Scheme 2. Synthesis of N’-(2-oxo-1,2-dihydro-indol-3-ylidene)-benzohydrazide 6a using
isatin and N′-(chloro-phenyl-methylene)-tert-butylcarbazate 4a
At first, we chose the model reaction between isatin and N′-(chloro-phenyl-
methylene)-tert-butylcarbazate (4a) in 1.20: 1.00 molar ratio under refluxing condition in
water medium (Scheme 2, Table 1, entry 1). But yield of the product was very low (<5%). In
the absence of any catalyst, on varying the reaction medium from ethanol, acetonitrile to
acetic acid, the yield of the reaction increases intriguingly from 5% to 68% (Table 1, entry 2-
4). From this result, we envisioned that a Brønsted acid activation was essential for initiation
and higher yield of this reaction to achieve. The structure of the product 6a was assigned and
confirmed by IR, 1H NMR, 13C NMR spectroscopy, elemental analysis and also by matching
the melting point of the product with the reported value.11e These significant results
motivated us to test the reaction at higher acidic condition. We increased the acidic strength
of the acetic acid solution of the reaction mixture by adding a few drops of H2SO4. But the
reaction mixture gets charred instantaneously with no product formation. It suggested that
harsh reaction condition was not suitable for performing the reaction (Table 1, entry 5). To
obtain the desired product with satisfactory yield under milder reaction condition, we tested
several Brønsted catalysts such as HCl, p-TSA, and acetic acid etc. along with some organo-
acid catalysts e.g. lactic acid, formic acid and citric acid in water medium (Table 1, entry 6-
11).In all these cases, the desired product was isolated with considerable purity, but
5

unsatisfying yield. Interestingly we observed that the yield of the reaction improved
significantly (78%) when melamine sulfonic acid (MSA) was employed as the insoluble solid
acid-catalyst (Table 1, entry 12). This observation motivated us to choose a Brønsted acid-
phase transfer catalyst (PTC) which could help the reaction to run in water medium smoothly
with easier work-up procedure and operational simplicity. At first, we performed the model
reaction taking PEG400-OSO3H as the acid-surfactant combined catalyst. Though the reaction
time was reduced to 45 min, yield of the product was moderate (48%), (Table 1, entry 13).
On increasing the molecular weight of polyethyleneglycol hemisulfates and hence the size of
the crown-shape moiety (PEG4000-OSO3H), reaction time was further diminished to 25 min
and yield of the product became moderate to good (69%), (Table 1, entry 14). Gratifyingly,
PEG6000-OSO3H gave our desired product in almost quantitative yield and with concomitant
reduction of reaction time (from 60 min to 15 min) (Table 1, entry 17). On varying the
percentage of catalyst load (10 mol% - 25 mol %), maximum yield of the product (95%) was
obtained at 20 mol % (Table 1, entry 16-19). Similar optimization study was also carried out
with ninhydrin (1.00 mmol) and N′-(chloro-phenyl-methylene)-tert-butylcarbazate (4a) (1.00
mmol) in presence or absence of various catalysts under refluxing condition in different
solvents. Best yield of the desired product within a short span of reaction time was achieved
with PEG-OSO3H (20 mol%) in water medium (86%) (See supplementary material). On the
basis of these promising results with PEG-OSO3H as catalyst and water as the reaction
medium, we had performed a library synthesis of several hydrazone derivatives of ninhydrin
and isatins (Table 2 and Table 3).
6

Table 1. Optimization of reaction conditions for the synthesis of 6a from 4a
Entry
Solvent
Catalyst
Catalyst Load
(mol %)
__
Time
(min)
60
Yield
(%)a
<5
1
2
H2O
Acetonitrile
Ethanol
Acetic acid
Acetic acid
H2O
__
__
__
__
__
20
20
20
20
20
20
20
20
60
60
60
__
15
60
60
60
60
60
60
5
3
__
12
68
__
61b
27
44
42
25
37
78
4
__
5
H2SO4
HCl
6
7
H2O
p-TSA
Acetic acid
Lactic acid
Formic acid
Citric acid
8
H2O
9
H2O
10
11
12
H2O
H2O
H2O
Melamine sulfonic acid
(MSA)
13
14
15
16
17
H2O
H2O
H2O
H2O
H2O
H2O
HO3SO-PEG400-OSO3H
20
20
10
15
20
25
45
25
15
15
15
15
48
69
81
86
95
95
HO3SO-PEG4000-SO3H
HO3SO-PEG6000-OSO3H
HO3SO-PEG6000-OSO3H
HO3SO-PEG6000-OSO3H
HO3SO-PEG6000-OSO3H
18
a
Isolated yield.
b
After 15 min, the reaction mixture started to get charred.
7

Table 2. Formation of hydrazones 5 from 4
Entry
1
Ar
Adduct
Product
Yield
(%)a,b
Melting
point(ºC)
86
200-201
4a
5a
2
3
83
81
163-164
258-260
4b
4c
5b
5c
NO2
NO2
4
5
88
80
234-236
190-191
4d
4e
5d
5e
F
6
85
208-209
4f
5f
Cl
7
8
87
85
89
174-176
202-204
238-240
4g
4h
4i
5g
5h
5i
Cl
Br
9
CN
a
Isolated yield
b
All the reactions were performed for 30 min.
8

Table 3. Formation of hydrazones 6 from 4
Entry
Ar
Adduct
R1
R2 Product
Yield
(%)a,b
Lit m.p11/ Observed
m.p (ºC)
1
2
H
H
H
95
93
27811e/ 284-286
284-286c
4a
4b
6a
H
6b
3
4
NO2
F
H
H
H
90
88
>26511e/ >300
4d
4e
6c
H
>27011f/ 282-284
6d
5
6
H
H
H
87
89
23511g/ 234-236
4f
6e
Cl
H
>300c
4h
6f
Br
7
8
H
F
H
96
94
>300c
>300c
4i
6g
CN
H
4a
6h
9
Cl
H
95
>27511h/ >300
4a
6i
10
11
Br
I
H
91
89
>26011h/ >300
290-292c
4a
4a
6j
H
6k
12
13
NO2
H
H
92
86
>300c
4a
4a
6l
Me
179-18011h/180-182
6m
9

14
H
H
Et
Et
84
88
164-165c
194-196d
4a
4i
6n
6o
15
CN
a
Isolated yield.
b
All the reactions were performed for15 min.
c
In the literature, melting points of these compounds are not reported, formation of these compounds were
confirmed on the basis of spectral analyses..
d
The compound is new.
A reasonable mechanistic aspect has been depicted for the formation of hydrazone
derivatives of ninhydrin and isatin from N′-(chloro-aryl-methylene)-tert-butylcarbazates 4 in
Scheme 3. At first, the carbon centre, having C-Cl bond of compound 4 becomes
electronically deficient due to the activation by the -SO3H group of PEG-OSO3H catalyst
which instigates the solvent water molecule to attack. Simultaneously the acid catalyzed
removal of Boc group leads to in situ formation of arylhydrazides which subsequently
condenses with the C-2 carbon of ninhydrin and C-3 position of isatins, assisted by the
Brønsted acidity of PEG-OSO3H catalyst to furnish the final product 5 and 6 respectively.
Excellent yield of the product may be attributed to the fact that, the hydrophobic
supramolecular cavity of the catalyst encapsulates the organic substrates, brings them closer
to one another and after the formation of the product via several intermediates through the
activation of reactants, the product gets precipitated out from the reaction mixture due to its
insolubility in water. Rapid exclusion of water molecules from the hydrophobic core of the
catalyst, generated during the condensation reactions may also facilitate the condensations.
10

O
S
O
S
O
S
O
S
O
O
O
O
O
O
O
O
O
H
O
O
O
:
O
H
H
H
O
O
PEG
O
H
O
H
O
H
O
O
O
O
Cl
N
-CO2
H
N
HO
Ar
NH2
O
O
-tBuOH
-HCl
N
Ar
O
HO
O
O
4
O
O
(
O
O
(
O
)
n
)
n
O
O
S
O
S
HO3 SO
H
O
O
S
O
H
O
O
PEG
O
O
O
O
O
H
O
H
H
O
O
N
HO
Ar
N
H
H
N
O
Ar
O
N
H
O
H2O
5
O
O
O
O
(
O
)
n
Scheme 3. Plausible reaction pathway for the formation of compounds 5
Furthermore, a recovering and reusability test of PEG-OSO3H for the formation of 6a
was performed up to five times without any serious loss of its activity or efficiency. After
refluxing the mixture of isatin, N′-(chloro-phenyl-methylene)-tert-butylcarbazates 4a and
PEG-OSO3H in water medium for 15 min, the product (insoluble in water) was simply
filtered and washed with methanol for purification. In order to recover the catalyst, methanol
and water were evaporated under reduced pressure, and the resulting gummy mass was
washed with diethylether, and dried. The recovered catalyst was reused directly for a new
reaction cycle and after five consecutive cycles, the yield of the product 6a varied from 95-
88% (Figure 2).
11

100
90
80
70
60
50
40
30
20
10
0
1
2
3
4
5
Number of Runs
Figure 2. Reuse of PEG-OSO3H in the synthesis of 6a
In conclusion, we have successfully developed a highly efficient, general and green
synthetic methodology for the hydrazone derivatives of ninhydrin and isatin, using PEG-
OSO3H as a recoverable and biodegradable polymeric catalyst in water medium. Cost
effectivity, mild reaction conditions, operational simplicity, enhanced rates, ease of handling
of the catalyst, cleaner reaction profile, high isolated yields of pure products and use of water
as the solvent are the significant advantages of the procedure described here.Therefore this
may be a very attractive method for the synthesis of this biologically active hydrazone library
in chemical and pharmaceutical industries fulfilling the demand of the green chemistry
protocols.
Acknowledgements
K.D. and S.P. thank UGC and CSIR, New Delhi, India for offering them Junior Research
Fellowship (JRF) and Senior Research Fellowship (SRF), respectively. The financial
assistance of CSIR, New Delhi is gratefully acknowledged [Major Research Project,
No.02(0007)/11/EMR-II]. Crystallography was performed at the DST-FIST, India-funded
12

Single Crystal Diffractometer Facility at the Department of Chemistry, University of
Calcutta.
Supporting Information
Supplementary data (IR, 1H, 13C data of compounds 5 and 6 and crystallographic data for 5g)
associated with this article can be found, in the online version, at -----------------------------
References and notes:
1. Masunari, A.; Tavares, L. C. Bioorg. Med. Chem. 2007, 15, 4229.
2. Ragavendran, J. V.; Sriram, D.; Patel, S. K.; Reddy, I. V.; Bharathwajan, N.; Stables, J.;
Yogeeswari, P. Eur. J. Med. Chem. 2007, 42, 146.
3. Lima, P. C.; Lima, L. M.; Da Silva, K. C. M.; Léda, P. H. O.; De Miranda, A. L. P.; Fraga,
C. A. M.; Barreiro, E. J. Eur. J. Med. Chem. 2000, 35, 187.
4. Salgin-Gökşen, U.; Gökhan-Kelekçi, N.; Göktaş, Ö.; Köysal, Y.; Kiliç, E.; Işik, Ş.; Aktay,
G.; Özalp, M. Bioorg. Med. Chem. 2007, 15, 5738.
5. Silva, G. A.; Costa, L. M. M.; Brito, F. C. F.; Miranda, A. L. P.; Barreiro, E. J.; Fraga, C.
A. M. Bioorg. Med. Chem. 2004, 12, 3149.
6. (a) Bernhardt, P. V.; Sharpe, P. C.; Islam, M.; Lovejoy, D. B.; Kalinowski, D. S.;
Richardson, D. R. J. Med. Chem. 2009, 52, 407; (b) Whitnall, M.; Howard, J.; Ponka, P.;
Richardson, D. R. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 14901.
7. Katyal, M.; Dutt, Y. Talanta 1975, 22, 151.
8. Mok, N. Y.; Chadwick, J.; Kellett, K. A. B.; Hooper, N. M.; Johnson, A. P.; Fishwick , C.
W. G. Bioorg. Med. Chem. Lett. 2009, 19, 6770.
9. Wang, J.; Tan, H.; Li, Y.; Ma, Y.; Li, Z.; Guddat, L. W. J. Agric. Food Chem. 2011, 59,
9892.
13

10. Liu, W.-S.; Wu, D.-X., Chen, J.-Y.; Wang, H.-J.; Tang, X.-L. Acta Crystallographica
Section E 2008, E64, m1088.
11. (a) Srivastava, A. K.; Pandey, O. P.; Sengupta, S. K. Synthesis and Reactivity in
Inorganic and Metal-Organic Chemistry 2000, 30, 1405; (b) Zhong, X.; Wei, H.-L.; Liu, W.-
S.; Wang, D.-Q.; Wang, X. Bioorg. Med. Chem. Lett. 2007, 17, 3774; (c) Somogyi, L. Bull.
Chem. Soc. Jpn. 2001, 74, 873; (d) Liang, Z.; Zhang, D.; Ai, J.; Chen, L.; Wang, H.; Kong,
X.; Zheng, M.; Liu, H.; Luo, C.; Geng, M.; Jiang, H.; Chen, K. Bioorg. Med. Chem. Lett.
2011, 21, 3749; (e) Varma, R. S. J. Indian Chem. Soc. 1978, 55, 1052; (f) Varma, R. S.;
Pandey, R. K. J. Indian Chem. Soc. 1982, 59, 1174; (g) Ali, R. A.; Mishra, B.; Nizamuddin
Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry
1989, 28B, 526; (h) Varma, R. S.; Khan, I. A. J. Indian Chem. Soc. 1981, 58, 811; (i) Kaupp,
G.; Schmeyers, J.; Boy, J. Journal fuer Praktische Chemie 2000, 342, 269.
12. For a price list of available arylhydrazides, see: sigma-aldrich.com/hydrazide.
13. (a) Wang, X.-Q.; Zhao, Z.-G.; Liu, X.-L.; Li, W.-J., J. Chem. Res. 2010, 34, 307.
14. (a) Huang, Y.; Hu, X.-Q.; Shen, D.-P.; Chen,Y.-F.; Xu, P.-F. Molecular Diversity 2007,
11, 73; (b) Mohamed, R. R. J. vinyl and additive tech. 2008, 14, 184; (c) Kümmerle, A. E.;
Schmitt, M.; Cardozo, S. V. S.; Lugnier, C.; Villa, P.; Lopes, A. B.; Romeiro, N. C.;
Justiniano, H.; Martins, M. A.; Fraga, C. A. M.; Bourguignon, J.-J.; Barreiro, E. J. J. Med.
Chem. 2012, 55, 7525.
15. Clark, J. H.; Macquarrie, D. Handbook of Green Chemistry &Technology; Blackwell
Publishers: Oxford, 2002.
16. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University
Press: Oxford, 1998.
17. (a) Grieco, P. A. Organic Synthesis in Water, Blackie Academic and Professional,
London, 1998; (b) Green Chemistry, ed. P. T. Anastas and T. C. Williamson, ACS
14

Symposium Series 626, American Chemical Society, Washington, DC, 1996; (c) Li, V. J.;
Chan, T. H. Organic Reactions in Aqueous Media, Wiley, New York, 1997; (d) Li, C.-J.
Chem. Rev. 2005, 105, 3095.
18. Preparation of PEG-OSO3H: At 0 oC, chlorosulfonic acid (10 mmol) was added to a
solution of PEG-6000 (1 mmol) in CH2Cl2 (10 mL), and the resulting solution was stirred at
room temperature overnight. Then, the solution was concentrated under vacuum, and ether
was added to it. The resulting precipitate was filtered and washed with ether three times to
afford PEG-OSO3H as a gummy solid.19a 1HNMR (CDCl3, 500 MHz): (ppm) 3.40–3.54 (m,
PEG), 4.18 (s, 2H, CH2OSO3H), 12.69 (s, 1H, SO3H).
19. (a) Wang, X.; Quan, Z.; Wang, F.; Wang, M.; Zhang, Z.; Li, Z. Synth. Commun. 2006, 36,
451; (b) Kiasat, A. R.; Mehrjardi, M. F. Catal. Commun. 2008, 9, 1497; (c) Kiasat, A. R.;
Mehrjardi, M. F. Synth. Commun. 2008, 38, 2995; (d) Hasaninejad, A.; Shekouhy, M.; Zare,
A.; Ghattali, S. M. S. H.; Golzar, N. J. Iran. Chem. Soc. 2011, 8, 411; (e) Hasaninejad, A.;
Zare, A.; Shekouhy, M.; Ameri-Rad, J. Green Chem. 2011, 13, 958; (f) Hasaninejed, A.;
Kazerooni, M. R.; Zare, A. Catal. Today 2012, 196, 148.
20. Shiri, M.; Zolfigol, M. A. Tetrahedron 2009, 65, 587.
21. Debnath. K.; Pathak, S.; Pramanik, A. Tetrahedron lett. 2013, 54, 896.
22. General procedure for the synthesis of N′-(chloro-aryl-methylene)-tert-
butylcarbazates (4): Aromatic aldehydes 1 (1.00 mmol) and tert-butylcarbazate 2 (1.00
mmol) were placed in a 50 ml round bottomed flask where condensation between 1 and 2
took place instantaneously to form the carbo-tert-butoxyhydrazones 3. In the case of solid
aldehydes, 5.0 ml of methanol was required to add to the mixture of 1 and 2 and heated
slightly on water bath to furnish the condensation. Subsequently, N-chlorosuccinamide (1.00
mmol) was added to the dry DMF (10 mL) solution of compounds 3 (1.00 mmol) at cold
o
condition (temperature around 0 C) and then stirred for 3 h at room temperature. The
15

progress of the reaction was monitored by TLC analysis. After completion of the reaction, the
reaction mixture was poured into ice-cold water and the solid residue 4 was filtered out,
which was washed several times with distilled water, dried in open air and then crystallized
from acetone.
Typical procedure employed for the synthesis of N’-(1,3-dioxo-indan-2-ylidene)-
benzohydrazide (5a): A mixture of ninhydrin ( 0.178 g, 1.00 mmol), N’-(chloro-phenyl-
methylene)-tert-butylcarbazates (4a) ( 0.254 g, 1.00 mmol), and PEG-OSO3H (20 mol %)
was refluxed in water (10 mL) for 30 min. Progress of the reaction was monitored by TLC
checking. A yellow solid product was precipitated out from the reaction mixture while
cooling. The crude yellow solid product 5a was isolated through filtration and washed
thoroughly with water for several times. Then the compound 5a was crystallized from
methanol.
Typical procedure employed for the synthesis of N’-(2-oxo-1,2-dihydro-indol-3-
ylidene)-benzohydrazide (6a): A mixture of isatin ( 0.176 g, 1.20 mmol), N’-(chloro-
phenyl-methylene)-tert-butylcarbazates (4a) ( 0.254 g, 1.00 mmol), and PEG-OSO3H (20
mol %) was refluxed in water (10 mL) for 15 min. Progress of the reaction was monitored by
TLC checking. A reddish-yellow solid product was precipitated out from the reaction mixture
while cooling. The crude yellow solid product 6a was isolated through filtration and washed
thoroughly with water-methanol to afford pure product 6a.
Representative spectral data of compounds: N’-(1,3-dioxo-indan-2-ylidene)-
1
benzohydrazide (5a): H NMR (300 MHz, CDCl3):  13.79 (bs,1H), 8.10-7.89 (m, 6H),
13
7.69-7.28 (m, 3H); C NMR (75 MHz, CDCl3):  187.6, 184.4, 162.3, 141.9, 139.3, 138.1,
137.1, 136.9, 136.3, 133.5, 131.0, 129.0, 128.5, 124.0; IR (KBr): 3076, 1725, 1692 cm-1;
Anal calcd for C16H10N2O3: C, 69.06; H, 3.62; N, 10.07% Found C, 68.97; H, 3.55; N,
10.00%.
16

1
N’-(1,3-dioxo-indan-2-ylidene)-4-nitro-benzohydrazide (5d): H NMR (300 MHz, d6-
DMSO):  13.43 (s,1H), 8.38 (d, J= 8.7 Hz, ,2H), 8.08 (d, J= 8.7 Hz, 2H), 7.96 (m, 4H); 13C
NMR (75 MHz, d6-DMSO):  186.9, 185.2, 164.2, 150.3, 141.8, 141.0, 139.8, 137.3, 137.2,
137.0, 130.0, 124.5, 124.2, 123.8; IR (KBr): 3079, 1727, 1690 cm-1; Anal calcd for
C16H9N3O5: C, 59.45; H, 2.81; N, 13.00% Found C, 59.36; H, 2.73; N, 12.94%.
1
N’-(1-ethyl-2-oxo-1,2-dihydro-indol-3-ylidene)-4-cyano-benzohydrazide (6o): H NMR
(300 MHz, d6-DMSO): ; 13.88 (bs, 1H), 8.08-7.89 (m, 4H), 7.61-7.43 (m, 2H), 7.22-7.12
(m, 2H), 3.78 (q, J= 6.9 Hz, 2H), 1.20 (t, J= 6.6 Hz, 3H); 13C NMR (75 MHz, d6-DMSO): 
161.2, 143.2, 136.4, 133.5, 132.5, 129.5, 128.7, 127.9, 123.7, 121.4, 119.5, 118.5, 115.4,
110.6, 34.8, 12.9; IR (KBr): 2227, 1696, 1679 cm-1; Anal calcd for C18H14 N4O2: C, 67.92; H,
4.43; N, 17.60% Found C, 67.83; H, 4.36; N, 17.52%.
23. Crystallographic data for the structure 5a and 5g in this paper have been deposited with
Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 919629,
and 919941 respectively. Copies of the data can be obtained, free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 01223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
17

Graphical abstract
Facile synthesis of ninhydrin and isatin based hydrazones in water using
PEG-OSO3H as a highly efficient and homogeneous polymeric acid-
surfactant combined catalyst
Kamalesh Debnath, Sudipta Pathak and Animesh Pramanik*
O
O
O
O
R1
Ar
HO
HO
N
O
Cl
O
N
H
O
O
O
N
R1
R2
Ar
N
N
O
Ar
N
N
H
O
NH
OSO3H
PEG6000
OSO3H
PEG6000
R2
20 mol%, 30 min
H2O, Reflux
20 mol%, 15 min
H2O, Reflux
9 Examples
81-89 % yield
15 Examples
84-96 % yield
18