A facile, aqueous phase green synthetic protocol for the synthesis of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-thiols

Article abstract of DOI:10.1016/j.tetlet.2011.06.098

5,9b-Dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-thiols were synthesized for the first time in water under neutral conditions by using isatin, semicarbazide/thiosemicarbazide, mediated by β-cyclodextrin in

Full text of DOI:10.1016/j.tetlet.2011.06.098

Tetrahedron Letters 52 (2011) 4734–4737
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile, aqueous phase green synthetic protocol for the synthesis
of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-
1H-[1,2,4]triazino[5,6-b]indole-3-thiols
⇑
K. Ramesh, S. Narayana Murthy, K. Karnakar, Y. V. D. Nageswar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
5,9b-Dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-thiols
were synthesized for the first time in water under neutral conditions by using isatin, semicarbazide/
thiosemicarbazide, mediated by b-cyclodextrin in excellent yields. b-Cyclodextrin has been recovered
and reused without any loss of catalytic activity.
Received 6 June 2011
Revised 22 June 2011
Accepted 26 June 2011
Available online 13 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isatin
Semicarbazide/thiosemicarbazide
b-Cyclodextrin
Water
Over the years synthetic heterocyclic chemistry is providing
impetus to the development of new drug scaffolds through itera-
tive manipulation of functional groups around the rudimentary
skeletal systems. Among these, heterocyclic compounds have been
given special emphasis due to a wide variety of medicinal and bio-
logical properties associated with them1 (Fig. 1).2 In view of this,
globally researchers started exploring simple and novel one-pot
procedures to obtain potential new molecular entities,3 belonging
and antibacterial activity.14,15 Recently Ivachtchenko et al., re-
ported the synthesis of 5H-[1,2,4]triazino[5,6-b]indole-3-thiol by
using isatin, and thiosemicarbazide mediated by base followed
by acid.16
In view of different biological activities associated with various
5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-
1H-[1,2,4]triazino[5,6-b]indole-3-thiol derivatives and in continu-
ation of our interest in the use of cyclodextrins as mild and
efficient biomimetic catalysts in promoting various transforma-
tions,17 we have attempted a novel aqueous phase synthesis of
5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ols/5,9b-dihydro-
1H-[1,2,4] triazino[5,6-b]indole-3-thiols by the reaction of isatin
derivatives with semicarbazide/thiosemicarbazide under neutral
conditions involving supramolecular catalysis using b-cyclodex-
trin. Cyclodextrins (CDs) are cyclic oligosaccharides possessing
hydrophobic cavities, which bind substrates selectively and cata-
lyze chemical reactions with high selectivity. They catalyze reac-
tions by supramolecular catalysis involving reversible formation
of host–guest complexes by non-covalent bonding as seen in en-
zymes. We describe, herein, the first aqueous phase synthesis of
to
a broad range of heterocyclic systems. 5,9b-Dihydro-1H-
[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4]triaz-
ino[5,6-b]indole-3-thiols and their analogues exhibit varied bio-
logical activities/medicinal applications such as antimicrobial,4–8
antiviral,9 antihypertensive,9,10 blood-platelet aggregation inhibi-
tory,10,11 and analgesic12 activities. In addition, 3-arylidene-and
3-alditol-1-ylidenehydrazino-1,2,4-triazino[5,6-b]indoles showed
antitumor activity against P388 lymphocytic leukemia in mice13
N
N
N
S
a
5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ols/5,9b-dihy-
dro-1H-[1,2,4] triazino[5,6-b]indole-3-thiol derivatives demon-
strating the remarkable catalytic activity of b-cyclodextrin
(Schemes 1 and 2). In general, the reaction was carried out by
the in situ formation of b-CD complex of isatin in water followed
by the addition of semicarbazide/thiosemicarbazide and stirring
N
N
H
Figure 1. Polycyclic fused heteroaromatic skeleton with good biological activities.
at 50–55 °C to give the corresponding
a 5,9b-dihydro-1H-
⇑
[1,2,4]triazino[5,6-b]indole-3-ols/5,9b-dihydro-1H-[1,2,4] triazi-
no[5,6-b]indole-3-thiols in high yields (80–90%). These reactions
Corresponding author. Tel.: +91 40 27191654; fax: +91 40 27160512.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.098

K. Ramesh et al. / Tetrahedron Letters 52 (2011) 4734–4737
4735
O
N
HN
N
H
OH
-CD/H O
N
NH2
β
2
R
O
+
N
H2N
R
N
R1
50-55 o
C
O
R1
R1= -H, -CH3, -C6H5,
-CH2C6H5.
R = -H, -F, -Br, -Cl,
-CH3, -OCH3, -NO2.
Scheme 1. Synthesis of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-ols.
O
N
N
HN
H
N
SH
NH2
-CD/H O
50-55 oC
β
O
2
+
R
H2N
R
N
R1
N
R1
S
R1= -H, -CH3, -CH2C6H5.
R = -H, -F, -Br, -Cl,
-CH3, -OCH3, -NO2.
Scheme 2. Synthesis of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3thiols.
proceeded efficiently without the need of any metal or acid cata-
lyst. The reaction goes to completion in a short time (4–5 h). This
methodology is also compatible with various substituted isatins.
In this study, a model reaction was conducted by reacting isatin
and semicarbazide in water at 50–55 °C to obtain the correspond-
ing 5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ol in low
yields (18%). Because of poor solubility of isatin in water, reaction
at elevated temperature also resulted in the formation of undesired
products. When the same reaction was conducted using b-CD at
room temperature the product was obtained in moderate yield
(55%). However in a controlled experiment using b-CD as a supra-
molecular catalyst at 50–55 °C, the product was obtained in excel-
lent yield (89%) (Scheme 1). In due course of the methodology
Even though these reactions take place with
a-CD, c-CD also ef-
fects this reaction albeit in lower yield. Therefore b-CD has been
chosen as the mediator as it is inexpensive and easily accessible.
Several examples illustrating this simple and practical methodol-
ogy are summarized in Tables 3 and 4. No byproduct formation
was observed. b-Cyclodextrin can be easily recovered and reused.
All the compounds were characterized by 1H NMR, IR, and mass
spectrometry.18,19 The catalytic activity of cyclodextrins for these
reactions is established by the fact that no reaction was observed
in the absence of cyclodextrin. Evidence for the complexation be-
tween isatin and cyclodextrin is obtained by 1H NMR studies. Com-
parative 1H NMR studies of b-CD, b-CD/isatin complex indicated an
upfield shift of H3 (0.02 ppm) and H5 (0.02 ppm) protons of cyclo-
dextrin in the b-CD: isatin complex as compared to b-CD, confirm-
ing the formation of an inclusion complex of isatin with b-CD.17a
The complexation with b-CD increases the reactivity of the keto
group of isatin due to intermolecular hydrogen bonding with the
CD-hydroxyl groups facilitating the reaction with semicarbazide.
Here, b-CD not only forms an inclusion complex with isatin but
is also involved in the intermolecular hydrogen bonding with the
guest to promote the reaction. b-CD was recovered and reused.
After the reaction, the reaction mass was cooled to room tempera-
ture, b-CD was filtered, washed with ice-cold water and dried. The
recovered b-CD was further used with the same substrate as a cat-
alyst and checked for the yields and catalytic activity of recovered
catalyst (b-CD). As shown in Table 1, the yields of 5,9b-dihydro-1H-
[1,2,4] triazino[5,6-b]indole-3-ols (Entry 1, Table 1) after two to
three recycles were almost same.
development, for the first time various cyclodextrins such as
a-
cyclodextrin, b-cyclodextrin, and
c-cyclodextrin were examined
Table 2
Optimization of reaction conditions using different catalystsa
Entry
Catalyst
Yield [%]b
1
2
3
4
Water (without catalyst)
18
38
89
58
a
-Cyclodextrin
b-Cyclodextrin
-Cyclodextrin
c
a
All reactions was carried out using isatin (1.0 mmol), semicarbazide (1.0 mmol),
and b-CD (1.0 mmol).
b
Isolated yield.
H
N
NH2
H2N
O
O
O
Table 1
NH
Recyclability of b-CDa
Cycles
Yield [%]
Catalyst recoveredb [%]
Native
89
86
85
81
88
84
83
80
1
2
3
a
All reactions was carried out using isatin (1.0 mmol), semicarbazide (1.0 mmol),
and b-CD (1.0 mmol).
Figure 2. Possible mechanistic pathway for the formation of 5,9b-dihydro-1H-
[1,2,4] triazino[5,6-b]indole-3-ol using b-cyclodextrin.
b
Isolated yield.

4736
K. Ramesh et al. / Tetrahedron Letters 52 (2011) 4734–4737
Table 3
Table 4
Synthesis of 5,9b-dihydro-1H-[1,2,4]triazino[5,6-b]indole-3-olsa
Synthesis of 5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-thiolsa
O
O
N
N
N
N
R1
HN
N
HN
H
H
β−CD/H2O
OH
SH
N
NH2
β-CD/H
O
N
NH2
O
2
R
+ H2N
+
O
R
H2N
R
N
o
R
O
R1
N
50-55
C
50-55 °C
N
S
R1
R1
Entry
1
Isatin
Product
Yield (%)b
89
R = -H, -F, -Br. -Cl, R = -H, -CH , -CH C H .
-CH , -OCH , -NO .
1
3
2 6 5
3
3
2
O
H
N
N
Entry
1
Isatin
Product
Yield (%)b
83
O
O
OH
N
N
N
H
H
O
H
N
N
H
N
O
F
SH
N
F
N
N
N
N
H
H
O
OH
2
3
4
5
6
90
88
87
85
83
N
N
N
H
H
O
H
Cl
Cl
N
O
H
N
Cl
Cl
O
SH
2
3
4
5
84
83
81
80
N
N
H
N
O
N
OH
OH
N
N
H
N
H
H
O
H
N
Br
Br
N
O
H
N
Br
Br
O
SH
N
N
N
H
N
O
N
H
N
H
N
H
O
H
H3C
H3C
O
H
N
N
N
H3C
H3C
N
O
SH
O
O
N
OH
N
N
N
N
H
N
H
H
H
O
H
N
H3CO
H
N
H3CO
H3CO
H3CO
N
N
O
O
SH
OH
N
N
N
N
N
N
H
H
H
H
O
H
N
O
H
N
N
N
N
O
CH3
OH
OH
N
O
CH3
7
8
84
86
SH
SH
6
80
N
N
CH3
N
N
N
CH3
O
H
N
O
H
N
N
O
N
O
N
N
N
N
N
7
8
82
85
N
O
H
N
N
O
H
O
O2N
OH
O2N
N
N
N
N
9
85
O
SH
N
N
N
H
H
O
H
a
N
N
Reaction conditions: isatin (1.0 mmol), thiosemicarbazide (1.0 mmol), b-CD
(1.0 mmol), and water (10 mL).
O
OH
10
11
87
90
N
H
N
b
N
Cl
Isolated yield.
Cl
H
O
H
N
O2N
O2N
N
O
yields under neutral conditions in one pot involving supramolecu-
lar catalysis by b-cyclodextrin in water. This simple and facile
method will be a useful addition to green chemistry with an advan-
tage that the reaction excludes highly flammable organic solvents,
moisture sensitive or hazardous catalysts and elevated reaction
temperatures.
OH
N
N
N
H
H
a
Reaction conditions: isatin (1.0 mmol), semicarbazide (1.0 mmol), b-CD
(1.0 mmol), and water (10 mL).
b
Isolated yield.
Acknowledgments
for their efficiency as promoters in carrying out the reaction under
supramolecular catalysis (Table 2).
Cyclodextrin forms an inclusion complex with isatin, which fur-
ther reacts with semicarbazide/thiosemicarbazide leading to the
desired product as indicated in Figure 2.
We thank CSIR, New Delhi, India, for fellowships to S.N.M., K.K.
and UGC for fellowship to K.R.
Supplementary data
In summary, we have developed an eco-friendly protocol for the
synthesis of 5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-ols/
5,9b-dihydro-1H-[1,2,4] triazino[5,6-b]indole-3-thiols in excellent
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.098.

K. Ramesh et al. / Tetrahedron Letters 52 (2011) 4734–4737
4737
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References and notes
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18. General experimental procedure for the synthesis of 5,9b-dihydro-1H-[1,2,4]-
triazino[5,6-b]indole-3-ol: (Table 3, Entry 1): b-Cyclodextrin (1.0 mmol) was
dissolved in water (10 mL) by warming to 50–55 °C until a clear solution was
formed. Then, isatin (1.0 mmol) dissolved in methanol (0.5 mL) was added
followed by semicarbazide (1.0 mmol) and the mixture was stirred at 50–55 °C
until the reaction was complete (as monitored by TLC). After completion of the
reaction, mixture was cooled to room temperature and b-cyclodextrin was
filtered. The aqueous layer was extracted with ethyl acetate (3 Â 10 ml). The
combined organic layers were extracted with water, saturated brine solution
and dried over anhydrous Na2SO4. The combined organic layers were
evaporated under reduced pressure and the resulting crude product was
purified by column chromatography by using ethyl acetate and hexane (4:6) as
eluent. The aqueous layer was cooled to 5 °C to recover b-CD (Table 1). The
product was confirmed by IR, 1H & 13C NMR, mass spectra.
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19. Data for the representative examples of synthesized compounds: 5,9b-dihydro-1H-
[1,2,4]triazino[5,6-b]indol-3-ol (Table 3, Entry 1); Light yellow solid. M.p. 244–
246 °C; IR mmax (KBr): 3467, 3302, 3234, 3131, 2924, 2822, 1708, 1621, 1573,
1465, 1390, 1348, 1303, 1211 cmÀ1 1H NMR (300 MHz,CDCl3+DMSO,TMS)
;
d = 10.34 (s, 1H, –OH), 7.27–7.19 (m, 1H), 7.00 (d, 1H, J = 7.3 Hz), 6.69 (s, 1H), 6.45
(t, 1H), 6.35 (d, 1H, J = 7.7 Hz), 6.1 (s, 2H); 13C NMR (75 MHz, DMSO,TMS)
d = 162.70, 154.96, 141.68, 131.04, 130.26, 122.03, 120.31, 120.08, 110.83; Mass
(ESI-MS): m/z 189 (M+H)+; Anal. Calcd for: (C9H8N4O) C: 57.44, H: 4.28, N:
29.77; found C: 57.39, H: 4.22, N: 29.71.
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