β-Cyclodextrin catalysed synthesis of tryptanthrin in water

Article abstract of DOI:10.1039/c0gc00523a

An efficient and green method has been developed for the synthesis of tryptanthrin employing β-cyclodextrin as a catalyst in aqueous media at room temperature from isatoic anhydride and isatin. The reactions were performed under mild conditions to afford biologically active natural product tryptanthrin in excellent yields.

Full text of DOI:10.1039/c0gc00523a

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COMMUNICATION
b-Cyclodextrin catalysed synthesis of tryptanthrin in water†
Atul Kumar,* Vishwa Deepak Tripathi and Promod Kumar
Received 6th September 2010, Accepted 11th October 2010
DOI: 10.1039/c0gc00523a
An efficient and green method has been developed for
the synthesis of tryptanthrin employing b-cyclodextrin as a
catalyst in aqueous media at room temperature from isatoic
anhydride and isatin. The reactions were performed under
mild conditions to afford biologically active natural product
tryptanthrin in excellent yields.
In recent years growing awareness about environmental safety
and global warming has attracted worldwide concern towards
use of renewable sources and reduction of waste. This has
shifted paradigm towards the use of ecofriendly and green
protocols in organic synthesis. A catalyst derived from biomass
Fig. 1 Representative biologically active molecules that posses 3-
and green solvent increases the greenness of a process. Tryptan-
thrin (indolo[2,1-b]quinazoline-6,12-dione) is weak basic alka-
loid found in a number of plant species.1 Tryptanthrin and
its analogues have emerged as potential biologically active
molecules because of their broad spectrum of activity against
various pathogens. Tryptanthrin possesses antibacterial activ-
ity against Bacillus subtilis, Mycobacterium tuberculosis and
resistant strains of tuberculosis,2 antifungal activity against
Leishmania donovani, Trypanosoma brucei and Plasmodium
falciperum. Tryptanthrin and derivatives are also well known
to be potential anticancer agents against MCF-7, NCI-H460
and SF-268 human cancer cell lines.3–6 Tryptanthrin consists of
quinazoline and indole core structures. The quinazoline core
itself forms the building block for approximately 150 naturally
occurring alkaloids isolated from a number of plant families,
animals and microorganisms, such as batracylin, (-)-vascicine
and lutonin (Fig. 1). Hence indolo[2,1-b]quinazoline-6,12-dione
is a very important class of heterocyclic compound for its
structural diversity as well as pharmacological value.7–8
arylquinazoline structural motif.
from isatin.9b Weaver et al. have reported oxidative radical
cyclization for synthesis of quinazolines from quinazolin-4(3H)-
one.10–11 Mitscher et al. have described intramolecular aza-Wittig
reaction using triethylamine.12 Jao synthesized tryptanthrin
from isatin and POCl3.13 Though different approaches have been
reported, there are many limitations such as use of strong basic
conditions, elevated temperatures, long reaction time, hazardous
organic solvents, reagents, catalyst for activation and low yield.
Synthesis of compounds via a green, mild and simpler procedure,
eliminating the use and generation of hazardous substances is
the foremost goal of green chemistry today. Hence, in a quest
for a new easy and ecofriendly procedure for the synthesis of
tryptanthrin, we planned our strategy to exploit cyclodextrins
as catalysts in aqueous medium. Cyclodextrin-mediated organic
reactions in aqueous medium are very useful both from econom-
ical and environmental point of view. Cyclodextrins apart from
being nontoxic are considered to be metabolically safe.
Tryptanthrin can be produced by Candida lipolytica when
grown in media containing an excess of tryptophan, hence name
tryptanthrin.9 In view of the importance of these heterocycles
various synthetic methods have been developed for synthesis
of tryptanthrin. The current methods available for synthesis of
quinazoline nucleus involve use of anthranilic acid, primary
amines, thionyl chloride and pyridine.9a Electrosynthesis of
tryptanthrin also has been reported by Barba et al. starting
In this communication we have reported the synthesis of
tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) derivatives
with b-cyclodextrin as catalyst in aqueous medium from isatoic
anhydrides and isatins at room temperature (Scheme 1). Cy-
clodextrins are cyclic glucose oligomers with cylindrical shape
having primary hydroxyl groups at the more restricted rim
of the cylinder. They catalyze reactions by supramolecular
Medicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow, India. E-mail: dratulsax@gmail.com;
Fax: +91-522-26234051; Tel: +91-522-2612411
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0gc00523a
Scheme 1 Synthesis of tryptanthrin derivatives.
Green Chem., 2011, 13, 51–54 | 51
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Table 2 Synthesis of different tryptanthrin derivatives
catalysis involving the formation of a host–guest complex by
noncovalent bonding interactions.14 Supramolecular catalysis
is the discipline of chemistry which involves all intermolecular
interactions where covalent bonds are not established between
the interacting species i.e., molecules, ions, or radicals.15 The
majority of these interactions are of the host–guest type. The
internal cavity of the cyclodextrin (CD) molecule is strongly
hydrophobic in nature and this particular characteristic of CD
molecules enables them tobinda widerangeof guest molecules.16
Cyclodextrins bind substrates in its hydrophobic cavity and
catalyze reactions in a selective manner. Cyclodextrin used in
the reaction can be recovered after completion.
The three most common cyclodextrins are a, b and g-species
having 6, 7 and 8 sugar molecules respectively in the ring system.
For optimization of the catalyst, the reaction of isatoic anhydride
and isatin (without any substitution) was taken as the model
reaction and all three forms of cyclodextrin were explored as
catalysts. Very good results were obtained with b-CD as catalyst
Table 1. Product yield was low with a and g-cyclodextrins.
No product formation was detected in absence of cyclodextrin,
which showed that cyclodextrin plays an essential role to catalyze
the reaction. Hence b-CD was chosen as catalyst for the reaction.
We also screened different solvents such as CH3OH, CHCl3,
DMF, DMSO, THF, acetonitrile and water with cyclodextrin
as catalyst. After some optimization we found promising results
with water as a solvent due to better solubility of cyclodextrin in
water. Subsequently to verify the general procedure of reaction,
various substituted isatins and substituted isatoic anhydride
were tested under optimised reaction conditions, the results have
been summarised in Table 2.
Entry Compound R1
R2
R3
Timea Yield(%)b
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
H
H
H
Br
NO2
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
OCH3
H
6
6
6
5
6
5
5
8
6
9
5
5
6
7
5
9
8
9
8
6
7
7
6
90
82
81
86
86
83
86
82
87
80
82
81
84
80
85
79
81
80
82
83
84
86
85
OCH3 NO2
H
Br
OCH3
CH3
Cl
NO2
F
I
Br
Br
Br
NO2
NO2
NO2
Cl
Cl
F
F
NH2
H
H
H
H
H
H
H
OCH3
NO2
NH2
Br
OCH3
Cl
NO2
OCH3
Cl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3s
3t
3u
3v
3w
H
OCH3
H
H
H
NO2
OCH3 Cl
a Time in hours. b Isolated yields of purified fractions.
The reaction was carried out by dissolving cyclodextrin in
water followed by addition of substituted isatoic anhydride
(1) and isatin (2). The reaction mixture was stirred at room
temperature to give the desired compound in excellent yields.
Reaction goes smoothly without formation of any side product.
The fact that these reactions do not take place in absence of
cyclodextrin indicates the essential role of cyclodextrin, which
appears to activate the carbonyl carbon at position 4 of isatoic
anhydride leading to cleavage of anhydride ring and formation
of intermediate (5). Which then reacts at position 2 of isatin to
form the product (6) (Fig. 2).
Fig. 2 Plausible mechanistic pathway for reaction.
b-cyclodextrin. It is further observed from spectra of reaction
mixture after two hours that the upfield character of protons
retains in the reaction mixture showing retention of complex
during reaction after 2 h. This indicates the formation of b-
CD complex from primary rim of cylinder. Thus the role of
cyclodextrin is not only to catalyze the reaction, but also to
provide a new mechanistic pathway to the reaction.
The catalyst reusability was studied five times including the
use of fresh catalyst for the synthesis of compound (3a) and there
was inevitable loss of catalyst during recovery process. Besides
this no significant loss in catalytic activity was observed (Fig. 4)
and catalyst was reused in next batch without any treatment.
Evidence for association of isatoic anhydride and cyclodextrin
1
is provided by 1H NMR spectroscopy. A comparison of H
NMR spectra (D2O solutions) of b-CD, b-CD-isatoic anhydride
complex and freeze-dried reaction mixture after 2 h were
undertaken (Fig. 3). It is evident from Fig. 3 that there is
an upfield shift of H-3 (0.034 ppm) and H-5 (0.058 ppm) of
cyclodextrin in complex as compared to b-CD indicating the
formation of an inclusion complex of isatoic anhydride with
Conclusions
Table 1 Summary of different catalysts used for synthesis of (3a)
In conclusion, an extremely efficient and green process has been
developed for the synthesis of biologically active natural product
tryptanthrin, using b-cyclodextrin as a catalyst in aqueous
medium. This method is bestowed with merits like high yield,
cost effectiveness, biomimetic, neutral aqueous phase conditions
and environmentally benign nature. These advantages of the
catalyst made this process very useful for the synthesis of
tryptanthrin derivatives.
Entry
Catalyst
Solvent
Time/h
Yield (%)a
1
2
3
4
a- CD
b- CD
g- CD
—
Water
Water
Water
Water
10
6
11
—
21
90
20
—
a Isolated yields of purified fractions.
52 | Green Chem., 2011, 13, 51–54
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spectrometer as KBr pellets. Elemental analysis was preformed
using a Perkin Elmer Autosystem XL Analyzer. Melting points
were measured using a COMPLAB melting-point apparatus.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates visualized with UV light.
General procedure for synthesis of compounds 3(a–x)
Isatin (1 mmol.) and isatoic anhydride (1 mmol.) were combined
with 10 ml distilled water in a 50 ml roundbottomed flask
equipped with a stir bar. b-cyclodextrin (20 mol%) was added.
Reaction was allowed to stir at room temperature for the
appropriate amount of time. After completion of reaction, the
reaction mixture was extracted with ethyl acetate. Organic layer
was dried over Na2SO4 and concentrated in vacuo to give crude
product which was further purified by column chromatography.
Indolo[2,1-b]quinazoline-6,12-dione (3a)
◦
Yellow solid. mp > 250 C. Found C, 72.52, H, 3.19, N, 11.22
C15H8N2O2 requires C, 72.58, H, 3.25, N, 11.28%. nmax(KBr):
3062, 1721, 1645, 1435, 1256, 804, 747 cm-1. 1H NMR (300 MHZ,
CDCl3) d = 8.61 (d, 1H, J = 3.4 Hz), 8.44 (d, 1H, J = 5.4 Hz),
8.06 (d, 1H, J = 8.1 Hz), 7.94–7.80 (m, 3H), 7.69 (t, 1H, J =
7.08 Hz), 7.28 (t, 1H, J = 7.1 Hz). 13C NMR (75 MHZ, CDCl3)
d = 117.5, 120.6, 125.4, 126.3, 127.1, 129.7, 130.0, 133.2, 134.6,
145.3, 146.6, 160.4, 183.8.∑ ESIMS: m/z 249 (M+H).
2-Bromoindolo[2,1-b]quinazoline-6,12-dione(3b)
Light yellow solid; mp > 250 ◦C. Found C, 54.98, H, 2.13
N, 8.48 C15H7BrN2O2 requires C, 55.07; H, 2.16; N, 8.56%.
n
max(KBr):3124, 1724, 1647, 1440, 1255, 812, 746 cm-1. 1H NMR
(300 MHZ, CDCl3) d = 8.24 (s, 1H), 8.10–8.02 (m, 2H), 7.98–7.82
(m, 2H), 7.63 (t, 1H, J = 7.2 Hz), 7.38 (t, 1H, J = 6.3 Hz). 13C
NMR (75 MHZ, CDCl3) d = 117.8, 120.7, 123.0, 123.5, 125.7,
129.4, 129.9, 132.3, 134.8, 136.2, 146.4, 160.8, 182.5. ESIMS:
m/z 326 (M+H).
Fig. 3 1H NMR spectra of A) b-CD B) b-CD complex C) freeze-dried
reaction mixture after 2 h.
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