Synthesis of substituted tryptanthrins via oxidation of isatin and its derivatives

Article abstract of DOI:10.1134/S1070428013120051

Oxidation of isatin and its 5-substituted analogs with potassium permanganate in anhydrous acetonitrile gave indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) and its 2,8-dimethyl-, 2,8-dibromo-, and 2,8-diiodo derivatives. Oxidative coupling of 5,7-dichloroisatin with isatin under analogous conditions afforded 2,4-dichloroindolo[2,1-b]quinazoline-6,12-dione, while 1,4-dichloroindolo[2,1-b]quinazoline-6,12-dione and 1,4-dichloro-8- methylindolo[2,1-b]quinazoline-6,12-dione were obtained by oxidative coupling of 4,7-dichloroisatin with isatin and 5-methylisatin, respectively.

Full text of DOI:10.1134/S1070428013120051

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 12, pp. 1740–1743. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © T.V. Moskovkina, M.V. Denisenko, A.I. Kalinovskii, V.A. Stonik, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49,
No. 12, pp. 1760–1763.
Synthesis of Substituted Tryptanthrins via Oxidation
of Isatin and Its Derivatives
T. V. Moskovkinaa, M. V. Denisenkob, A. I. Kalinovskiib, and V. A. Stonikb
a Far East Federal University, ul. Oktyabr’skaya 27, Vladivostok, 690000 Russia
e-mail: moskovkinataisiya@mail.ru
b Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Sciences,
Vladivostok, Russia
Received June 14, 2013
Abstract—Oxidation of isatin and its 5-substituted analogs with potassium permanganate in anhydrous
acetonitrile gave indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) and its 2,8-dimethyl-, 2,8-dibromo-, and
2,8-diiodo derivatives. Oxidative coupling of 5,7-dichloroisatin with isatin under analogous conditions afforded
2,4-dichloroindolo[2,1-b]quinazoline-6,12-dione, while 1,4-dichloroindolo[2,1-b]quinazoline-6,12-dione and
1,4-dichloro-8-methylindolo[2,1-b]quinazoline-6,12-dione were obtained by oxidative coupling of 4,7-di-
chloroisatin with isatin and 5-methylisatin, respectively.
DOI: 10.1134/S1070428013120051
Tryptanthrin (IIa, indolo[2,1-b]quinazoline-6,12-di-
one) is a natural alkaloid isolated from plants and some
microorganisms, including marine bacteria [1–3]. This
compound exhibits a broad spectrum of biological ac-
tivity, in particular immunomodulating, antitubercular,
and anti-protozoa. Several halogen-substituted tryptan-
thrins were also found to be biologically active [4, 5].
A widely used procedure for the synthesis of tryp-
tanthrin and its derivatives is based on the condensa-
tion of isatoic anhydride with isatin or its substituted
derivatives [1, 7]. The reactions are carried out by
heating the reactants in pyridine in the presence of
N-methylpiperidine as catalyst. This approach ensured
preparation of a large number of tryptanthrin deriva-
tives containing various substituents in both indole and
quinazoline moieties. A drawback of this procedure is
the necessity of preliminarily preparing appropriately
substituted isatoic anhydride and isatin derivatives,
which makes the procedure multistep.
We have previously developed a one-step synthesis
of tryptanthrin and its 2,8-disubstituted derivatives by
treatment of isatin and 5-R-substituted isatins (R = Me,
Br, I) with phosphoryl chloride [6]. While carrying out
these studies we have revealed different reactivity of
5-haloisatins Ic and Id. Compounds Ic and Id were
less reactive than unsubstituted isatin or 5-methyl-
isatin, whereas 5,7-dichloro- and 4,7-dichloroisatins
III and V failed to react with formation of the corre-
sponding tetrachloro-substituted tryptanthrins under
analogous conditions.
Friedlander and Roschdestwensky [8] described
a fairly simple transformation of isatin into tryptan-
thrin via oxidation with potassium permanganate in
water, but the yield was very poor (10–15%); there-
fore, the practical value of this procedure is low. It is
reasonable to presume that the reaction involves partial
Scheme 1.
10
O
O
1
4
12
R
R
KMnO4, MeCN
85–90°C
R
N
7
O
6
N
N
H
O
Ia–Id
IIa–IId
R = H (a), Me (b), Br (c), I (d).
1740

SYNTHESIS OF SUBSTITUTED TRYPTANTHRINS
1741
oxidation of isatin to isatoic anhydride which then
reacts in situ with isatin. However, isatoic anhydride
undergoes hydrolysis in aqueous medium, so that the
yield of tryptanthrin is reduced. Taking the above
stated into account, we tried to oxidize isatin in anhy-
drous acetonitrile which is capable of dissolving both
isatin and KMnO4. As a result, we succeeded in
improving the yield of tryptanthrin to 50%. Moreover,
5-substituted isatins Ib–Id were successfully oxidized
to the corresponding tryptanthrin derivatives according
to the proposed procedure (Scheme 1).
oxidation of two differently substituted isatin deriva-
tives simultaneously. The oxidative coupling of isatin
Ia with 5,7-dichloroisatin (III) afforded previously un-
known 2,4-dichloroindolo[2,1-b]quinazoline-6,12-di-
one (IV) (Scheme 2) which precipitated from the reac-
tion mixture. The other product was tryptanthrin (IIa).
The formation of structure IV rather than alternative
8,10-dichloroindolo[2,1-b]quinazoline-6,12-dione led
us to presume that 5,7-dichloroisatin is initially con-
verted into dichloro-substituted isatoic anhydride
which then reacts with isatin.
Thus, we have developed a new simple procedure
for the synthesis of tryptanthrin and its derivatives with
“pseudosymmetric” arrangement of substituents in the
benzene rings of the indolo[2,1-b]quinazoline system.
The structure of the isolated compounds was con-
firmed by comparing their NMR and mass spectra with
those of authentic samples described in [6].
Likewise, by oxidation of equimolar mixtures of
4,7-dichloroisatin (V) with isatin (Ia) and 5-methyl-
isatin (Ib) with potassium permanganate we obtained
1,4-dichloroindolo[2,1-b]quinazoline-6,12-dione (VIa)
and 1,4-dichloro-8-methylindolo[2,1-b]quinazoline-
6,12-dione (VIb) (Scheme 3).
2,4-Dichloro- and 1,4-dichlorotryptanthrins IV,
VIa, and VIb were not reported previously. Their
structure was proved by 1H and 13C NMR spectroscopy
In order to further develop oxidative synthesis of
tryptanthrin derivatives we made an attempt to perform
Scheme 2.
O
O
O
O
Cl
Cl
KMnO4, MeCN
O
O
+
O
O
+
N
N
N
O
N
H
H
H
H
Cl
Cl
Ia
III
O
Cl
N
–CO2
N
O
Cl
IV
Scheme 3.
Cl
Cl
O
Cl
Cl
O
O
O
R
R
KMnO4, MeCN
O
O
+
O
O
+
N
N
N
O
N
H
H
H
H
Ia, Ib
V
O
N
Cl
Cl
R
N
–CO2
O
VIa, VIb
R = H (a), Me (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 12 2013

MOSKOVKINA et al.
1742
H
H
H
H
H
H
O
N
H
1
O
N
Cl
O
N
Cl
Cl
10
10a
H
H
Me
12a
4a
Cl
H
H
H
H
H
N
N
N
7
6a
H
H
H
6
4
O
O
O
Cl
Cl
IV
VIa
VIb
COSY
HMBC
Key COSY and HMBC correlations in the NMR spectra of compounds IV, VIa, and VIb.
using COSY, HMQC, and HMBC techniques, as well
as by mass spectrometry. According to the high-resolu-
tion mass spectrum, compound IV has the composition
C15H6Cl2N2O2. Its 1H NMR spectrum showed the pres-
ence of one ortho-disubstituted and one tetrasubstitut-
ed benzene rings, the latter containing two protons in
the meta position with respect to each other. These
protons appeared in the spectrum as doublets at δ 8.32
and 7.9 ppm with a coupling constant J of 2.4 Hz.
Signals from the amide and ketone carbonyl carbon
atoms were observed in the 13C NMR spectrum at
δC 156.4 and 181.4 ppm, respectively. The signals were
assigned on the basis of the COSY, HSQC, and HMBC
data (see figure). The position of the di- and tetrasub-
stituted benzene rings in molecule IV unambiguously
followed from the COSY and HMBC data. The COSY
spectrum of IV revealed the presence of 7-H–10-H
spin system, and the key cross peaks in the HMBC
spectrum were 1-H/C12 (s, δ 8.32 ppm/s, δC 156.4 ppm),
7-H/C6 (br.d, 7.94/s, 181.4), and 3-H/C1 (7.90/125.6).
These findings showed that the disubstituted benzene
ring in IV is fused to five-membered ring and that the
benzene ring bearing two chlorine atoms is fused to
six-membered pyrimidine ring.
To conclude, we have developed a one-step prepar-
ative synthesis of tryptanthrin by oxidation of isatin.
The procedure was extended to 5-substituted isatins,
and 2,8-disubstituted tryptanthrin analogs were thus
obtained, while oxidative coupling of isatin or
5-methylisatin with 4,7- or 5,7-dichloroisatin gave pre-
viously unknown 1,4- and 2,4-dichlorotryptanthrins.
As shown in [4], halogen-substituted tryptanthrin
derivatives exhibit a higher anti-protozoa activity in
vitro against Toxoplasma gondii as compared to other
substituted tryptanthrins and are simultaneously less
cytotoxic than tryptanthrin with respect to human cells.
The new halogen-containing tryptanthrin derivatives
synthesized in the present work attract interest as
potential biologically active compounds.
EXPERIMENTAL
The IR spectra were measured from solutions in
chloroform on a Perkin Elmer Spectrum BX-II FT-IR
1
System. The H and 13C NMR spectra (including
DEPT spectra) were recorded on a Bruker Avance III-
1
700 spectrometer at 700.13 MHz for H and
176.04 MHz for 13C using CDCl3 as solvent and tetra-
methylsilane as internal reference. The mass spectra
(electron impact, 70 eV) were recorded on an AMD-
604S mass spectrometer with direct sample admission
into the ion source. The melting points were deter-
mined on a Boetius melting point apparatus.
The structure of compounds VIa and VIb was
proved in a similar way. Spin systems in the two
aromatic rings were identified by COSY experiments.
One aromatic ring in molecule VIa is ortho-disub-
stituted, and four protons therein are attached to con-
tiguous carbon atoms, while the other aromatic ring
containing chlorine atoms is tetrasubstituted with two
protons in the ortho position with respect to each other.
Unlike VIa, molecule VIb contains trisubstituted
aromatic ring with protons in the 1,2,4-positions. The
C6=O carbonyl group in both VIa and VIb is closer
to the chlorine-free benzene ring, as follows from the
presence of a cross peak between 7-H and C6 in the
HMBC spectra of these compounds (VIa: 7-H,
δ 7.94 ppm, br.d/C6, δC 181.6 ppm; VIb, 7-H,
δ 7.73 ppm, br.s/C6, δC 181.7 ppm).
Acetonitrile of analytical grade contained no more
than 0.1% of water; a solution of potassium perman-
ganate therein should retain its original color and
should not decompose (with formation of manganese
dioxide) over a period of at least 5 h. Acetonitrile of
ultrapure grade (sort “0,” manufactured by Kriokhrom,
St.-Petersburg, Russia) meets these requirements, and
it can be used without additional purification.
General procedure for the oxidation of isatin
and 5-substituted isatins with potassium permanga-
nate. A two-necked flask was charged with 0.01 mol
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 12 2013

SYNTHESIS OF SUBSTITUTED TRYPTANTHRINS
1743
of isatin (Ia) or 5-substituted isatin Ib–Id in 250 mL of
acetonitrile and a magnetic stir bar. The flask was con-
nected to a dropping funnel with pressure-equalizing
arm, which was connected in turn to a water-cooled
reflux condenser. The dropping funnel was charged
with 1.6 g (0.01 mol) of KMnO4 in a perforated poly-
ethylene bag. The mixture was heated to the boiling
point under stirring with a magnetic stirrer. Boiling
acetonitrile entering into the dropping funnel dissolved
potassium permanganate, and the solution evenly
dropped into the reaction mixture. The progress of
reactions was monitored by TLC. The reaction time
was 6 (Ia), 8 (Ib), 10 (Ic), and 12 h (Id). The mixture
was filtered through a Schott filter to remove manga-
nese dioxide, the precipitate was washed with hot
acetonitrile (3×10 mL), the solvent was distilled off
from the filtrate on a rotary evaporator, 30 mL of
ethanol was added to the residue, the solid material
was ground, and the undissolved substance was filtered
off, washed with ethanol (2 ×5 mL), and dried to
isolate compounds IIa–IId whose spectral parameters
and physical constants coincided with those given in
[6]. Yield 0.63 g (50%) (IIa), 0.55 g (40%) (IIb),
0.65 g (32%) (IIc), 0.67 g (27%) (IId).
(0.01 mol) of isatin (Ia) and 2.16 g (0.01 mol) of
4,7-dichloroisatin (V); reaction time 15 h. Yield 0.95 g
(30%), mp 336–338°C (CHCl3). IR spectrum, ν, cm–1:
1
1720 (C6=O), 1689 (C12=O). H NMR spectrum, δ,
ppm: 7.46 t (8-H, J = 7.6 Hz), 7.58 d (2-H, J = 8.6 Hz),
7.79 d (3-H, J = 8.6 Hz), 7.80 t (9-H, J = 7.8 Hz),
7.94 d (7-H, J = 7.5 Hz), 8.65 d (10-H, J = 8.1 Hz).
13C NMR spectrum, δC, ppm: 118.2 (C10), 121.8 (C6a),
121.1(C12a), 125.6 (C7), 127.6 (C8), 132.8 (C2), 134.3
(C1), 134.7 (C4), 134.9 (C3), 138.4 (C9), 144.7 (C5),
145.7 (C4a), 145.8 (C10a), 155.9 (C12), 181.6 (C6).
Found: m/z 315.98 [M]+. C15H6Cl2N2O2. Calculated:
M 315.9801.
1,4-Dichloro-8-methylindolo[2,1-b]quinazoline-
6,12-dione (VIb) was synthesized from 1.61 g
(0.01 mol) of 5-methylisatin (Ib) and 2.16 g (0.01 mol)
of 4,7-dichloroisatin (V) using 2.0 g (0.013 mol) of
KMnO4. Yield 0.86 g (27%), mp 318–320°C (from
CHCl3–EtOAc, 1:1). IR spectrum, ν, cm–1: 1720
1
(C6=O), 1689 (C12=O). H NMR spectrum, δ, ppm:
2.46 s (CH3), 7.56 d (3-H, J = 7.5 Hz), 7.59 br.d (9-H,
J = 8.5 Hz), 7.73 br.s (7-H), 7.79 d (2-H, J = 7.6 Hz),
8.50 d (10-H, J = 8.3 Hz). 13C NMR spectrum, δC,
ppm: 21.0 (CH3), 118.0 (C10), 121.9 (C6a), 122.2 (C12a),
125.7 (C7), 132.7 (C3), 134.2 (C1), 134.7 (C4), 134.8
(C2), 138.0 (C8), 139.0 (C9), 143.8 (C10a), 145.0 (C5),
145.7 (C4a), 155.8 (C12), 181.7 (C6). Found: m/z 330.001
[M]+. C16H8Cl2N2O2. Calculated: M 329.9968.
2,4-Dichloroindolo[2,1-b]quinazoline-6,12-dione
(IV). A mixture of 1.47 g (0.01 mol) of isatin (Ia) and
2.16 g (0.01 mol) of 5,7-dichloroisatin (III) in 500 mL
of acetonitrile was heated for 15 h under reflux using
2.0 g (0.013 mol) of KMnO4. The mixture was filtered,
the solvent was distilled off from the filtrate under
reduced pressure, the residue was treated with 50 mL
of ethanol, and the undissolved material was filtered
off. The product was 1.16 g of a mixture of compounds
IIa and IV at a ratio of 1:3 (according to the GC/MS
data). Recrystallization from chloroform gave 0.92 g
(29%) of compound IV, mp 310–312°C (from CHCl3).
IR spectrum, ν, cm–1: 1720 (C6=O), 1689 (C12=O).
1H NMR spectrum, δ, ppm: 7.47 t (8-H, J = 7.5 Hz),
7.81 t.d (9-H, J = 7.6, 1.3 Hz), 7.90 d (3-H, J =
2.4 Hz), 7.94 br.d (7-H, J = 7.5 Hz), 8.32 d (1-H, J =
2.4 Hz), 8.61 d (10-H, J = 8.1 Hz). 13C NMR spectrum,
δC, ppm: 118.1 (C10), 121.9 (C6a), 125.6 (C7), 125.9
(C1), 126.2 (C12a), 127.8 (C8), 135.6 (C3), 136.3 (C2),
136.7 (C4), 138.3 (C9), 142.4 (C4a), 144.4 (C10a), 145.6
(C5a), 156.4 (C12), 181.4 (C6). Mass spectrum, m/z:
316, 318 (2:1) [M]+; 288, 290 [M – CO]+. Found:
m/z 315.9806 [M]+. C15H6Cl2N2O2. Calculated:
M 315.9801.
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