Synthesis of tryptanthrin (couroupitine) derivatives by reaction of substituted isatins with phosphoryl chloride

Article abstract of DOI:10.1134/S1070428012010204

Reaction of 5-methyl-, 5-bromo-, and 5-iodoisatins with phosphoryl chloride gave the corresponding 2,8-disubstituted indolo[2,1-b]quinazoline-6,12-diones in moderate yield. 5,7-Dichloroisatin failed to react with POCl3. Treatment of an equimolar mixture of isatin and 5-bromoisatin with POCl3 afforded indolo[2,1-b]-quinazoline-6,12-dione (tryptanthrin), 2,8-dibromoindolo[2,1-b] quinazoline-6,12-dione, and two isomeric monobromo-substituted tryptanthrin derivatives, the 2-bromo isomer prevailing. Pleiades Publishing, Ltd., 2012.

Full text of DOI:10.1134/S1070428012010204

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 1, pp. 123–126. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © T.V. Moskovkina, A.I. Kalinovskii, V.V. Makhan’kov, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 1,
pp. 128–131.
Synthesis of Tryptanthrin (Couroupitine) Derivatives by Reaction
of Substituted Isatins with Phosphoryl Chloride
T. V. Moskovkinaa, A. I. Kalinovskiib, and V. V. Makhan’kovb
a Far East Federal University, ul. Oktyabr’skaya 27, Vladivostok, 690600 Russia
e-mail: moskovkinataisiya@mail.ru
b Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences,
Vladivostok, Russia
Received February 12, 2011
Abstract—Reaction of 5-methyl-, 5-bromo-, and 5-iodoisatins with phosphoryl chloride gave the correspond-
ing 2,8-disubstituted indolo[2,1-b]quinazoline-6,12-diones in moderate yield. 5,7-Dichloroisatin failed to react
with POCl3. Treatment of an equimolar mixture of isatin and 5-bromoisatin with POCl3 afforded indolo[2,1-b]-
quinazoline-6,12-dione (tryptanthrin), 2,8-dibromoindolo[2,1-b]quinazoline-6,12-dione, and two isomeric
monobromo-substituted tryptanthrin derivatives, the 2-bromo isomer prevailing.
DOI: 10.1134/S1070428012010204
Tryptanthrin (couroupitine) or indolo[2,1-b]quin-
azoline-6,12-dione [1] is an alkaloid isolated from
Candida lipolytica microscopic fungi which proliferate
in the presence of a large amount of L-tryptophan [2],
from higher terrestrial indigo-containing plants of the
families Couroupita [3], Polygonum, Isatis [4], etc.,
and recently from the marine bacteria Oceanibulbus
indolifex gen. nov., sp. nov. [5]. This compound exhi-
bits antifungal activity [3], inhibits growth of Myco-
bacterium tuberculosis [6], as well as of Trypanosoma
brucei and Leishmania donoivani protozoa which in-
duce dangerous diseases [7, 8], and displays anti-in-
flammatory [9] and cancer-preventive properties [10].
scheme of transformations involved. For this purpose,
we examined reactions of 5-methyl-, 5-bromo-,
5-iodo-, and 5,7-dichloroisatins with POCl3 and deter-
mined the composition of product mixture formed
from isatin and 5-bromoisatin under similar conditions.
By heating 5-methylisatin (Ib) with POCl3 in boil-
ing toluene over a period of 2 h we obtained 2,8-di-
methylindolo[2,1-b]quinazoline-6,12-dione (IIb)
(Scheme 1) which was isolated from the reaction mix-
ture in 37% yield as a yellow–green crystalline sub-
stance. Thus compound Ib relatively readily undergoes
cyclization. The structure of IIb was confirmed by
NMR and mass spectra. All signals in the NMR spectra
1
of compound IIb were assigned using H–1H COSY,
Alkaloid IIa was previously synthesized in high
yield [11] according to a simple one-step procedure
based on reaction of accessible isatin (Ia) with phos-
phoryl chloride. The goal of the present work was to
extend this procedure with a view to obtain biologi-
cally active derivatives of tryptanthrin and refine the
HSQC, and HMBC techniques, and the position of
methyl groups in the tetracyclic skeleton was unam-
biguously determined.
Likewise, 5-bromoisatin (Ic) was converted into
2,8-dibromoindolo[2,1-b]quinazoline (IIc) in 30%
Scheme 1.
O
10
10a
O
1
4
R
11
N
R
R
12a
4a
12
POCl3
O
7
6a
5
N
6
5a
N
H
O
Ia–Id
IIa–IId
R = H (a), Me (b), Br (c), I (d).
123

MOSKOVKINA et al.
124
Scheme 2.
O
O
O
O
POCl3
H2O
Ia
O
Cl
N
N
N
N
N
N
HO
O
O
H
H
O
Ia
III
IV
V
O
O
N
N
5
[O]
N
N
12
–CO2
1
HO
VI
COOH
O
IIa
yield by heating in POCl3 for 7 h. According to the
TLC and HPLC data, the reaction mixture contained
unreacted initial compound Ic, in contrast to analogous
reactions of compounds Ia and Ib. When compound Ic
was treated with POCl3 in boiling toluene over a peri-
od of 8–10 h, no cyclization products were detected,
whereas unsubstituted isatin (Ia) was readily converted
into tryptanthrin under the same conditions. These
findings indicate that bromoisatin (Ic) is less reactive
than isatin in the examined reaction. The structure of
dibromotryptanthrin IIc was confirmed by IR and
NMR spectroscopy and mass spectrometry. The posi-
than isatin (Ia) in this reaction, we expected that treat-
ment of a mixture of compounds Ia and Ic with POCl3
should result in predominant formation of just com-
pound III rather than analogous derivative of bromo-
isatin (Ic). In this case, 2-bromotryptanthrin (VII)
should be formed mainly among two possible mono-
bromo tryptanthrin derivatives VII and VIII.
O
Br
N
N
1
tions of hydrogen atoms were determined by H–1H
O
VII
COSY experiments, and the positions of bromine
atoms, by HMBC technique.
O
Br
Analogous results were obtained while studying the
reaction of 5-iodoisatin (Id) with POCl3. 2,8-Diiodo-
indolo[2,1-b]quinazoline (IId) was isolated in 27%
yield. No tryptanthrin derivative was formed from
5,7-dichloroisatin on heating in POCl3.
N
N
O
VIII
Scheme 2 illustrates a probable reaction mechan-
ism. Initially, chlorination of isatin (Ia) with POCl3
gives 2-chloro-3H-indol-3-one (III) which reacts with
the second isatin molecule. Hydrolytic cleavage of the
N–CO bond in the dioxopyrrolidine ring of adduct IV
leads to aminobenzoic acid derivative V which under-
goes cyclization with migration of the double bond to
produce hydroxy acid VI, and the subsequent oxidative
decarboxylation yields tryptanthrin (IIa).
In fact, according to the HPLC data and mass
spectra, the reaction gave tryptanthrin (IIa) (m/z 248),
dibromotryptanthrin IIc (m/z 406), and a mixture of
monobromotryptanthrins VII (m/z 326) and VIII
(m/z 328) at a ratio of 10:1. Compounds IIa, IIc, and
VII were isolated by preparative TLC, while we failed
to isolate bromotryptanthrin VIII as individual sub-
stance. These findings confirmed that in the reaction of
isatin with POCl3 chloro derivative III gives rise to the
indole fragment of tryptanthrin and that isatin is
converted into the quinazoline moiety.
It was interesting to elucidate which part of the
final molecule arises from isatin (Ia) and which from
chloroindol-3-one III. For this purpose, we examined
transformation of an equimolar mixture of isatin (Ia)
and 5-bromoisatin (Ic) by the action of POCl3. Taking
into account that 5-bromoisatin (Ic) was less reactive
Bergman et al. [12] previously described the syn-
thesis of substituted tryptanthrins by reaction of substi-
tuted isatins with isatoic anhydride derivatives. The
procedure proposed in the present work is more advan-
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SYNTHESIS OF TRYPTANTHRIN (COUROPITINE) DERIVATIVES
125
tageous due to its simplicity. It requires only one initial
compound, isatin derivative, and ensures preparation
of tryptanthrins having substituents in both benzene
rings; in some cases monosubstituted tryptanthrins can
be obtained.
2,8-Dibromoindolo[2,1-b]quinazoline-6,12-dione
(IIc). A mixture of 1 g (4.5 mmol) of 5-bromoisatin
(Ic) and 10 ml of POCl3 was heated for 7 h under
reflux with stirring. The dark brown–red mixture was
filtered, and the precipitate was washed on a filter with
ethanol (2×5 ml). Yield 0.27 g (30%), mp 319–321°C
(from CH2Cl2); published data [12]: mp 326–328°C.
IR spectrum, ν, cm–1: 1725 (C6=O), 1675 (C12=O).
1H NMR spectrum, δ, ppm: 7.90 d (4-H, J = 8.5 Hz),
7.91 d.d (9-H, J = 8.5, 2.1 Hz), 7.95 d.d (3-H, J = 8.6,
2.3 Hz), 8.03 d (7-H, J = 1.9 Hz), 8.52 d (10-H, J =
8.6 Hz), 8.56 d (1-H, J = 2.3 Hz). 13C NMR spectrum,
δC, ppm: 118.2 (C2), 120.7 (C12a), 121.9 (C10), 122.8
(C8), 125.3 (C4), 130.1 (C1), 130.5 (C7), 136.3 (C6a),
137.4 (C9), 137.7 (C3), 141.8 (C4a), 145.8 (C10a), 151.0
(C5a), 157.6 (C12), 185.0 (C6). Mass spectrum: m/z 404
[M]+. Calculated: M 404.
EXPERIMENTAL
The melting ponts were determined on a Boetius
hot stage. The IR spectra were recorded in KBr on
a Perkin–Elmer Spectrum BX-II instrument. The mass
spectra (electron impact, 70 eV) were obtained on
an AMD-604S mass spectrometer with direct sample
admission into the ion source. The NMR spectra were
measured on Bruker DRX-500 and Bruker Avance III-
700 instruments at 500.13 and 700.13 MHz for 1H and
127.76 and 176.04 MHz for 13C, respectively, using
CDCl3 as solvent and TMS as internal reference.
Sorbfil plates were used for thin-layer chromatog-
raphy; spots were detected by treatment with iodine
vapor or under UV light. HPLC analysis was per-
formed on a La Chrom chromatograph (Merck,
Hitachi) equipped with an L-7400 UV detector
(λ 254 nm); 250×4-mm Hypersil ODS column (5 μm)
with a 4.0 × 4.0 mm guard column (Hypersil ODS,
5 μm); eluent MeCN–H2O (45 : 55) flow rate
0.7 ml/min; temperature 30°C.
The mother liquor was cooled with ice water, 10 ml
of ethanol was carefully added, and the resulting sus-
pension was cooled and filtered. The precipitate was
washed with ethanol and dried to obtain 0.23 g of
a mixture of initial 5-bromoisatin (Ic) and compound
IIc at a ratio of 3:1 (according to the HPLC data).
2,8-Diiodoindolo[2,1-b]quinazoline-6,12-dione
(IId). A suspension of 0.7 g (2.5 mmol) of 5-iodoisatin
(Id) in 15 ml of anhydrous toluene was heated to the
boiling point, a solution of 1 ml of POCl3 in 5 ml of
anhydrous toluene was added, and the mixture was
heated for 10 h under reflux. The mixture was then
cooled to room temperature, and the solution was
separated by decanting. The residue was a dark mate-
rial which was treated with 20 ml of ethanol, and the
precipitate was filtered off, washed with ethanol, and
dried under reduced pressure to isolate 0.42 g of a mix-
ture of unreacted 5-iodoisatin (Id) and compound IId.
Vacuum sublimation at 194°C (2 mm) gave 0.22 g of
5-iodoisatin, and subsequent sublimation at 240°C
(1 mm) afforded 0.15 g of IId. The toluene solution
was concentrated under reduced pressure, the residue
was treated with 15 ml of ethanol, and the precipitate
was filtered off to isolate an additional portion,
0.025 g, of compound IId. Overall yield 27%,
mp 338–340°C (sublimes). IR spectrum, ν, cm–1: 1725
2,8-Dimethylindolo[2,1-b]quinazoline-6,12-dione
(IIb). 5-Methylisatin (Ib), 1 g (6 mmol), was dissolved
in 25 ml of anhydrous toluene on heating, a mixture of
3 ml of POCl3 and 5 ml of anhydrous toluene was
added, and the mixture was stirred for 2 h at 110°C.
The toluene solution was separated from the dark tarry
material by decanting, the solvent was distilled off
under reduced pressure, the residue was treated with
25 ml of ethanol, and the precipitate was filtered off,
washed with ethanol, and dried under reduced pres-
sure. Yield 0.47 g (37%), mp 246–247°C (from ethyl
acetate or after sublimation). IR spectrum, ν, cm–1:
1
1724 (C6=O), 1675 (C12=O), 1606 (C=N). H NMR
spectrum, δ, ppm: 2.40 s (CH3), 2.50 s (CH3), 7.48 d.d
(9-H, J = 8.2, 1.6 Hz), 7.58 d.d (3-H, J = 8.1, 2.1 Hz),
7.58 d.d (4-H, J = 8.1, 2.1 Hz), 7.62 s (7-H), 8.11 d
(1-H, J = 1.5 Hz), 8.37 d (10-H, J = 8.2 Hz). 13C NMR
spectrum, δC, ppm: 21.00 (CH3), 21.50 (CH3), 117.50
(C10), 122.10 (C6a), 123.40 (C12a), 125.20 (C7), 127.10
(C1), 130.40 (C4), 136.10 (C3), 137.20 (C8), 138.60
(C9), 141.00 (C2), 143.90 (C5a), 144.10 (C10a), 144.50
(C4a), 157.70 (C12), 182.50 (C6). Found: m/z 276.0900
[M]+. C17H12N2O2. Calculated: M 276.0899.
1
(C6=O), 1675 (C12=O). H NMR spectrum, δ, ppm:
7.73 d (4-H, J = 8.5 Hz), 8.10 d.d (9-H, J = 1.8,
8.4 Hz), 8.15 d.d (3-H, J = 2.0, 8.5 Hz), 8.22 d (7-H,
J = 1.9 Hz), 8.38 d (10-H, J = 8.4 Hz) 8.77 d (1-H, J =
2.1 Hz). 13C NMR spectrum, δC, ppm: 91.30 (C8),
96.50 (C2), 119.80 (C10, C10a), 123.40 (C6a), 124.90
(C12a), 132.20 (C4), 134.10 (C7), 136.60 (C1), 143.70
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MOSKOVKINA et al.
126
(C5a), 144.30 (C3), 145.90 (C4a), 146.60 (C9), 156.40
(C12), 180.80 (C6). Found: m/z 499.8500 [M]+.
C15H6I2N2O2. Calculated: M 499.8519.
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(VII). A solution of 1 g (6.8 mmol) of isatin (Ia) and
1.6 g (6.8 mmol) of 5-bromoisatin (Ic) in 30 ml of
anhydrous toluene was heated to the boiling point,
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