A revised synthetic scheme of 6,6′-dibromoindirubin

Article abstract of DOI:10.1002/jhet.5570440525

(Chemical Equation Presented) The synthetic scheme of 6,6′- dibromoindirubin (2) was investigated in detail. The reaction of 6-fluoro-3-acetoxyindole (7) with isatin (8) in methanol with Na ₂CO₃ produced 6′-fluoroindirubin in moderate yields. Its structure determination was mainly undertaken using ¹H NMR spectroscopy. On the basis of this result, the synthetic scheme of 2 reported by Cooksey was revised.

Full text of DOI:10.1002/jhet.5570440525

Sep-Oct 2007
1135
A Revised Synthetic Scheme of 6,6ꢀ-Dibromoindirubin
Yasuhiro Tanoue*, Akari Hara and Norihisa Kai
Department of Food Science and Technology, National Fisheries
University, Nagatahonmachi, Shimonoseki 759-6595, Japan
E-mail: tanoue@fish-u.ac.jp
Kazunori Sakata and Mamoru Hashimoto
Department of Applied Chemistry, Faculty of Engineering, Kyushu Insitute of Technology, Tobata-ku,
Kitakyushu 804-8550, Japan
Takeshi Nagai
Department of Food Science and Technology, Tokyo University of Agriculture, Abashiri,
Hokkaido 099-2493
Received December 22, 2006
OAc
O
Na2CO3
+
O
NH
NH
N
H
N
H
F
F
in CH3OH
O
O
The synthetic scheme of 6,6ꢀ-dibromoindirubin (2) was investigated in detail. The reaction of 6-fluoro-3-
acetoxyindole (7) with isatin (8) in methanol with Na2CO3 produced 6ꢀ-fluoroindirubin in moderate yields.
Its structure determination was mainly undertaken using 1H NMR spectroscopy. On the basis of this result,
the synthetic scheme of 2 reported by Cooksey was revised.
J. Heterocyclic Chem., 44, 1135 (2007).
and B of 2 consist of the starting materials 5 and 6,
respectively. As we reported that the hydrolysis of 6 with
aqueous ethanol containing sodium hydroxide occurred
along with a dimerization which took place at position 2
of 6 to give 1 [6], we doubted whether the scheme is
correct. Moreover, it is known that carbon nucleophiles
add to isatin and its derivatives at position C-3 in most
cases [13].
INTRODUCTION
Tyrian purple, royal purple and ancient purple are all
synonyms for a dye of molluscan origin and were used as
valuable purple dyes of garments for ancient exalted
persons such as princes and nobles in the districts along
the Mediterranean [1-2]. The precursors of Tyrian purple
are contained in the hypobranchial glands of various
species of gastropods from the families Muricidae and
Thaidinae, and converted into Tyrian purple by the action
of sunlight and purpurase [3-4]. In 1909, Friedländer
isolated 1.4 g of the dye from 12,000 specimens of the
gastropod Murex brandaris and identified it as 6,6ꢀ-
dibromoindigo (1) [5].
X
O
O
H
N
Br
NH
N
H
N
H
Br
Y
O
O
We have already reported a convenient synthesis of
1 [6]. The hypobranchial glands mentioned above
contain 6,6ꢀ-dibromoindirubin (2) and 6-bromo-
indiubin (3) as minor components [7-10]. Their
compounds have become of interest from the
standpoint of glycogen synthase kinase (GSK)-3-
selective inhibitors [10]. In addition, indirubin (4)
exhibits strong antitumor [11] and potent aryl
hydrocarbon ligand activities [12].
1
2: X=Y=Br
3: X=Br, Y=H
4: X=Y=H
Figure 1
The present paper describes the detailed investigation
of the synthetic scheme of 6,6ꢀ-dibromoindirubin.
RESULTS AND DISCUSSION
Cooksey [9] reported that the reaction of 6-bromoisatin
(5) with 6-bromo-3-acetoxyindole (6) gave 2 in 76 %
yield in methanol at room temperature for 2 h and the
synthetic scheme of 2 is as follows (Scheme 1). Judging
from this scheme, it was postulated that the moieties A
As the F atom strongly couples with protons and the
proton - fluorine coupling constants are somewhat higher
than those of proton - proton in an NMR spectrum, a
compound containing a F atom is useful for a structure

1136
Y. Tanoue, A. Hara, N. Kai, K. Sakata, M. Hashimoto and T. Nagai
Vol 44
Scheme 1
Br
Br
O
O
Na2CO3, CH3OH
+
O
AcO
B
HN
NH
N
H
N
H
Br
Br
O
5
6
A
2
determination. Therefore, 6-fluoro-3- acetoxyindole (7)
was used as a starting material. The reaction of 7 with
isatin (8) was carried out in methanol with Na2CO3 at
room temperature.
The absorption of H-4 is split by H-5, giving rise to a
doublet (J4-5 = 7.5 Hz). The absorption of H-4ꢁ is split by
H-5ꢁ (J4ꢁ-5ꢁ = 8.5 Hz) and F-6ꢁ (J4ꢁ-F = 5.5 Hz). It could then
be proved that the structure of our product is 9a.
Therefore, the synthetic scheme of 2 reported by Cooksey
should be revised as follows (Scheme 3).
The structure of the product was either 9a or 9b shown
1
in Scheme 2. The H NMR spectrum is shown in Figure
Scheme 2
F
OAc
O
O
O
Na2CO3
+
or
O
NH
NH
N
H
N
H
N
H
N
H
F
F
in CH3OH
O
O
7
9b
8
9a
5
2. The H-4 signal (ꢀ 8.76) showed a remarkable down-
field shift relative to the H-4ꢁ signal (ꢀ 7.72). This shift is
ascribable to the hydrogen bond between H-4 and the
oxygen atom which bonds to C-3ꢁ as shown in Figure 3.
6
H
O
4'
4
3a'
7a'
7
3'
5'
NH
N
H
F
6'
7'
O
9a
Figure 3. The hydrogen bond between H-4 and oxygen atom
EXPERIMENTAL
1
The H NMR and 13C NMR spectra were obtained using a
JEOL JNM-A500 (500 MHz) spectrometer in chloroform-d and
dimethyl sulfoxide-d6 at room temperature. Chemical shifts are
given in ppm relative to tetramethylsilane as the internal
reference standard. The EI mass spectra were performed using a
JEOL JMS-SX 102A mass spectrometer. The infrared spectra
were recorded using a Shimadzu IR 470 spectrometer in
potassium bromide pellets. The melting points were obtained
using a Yanaco MS-S3 micro melting point apparatus (hot- plate
type). Elemental analyses were determined using a Yanaco CHN
Corder MT-3.
For preparative column chromatography,
Wakogel C-200 silica gel was employed. Indole, 6-fluoroindole
and isatin were purchased from Tokyo Kasei Kogyo Co. Ltd.
(Tokyo, Japan).
3-Acetoxy-6-fluoroindole (7). To a solution of 6-fluoroindole
(100 mg, 0.74 mmol) and sodium hydroxide (29.6 mg, 0.74
mmol) in methanol (10 ml) were added iodine (188 mg, 0.74
mmol) and an aqueous solution (1 ml) of potassium iodide (123
Figure 2. The spectrum of 6'-fluoroindirubin (9a)

Sep-Oct 2007
A Revised Synthetic Scheme of 6,6ꢀ-Dibromoindirubin
1137
Scheme 3
Br
Br
OAc
O
Na2CO3, CH3OH
+
O
NH
NH
N
H
N
H
Br
Br
O
O
6
5
2
mg, 0.74 mmol). After the mixture was stirred at room
temperature for 3 h, water (20 ml) was added. The resulting
precipitate was collected by filtration, washed with water, and
dried under reduced pressure to obtain 6-fluoro-3-iodoindole
(153 mg, 0.584 mmol), which was used for the following
reaction without purification because of its lability. Silver
acetate (146 mg, 0.876 mmol) was added to a solution of 6-
fluoro-3-iodoindole in acetic acid (10 ml). After stirring for 1 h
at 90°C, the mixture was cooled to room temperature and
filtered. The filtrate was evaporated to dryness under reduced
pressure. The residue was chromatographed on silica gel with
CHCl3 to give 3-acetoxy-6-fluoroindole (7) (73 mg, 51 % yield).
It was recrystallized from hexane as colorless plate crystals, mp
139 – 140 °C; ir (potassium bromide): NH 3380, C=O 1743,
1629, 1598, 1338, 1227, 1122, 806 cm-1; 1H nmr (chloroform-d):
ꢁ 2.36 (s, 3H, CH3), 6.88-6.92 (m, 1H, H-5), 6.96 (dd, 1H, H-7,
J7-F = 9.6, J7-5 = 1.8 Hz), 7.25 (d, 1H, H-2, J2-1 = 2.8 Hz), 7.45
(dd, 1H, H-4, J4-5 = 8.5, J4-F = 5.2 Hz), 7.91 ppm (br, 1H, NH);
7.5 Hz), 10.92 (s, 1H, NH), 11.12 (s, 1H, NH); 13C nmr
(dimethyl sulfoxide – d6): ꢁ 100.55 (d, C-7ꢀ, J7ꢀ-F = 26.9 Hz),
107.33, 108.80 (d, C-5ꢀ, J5ꢀ-F = 24.8 Hz), 109.63, 115.94, 121.21,
121.33, 124.92, 127.04 (d, C-4ꢀ, J 4ꢀ-F = 12.4 Hz), 129.59, 138.45,
141.12, 154.50 (d, C-7aꢀ, J7aꢀ-F = 15.6 Hz), 167.73 (d, C-6ꢀ, J6ꢀ-F
=
252.2 Hz), 170.74, 186.75; ms: m/z (relative intensity) 280 (M+,
100 %), 252 (52), 223 (29). Anal. Calcd for C16H9FN2O2: C,
68.57; H, 3.24; N, 10.00. Found: C, 68.40; H, 3.26; N, 10.28.
Acknowledgement. We are grateful to the Center for
Instrumental Analysis, Kyushu Institute of Technology for
elemental analyses, mass spectra and NMR spectra.
REFERENCES AND NOTES
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13C nmr (chloroform-d): ꢁ 20.93 (CH3), 97.62 (d, C-7, J7-F
=
26.9 Hz), 108.92 (d, C-5, J5-F = 24.8 Hz), 113.52 (C-2), 116.67
(C-9), 118.37 (d, C-4, J4-F = 9.2 Hz), 130.47 (C-3), 133.00 (d, C-
7a, J7a-F = 12.4 Hz), 160.32 (d, C-6, J6-F = 238 Hz), 168.77
(C=O); ms: m/z (relative intensity) 193 (M+, 58 %), 152 (55),
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(55), 75 (52). Anal. Calcd. for C10H8FNO2: C, 62.18; H, 4.17; N,
7.25. Found: C, 62.19; H, 4.20; N, 7.20.
6ꢀ-Fluoroindirubin (9a). A solution of 7 (30 mg, 0.155
mmol) and isatin (8) (22.8 mg, 0.155 mmol) in methanol (6 ml)
was stirred under a nitrogen atmosphere at room temperature for
25 minutes. To the mixture was added anhydrous sodium
carbonate (39.3 mg, 0.371 mmol). After the mixture was stirred
for 3 h, water was added. The resulting precipitate was collected
by filtration, washed with water and aqueous methanol (1:1).
The crude product (37.8 mg) was recrystallized from ethyl
acetate to give 9a (28.6 mg, 66 % yield) as a brown – purple
powder, mp > 300 °C; ir (potassium bromide): 3270 (NH), NH
3270, C=O 1668, 1620, 1591, 1453, 1291, 1207, 1128, 1090,
1009, 968 cm-1; 1H nmr (dimethyl sulfoxid – d6): ꢁ 6.82 (m, 1H,
H-5ꢀ), 6.90 (d, 1H, H-7, J7-6 = 7.5 Hz), 7.02 (m, 1H, H-5), 7.23
(dd, 1H, H-7ꢀ, J7ꢀ-F = 9.8, J7ꢀ-5ꢀ = 2.3 Hz), 7.27 (m, 1H, H-6), 7.72
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(dd, 1H, H-4ꢀ, J4ꢀ-5ꢀ = 8.5, J4ꢀ-F = 5.5 Hz), 8.76 (d, 1H, H-4, J4-5
=