One-pot synthesis of tryptanthrin by the Dakin oxidation of indole-3-carbaldehyde

Article abstract of DOI:10.1016/j.tetlet.2014.07.113

A one-pot approach to indolo[2,1-b]quinazolines from indole-3-carbaldehydes through the Dakin oxidation was developed. It was shown that the reaction proceeded through the condensation of indole-3-carbaldehydes with isatoic anhydrides, derived in situ from indole-3-carbaldehydes by the Dakin oxidation, and further oxidation/cyclization steps.

Full text of DOI:10.1016/j.tetlet.2014.07.113

Tetrahedron Letters 55 (2014) 5268–5270
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of tryptanthrin by the Dakin oxidation of
indole-3-carbaldehyde
Takumi Abe a, Tomoki Itoh a, Tominari Choshi b, Satoshi Hibino b, Minoru Ishikura a,
⇑
a School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
b Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot approach to indolo[2,1-b]quinazolines from indole-3-carbaldehydes through the Dakin oxida-
tion was developed. It was shown that the reaction proceeded through the condensation of indole-3-car-
baldehydes with isatoic anhydrides, derived in situ from indole-3-carbaldehydes by the Dakin oxidation,
and further oxidation/cyclization steps.
Received 25 June 2014
Revised 23 July 2014
Accepted 28 July 2014
Available online 1 August 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative coupling
Indole-3-carbaldehyde
Indolo[2,1-b]quinazoline
Urea hydrogen peroxide
Dakin oxidation
Tryptanthrin (2a), first obtained from the sublimation of natural
indigo1 and isolated from the culture of fungus Candida lipolytica,2
is a member of a unique class of alkaloid characterized by a novel
indolo[2,1-b]quinazoline core. Several related alkaloids, such as
candidine (3),3,4 phaitanthrins A (4),4 B (5),4 and C (6),4 and crucife-
rane (7),5 have also been found in a wide range of natural sources,
including plant materials and mammals (Fig. 1). Tryptanthrin (2a)
and several of its derivatives exhibit antitumor, antimalarial, anti-
parasitic, and antineoplastic activity, and inhibit COX-2, 5-LOX, and
PGE(2) expression.6–8
Because of their diverse biological activities and structural intri-
cacy, these alkaloids have been the target of numerous synthetic
studies.9,10 The most common synthetic approach to the indo-
lo[2,1-b]quinazoline core depends on the use of isatin, through
the reaction of isatin with isatoic anhydride,11 thermolysis of isat-
in,12 cathodic reduction of isatin,13 the reaction of anthranilic acid
with isatin in the presence of SOCl2,14 and the reaction of isatin
with POCl3.15 Moreover, the reaction of o-lithiophenyl isocyanide
with isocyanate,16 I2/TBHP-catalyzed intramolecular amination,17
and the insertion of an aryne intermediate to quinazolone18 have
been developed for the synthesis of tryptanthrin. Recently, the con-
struction of 2a through oxidative dimerization of isatin or indole
has been reported, including oxidation of isatin with KMnO4,19
Cu-catalyzed oxidation of indole,20 and oxone-induced oxidation
of indole-3-carbaldehyde.21
The Dakin oxidation is a widely used method for converting var-
ious aryl aldehydes to phenols.22 We recently used this method for
a one-pot conversion of a benzaldehyde moiety to the quinone sys-
tem of calothrixin B.23 However, the Dakin oxidation of heteroaryl
aldehydes has received less attention.24 In this work, we demon-
strate the use of the Dakin oxidation of indole-3-carbaldehydes
in the one-pot synthesis of tryptanthrin (2a).
Initially, aldehyde 1a was treated with m-CPBA and a 30% aque-
ous solution of H2O2; however, no reaction was observed (Table 1,
entries 1–3). Addition of a catalytic amount of (PhSe)2 (0.2 equiv)
markedly accelerated the reaction, producing 2a in 40% yield
(entry 4). Furthermore, 30% aqueous H2O2 solution was replaced
with urea hydrogen peroxide (UHP). Treating 1a with UHP
(10 equiv) in CH2Cl2 at room temperature resulted in a complex
mixture (entry 5), whereas 2a was obtained in 55% yield by heating
1a with UHP (5 equiv) in toluene at 75 °C (entry 8). To our surprise,
candidine (3) was obtained as a trimerization product in 21% yield
by treating 1a with excess amounts of UHP (10 equiv) in the pres-
ence of (PhSe)2 (0.2 equiv) in CH2Cl2 at room temperature (entry
9). Candidine (3) has so far been prepared by the condensation of
2a with 3-acetoxyindole in boiling AcOH and piperidine,25
although the one-pot formation of 3 from 1a through oxidative tri-
merization is, to our knowledge, hitherto unknown. The reaction
with aldehydes 1b–1g also produced 2b–2g (entries 10, 11, and
13–15), except the reaction of 1d (entry 12). No products were
⇑
Corresponding author. Tel./fax: +81 133 23 1245.
E-mail address: ishikura@hoku-iryo-u.ac.jp (M. Ishikura).
http://dx.doi.org/10.1016/j.tetlet.2014.07.113
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

T. Abe et al. / Tetrahedron Letters 55 (2014) 5268–5270
5269
O
OCHO
CHO
O
N
H2O2
[O]
[O]
N
N
NH
N
H
N
H
8
1a
9
O
O
N
O
O
1a
O
O
Tryptanthrin (2a)
O
N
H
N
H
Candidine (3)
10a
CH2COCH3
OH
OH
O
CHO
NH2
[O]
CH2COOCH3
N
O
N
N
NH2
N
N
N
11
O
12
O
O
O
4
(-)-(S)-Phaitanthrin A (
)
O
OH
O
5
(-)-(R)-Phaitanthrin B (
)
8
HO
N
N
O
O
N
N
O
N
N
2a
H
NH
O
O
N
N
Phaitanthrin C (6)
7
(+)-(S,S)-Cruciferane (
)
O
3
Figure 1. Tryptanthrin (2a) and related alkaloids.
Scheme 1. A plausible reaction path.
observed in reactions with 1h and 1i, which contained a substitu-
ent at the 7-position (entries 16 and 17).
Scheme 1 illustrates a plausible reaction path. The Dakin oxida-
tion of 1a first produces formate 8, followed by oxidation to isatoic
anhydride 10a via isatin 9. Then, 10a reacts with 1a to form amide
11, which is converted to 2a through oxidation of 11 to 12 followed
by intramolecular cyclization. The formation of 3 apparently
resulted from the condensation of 2a with 8. However, 3 was not
obtained as a product of the reaction of 2a with 8 in the presence
of UHP and (PhSe)2 in CH2Cl2. Therefore, the details of the forma-
tion of 3 are being investigated.
To support the proposed mechanism, the following experiments
were carried out (Scheme 2). When the oxidation of 1a with UHP
was stopped after 1 h, compounds 1a, 8, 10a, and 11 were isolated
from the reaction mixture. The oxidation of 8 produced a trace
amount of 2a, and no isolable products were obtained from the
reaction of 9 with 10a. In contrast, 2a was obtained in 80% yield
from the oxidation of 1a with 10a. Furthermore, the oxidation of
11, through the N-acylation of 1a with 10a in the presence of
Et3N, afforded 2a in 70% yield. However, the attempted oxidation
of 1h with 10a produced a complex mixture, and the N-acylation
of 1h with 10a in the presence of Et3N did not give the correspond-
ing amide 11. This may be caused by the presence of the Br group
at the 7-position of 1h, which hindered the N-acylation with 10a.
To our knowledge, the one-pot formation of 2a through oxida-
tion of 1a with 10a is unprecedented, although it is well-known
that heating 9 with 10a in the presence of Et3N in toluene gives
2a.26 Compounds 2 are hybrids of 1 and 10, and substituted alde-
Table 1
Dakin oxidation of indole-3-carbaldehydes 1
O
R
N
N
R
CHO
conditions
O
N
H
2
R
1
a: R = H
b: R = 4-Br
d
: R = 5-NO2
O
c
: R = 5-Br
e: R = 5-OMe f : R = 5-Me
NH
g
h
: R = 7-Br
: R = 6-Br
N
N
i : R = 7-Me
O
3
Entry
1
Conditions
Yielda
(%)
1
2
3
4
1a m-CPBA (3 equiv), CH2Cl2, 0 °C, 3 h
1a 30% aq. H2O2 (excess), CH2Cl2, rt, 3 h
1a 30% aq. H2O2 (excess), TFA (0.2 equiv), CH2Cl2, rt, 3 h N.R.
1a 30% aq. H2O2 (excess), (PhSe)2 (0.2 equiv), CH2Cl2, rt, 40 (2a)
N.R.
N.R.
UHP
O
+
10a
toluene
75 °C, 16 h
O
N
H
9
3 h
b
O
5
6
7
8
9
1a UHP(10 equiv), CH2Cl2, rt, 16 h
1a UHP (5 equiv), neat, 85 °C, 1 h
1a UHP (5 equiv), toluene, rt, 16 h
1a UHP (5 equiv), toluene, 75 °C, 16 h
1a UHP (10 equiv), (PhSe)2 (0.2 equiv), toluene, 75 °C,
16 h
1b UHP (5 equiv), toluene, 75 °C, 16 h
1c UHP (5 equiv), toluene, 75 °C, 16 h
1d UHP (5 equiv), toluene, 75 °C, 16 h
1e UHP (5 equiv), toluene, 75 °C, 16 h
—
UHP
toluene
75 °C, 16 h
25 (2a)
N.R.
55 (2a)
21 (3)
CHO
N
N
2a
N
H
80%
O
1a
O
70%
10
11
12
13
14
15
16
17
40 (2b)
48 (2c)
O
toluene
75 °C, 16 h
UHP
b
O
N
H
—
10a
CHO
62 (2e)
70 (2f)
43 (2g)
CHO
NH2
1f
UHP (5 equiv), toluene, 75 °C, 16 h
1g UHP (5 equiv), toluene, 75 °C, 16 h
1h UHP (5 equiv), toluene, 75 °C, 16 h
b
N
—
—
Et3N, toluene
23%
N
H
11
b
1i
UHP (5 equiv), toluene, 75 °C, 16 h
1a
O
a
Isolated yields.
Complex mixture.
b
Scheme 2. Experiments to confirm the proposed path.

5270
T. Abe et al. / Tetrahedron Letters 55 (2014) 5268–5270
Table 2
benzene provided phaitanthrin C (6) in 72% yield. Stirring 2a in
Oxidative coupling of 1 with 10
acetone and DMF in the presence of molecular sieves 4A at room
temperature produced ( )-phaitanthrin A (4) in 80% yield. The
Reformatsky reaction of 2a with methyl bromoacetate using Zn
and TMSCl was successfully performed to give ( )-phaitanthrin B
(5) in 90% yield. The reductive cyclization of 5 with NaBH4 in
MeOH/THF afforded ( )-cruciferane (7) in 88% yield.
R
CHO
O
R
UHP
N
H
(5 equiv)
N
1
N
+
2
O
toluene
75 °C, 16 h
O
X
O
In summary, we have demonstrated that the Dakin oxidation of
indole-3-carbaldehyde (1a) with urea hydrogen peroxide (UHP)
produced tryptanthrin (2a). The reaction proceeded through the
in situ generation of amide 11 from the condensation of 1a with
isatoic anhydride 10a, followed by oxidative intramolecular cycli-
zation. Moreover, the unprecedented one-pot formation of candi-
dine (3) via trimerization in the presence of UHP (10 equiv) and
a catalytic amount of (PhSe)2 (0.2 equiv) was also observed. The
Dakin oxidation of 1 and 10 was also developed for synthesizing
several derivatives of 2a. Further studies for exploring the scope
of the reaction are now in progress.
X
O
N
H
10
R of 1
Entry
X of 10
Yielda (%)
1
2
3
4
5
6
7
8
9
4-Br (1b)
4-Br (1b)
H (10a)
Br (10b)
H (10a)
H (10a)
Br (10b)
H (10a)
Br (10b)
H (10a)
Br (10b)
H (10a)
Br (10b)
76 (2j)
71 (2k)
75 (2l)
80 (2m)
71 (2c)
85 (2n)
70 (2o)
70 (2p)
4-OBn (1k)
5-Br (1c)
5-Br (1c)
5-Me (1f)
5-Me (1f)
6-Br (1g)
6-Br (1g)
7-Br (1h)
7-Br (1h)
65 (2q)
Complex mixture
Complex mixture
10
11
Acknowledgement
a
Isolated yields.
This work was supported in part by the Ministry of Education,
Culture, Sports, Sciences, and Technology of Japan through a
Grant-in Aid for Scientific Research (No. 26460012).
CH2COCH3
OH
O
References and notes
MS 4A
N
N
N
N
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5
)
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OBn
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benzene
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72%
6
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Scheme 3. Preparation of alkaloids 4, 5, 6, and 7 from 2a.
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hydes 1 are accessible more easily than substituted isatins. There-
fore, the scope of the one-pot oxidation of 1 with 10 was further
examined (Table 2). Heating 1 and 10 (1.5 equiv) with UHP in tol-
uene at 75 °C provided tryptanthrin derivatives 2 in good yields
(entries 1–9). However, no products were again obtained from
the reaction of 1h (entries 10 and 11).
Next, the conversion of 2a to ( )-phaitanthrins A (4), B (5), and C
(6), and ( )-cruciferane (7) was carried out (Scheme 3).18,27,28
Removal of the benzyl group of 2l with MgBr2OEt2 in boiling
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