Oligomerization of N-tosylindole with aluminum chloride

Article abstract of DOI:10.1271/bbb.68.764

The reactivity of N-tosylindole (4) in the presence of aluminum chloride was studied, and two types of oligomerization of 4 were observed. One type was condensation between both pyrrole parts (dimers 5 and 6 and trimer 7) and the other was between a pyrro

Full text of DOI:10.1271/bbb.68.764

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Oligomerization of N-Tosylindole with Aluminum
Chloride
Kazutaka FUJINOa, Emiko YANASEa, Yoshihiko SHINODAa & Shin-ichi NAKATSUKAa
a The United Graduate School of Agricultural Science, Gifu University
Published online: 22 May 2014.
To cite this article: Kazutaka FUJINO, Emiko YANASE, Yoshihiko SHINODA & Shin-ichi NAKATSUKA (2004) Oligomerization
of N-Tosylindole with Aluminum Chloride, Bioscience, Biotechnology, and Biochemistry, 68:3, 764-766, DOI: 10.1271/
bbb.68.764
To link to this article: http://dx.doi.org/10.1271/bbb.68.764
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Biosci. Biotechnol. Biochem., 68 (3), 764–766, 2004
Communication
Oligomerization of N-Tosylindole with Aluminum Chloride
y
Kazutaka FUJINO, Emiko YANASE, Yoshihiko SHINODA, and Shin-ichi NAKATSUKA
The United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received December 9, 2003; Accepted January 16, 2004
The reactivity of N-tosylindole (4) in the presence of
aluminum chloride was studied, and two types of
oligomerization of 4 were observed. One type was
condensation between both pyrrole parts (dimers 5 and
6 and trimer 7) and the other was between a pyrrole
part and a benzene part of each indole nucleus (dimers 8
and 9).
When the reaction was carried out with 1.0 eq. AlCl3
in CH2Cl2 at 25ꢀC for 25 min, the major product was
trimer 7, the tri-tosylamide of 3, in a 71% yield (entry
1). It is considered that trimer 7 was formed by 1) partial
coordination of 4 with AlCl3 at the pyrrole part, 2)
condensation between the electron-deficient tosylindole/
AlCl3 complex and electron-rich tosylindole, and 3)
subsequent ring-opening by the same oligomerization
mechanism as for the reaction of indole/HCl.17)
When the reaction was carried out with 5.0 eq. AlCl3
at 25ꢀC (entry 2), unique 3-30 dimer 5 was generated as
the major product, along with small amounts of similar
dimers 8a–c and 9a–c. It is considered that the electron-
withdrawing tosyl group made the reactivity of the
pyrrole part considerably weake by the coordination of
AlCl3, this being an unexpected result. At low temper-
ature (entries 3 and 4), the yields of 6 and 9a–c were
increased.
Since the structures of those products were very
similar to each other, it was very difficult to isolate each
component. However, we succeeded in their purification
by utilizing silica gel open column chromatography and
HPLC (ODS and silica gel).
N-Tosylindole 4 was stirred with 5.0 eq. AlCl3 in
CH2Cl2 at 25ꢀC for 2 min. The reaction mixture was
purified in a silica gel open column (80% CH2Cl2 in
hexane). After evaporating the fractions containing 5, 6,
8 and 9, pure dimer 5 (27% yield) was isolated by
recrystallizing the residue in CH3CN.
Key words: indole polymerization; 3,30-biindole; N-
tosylindole
Although many indole alkaloids containing functional
groups on the benzene part of the indole nucleus have
been reported, introduction of the functional groups at
specific positions was difficult, except in a few cases.1)
We have developed novel methods2–10) for introducing
various functional groups on the benzene part of such
stabilized indoles as N-pivaloylindole and applied these
to the total synthesis of teleocidin B11) and to an efficient
synthesis of the mitomycin skeleton.12–14) In a study of
the chemical reactivity of N-pivaloylindole, we found
novel dimerization of N-pivaloylindole in the presence
of AlCl3 to give 1a–c.15) These compounds were
completely different from oligomerization products 2
and 316–19) of indole itself under acidic conditions. We
report in this communication novel dimerization prod-
ucts of N-tosylindole (4).
The reactivity of N-tosylindole (4)20) was studied by
treating with AlCl3 under various conditions, and two
types of oligomerization of 4 were observed at low
temperature. One of these was condensation between
both pyrrole parts (dimers 5 and 6 and trimer 7) and the
other was between a pyrrole part and a benzene part of
each indole nucleus (dimers 8 and 9).
5: mp 222–223ꢀC; 1H-NMR ꢀ (500 MHz, CDCl3):
2.35 (3H, s), 2.41 (3H, s), 3.85 (1H, dd, J ¼ 7, 11 Hz),
4.34 (1H, dd, J ¼ 10, 11 Hz), 4.51 (1H, dd, J ¼ 7,
10 Hz), 6.87 (1H, d, J ¼ 8 Hz), 6.90 (1H, d, J ¼ 8 Hz),
6.97 (1H, s), 6.99 (1H, br.t, J ¼ 8 Hz), 7.02 (1H, br.t,
J ¼ 8 Hz), 7.18 (2H, br.d, J ¼ 8 Hz), 7.22 (2H, br.d,
J ¼ 8 Hz), 7.27 (1H, t, J ¼ 8 Hz), 7.30 (1H, br.t,
J ¼ 8 Hz), 7.61 (2H, d, J ¼ 8 Hz), 7.68 (2H, d,
J ¼ 8 Hz), 7.78 (1H, d, J ¼ 8 Hz), 7.93 (1H, d,
J ¼ 8 Hz); EI-MS m=z: 542 (Mþ).
H
N
N
N
N
H
N
H
NH2
O
N
H
O
In order to determine the structure of 6, an authentic
sample was prepared by tosylating indole dimer 218)
(NaH, TsCl in DMF, 31% isolated yield). Dimer 6 was
identical with those derived from dimer 2.
3
2
1a-c
Fig. 1. Structures of the Polymers of N-Pivaloylindole15) and In-
dole.18,19)
1
6: H-NMR ꢀ (500 MHz, CDCl3): 2.31 (3H, s), 2.32
(3H, s), 2.95 (1H, dd, J ¼ 3, 16 Hz), 3.23 (1H, dd,
y
To whom correspondence should be addressed. Tel/Fax: +81-58-293-2919; E-mail: nakatsu@cc.gifu-u.ac.jp

Oligomerization of N-Tosylindole
765
Ts
N
3'
3
N
Ts
N
Ts
N
Ts
N
+
+
NH
Ts
Ts
N
Ts
5
6
AlCl3
7
CH2Cl2
N
4'
Ts
5'
3
4'
5'
4
N
Ts
+
+
6'
N
Ts
N
Ts
9a-c
2
N
Ts
6'
8a-c
AlCl3 Temp.
1.0 eq.
Time
5
6
7
8a-c
9a-c
entry 1
10% 71%
25°C 25min
2%
2min 35%
5%
8%
12%
5%
3%
4%
entry 2 5.0eq.
25°C
-20°C
-40°C
5.0eq.
5.0eq.
entry 3
entry 4
14%
3%
65min
10%
2% 13%
180min
Scheme 1. Polymerization of N-Tosylindole in the Presence of Aluminum Chloride.
H
+
+
-
AlCl
-
3
AlCl
N
N
- Ts
AlCl
N
N
Ts
3
3
4
5
+
+
-+Ts
+
Ts
-
-
Cl Al
3
Cl Al
Cl Al
Cl Al
3
3
3
I
II
Scheme 2. Dimerization Mechanism for N-Tosylindole.
MnO2
KOH
5
N
Ts
N
Ts
dioxane
100°C
CHCl2CHCl2
N
H
N
H
100°C
10 (91%)
11 (57%)
Scheme 3. Synthesis of Bi-indole 11.21–23)
J ¼ 10, 16 Hz), 5.53 (1H, dd, J ¼ 3, 10 Hz), 7.02 (2H, d,
J ¼ 8 Hz), 7.07 (3H, m), 7.15 (1H, d, J ¼ 8 Hz), 7.21
(2H, d, J ¼ 8 Hz), 7.24 (1H, t, J ¼ 8 Hz), 7.29 (1H, m),
7.45 (2H, d, J ¼ 8 Hz), 7.58 (1H, s), 7.73 (1H, d,
J ¼ 8 Hz), 7.74 (2H, d, J ¼ 8 Hz), 7.89 (1H, d,
J ¼ 8 Hz); EI-MS m=z: 542 (Mþ).
5.65 (1H, dd, J ¼ 3, 10 Hz), 6.70 (1H, d, J ¼ 3 Hz), 7.12
(1H, t, J ¼ 8 Hz), 7.17 (1H, d, J ¼ 8 Hz), 7.19 (1H, d,
J ¼ 8 Hz), 7.25 (4H, d, J ¼ 8 Hz), 7.34 (1H, t, J ¼
8 Hz), 7.47 (1H, d, J ¼ 8 Hz), 7.62 (1H, d, J ¼ 3 Hz),
7.63 (2H, d, J ¼ 8 Hz), 7.71 (2H, d, J ¼ 8 Hz), 7.73 (1H,
d, J ¼ 8 Hz), 8.06 (1H, s); EI-MS m=z: 542 (Mþ).
The possible formation mechanism for dimer 5 is
shown in Scheme 2: 1) 2 eq. AlCl3 coordinates at both
the tosyl group and 2-position of 4, 2) electrophilic
attack at the 3-position of AlCl3 complex I to the 3-
position of 10, and 3) generation of 5.
The structure of dimer 5 was determined to be that of
the 3-30 dimer of N-tosylindole 4 from its spectroscopic
data. Although the synthesis of 3-30 biindole 11 has been
reported,21–23) no synthetic route via the dimerization of
indole has appeared in the literature.
The structures of dimers 8a–c were determined to be
those of the dimers between the benzene part
(60 > 40 > 50) and the 3-position by comparing with N-
pivaloyl indole dimers 1a–c. Dimers 9a–c were purified
by HPLC, major component 9c was isolated, and the
structure 9c was determined to be that of a novel 2-60
dimer between the benzene part (60-position) and the 2-
position of the indole nucleus by a spectroscopic
analysis.
1
9c: H-NMR ꢀ (500 MHz, d6-acetone): 2.31 (3H, s),
2.37 (3H, s), 2.91 (1H, m), 3.38 (1H, dd, J ¼ 10, 16 Hz),
Dimer 5 was oxidized with MnO2 in CHCl2CHCl2 at

766
K. FUJINO et al.
100ꢀC for 90 min to give bi-indole derivative 10 in a
91% yield. Hydrolysis of 10 with KOH in dioxane at
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trolled cyclization of 1-(3-methyl-2-butenoyl)indoles at
their 2 and 7-positions. Heterocyclic Communications, 2,
555–558 (1996).
10) Nakatsuka, S., Hayashi, T., Adachi, S., Harada, Y., and
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acetylindole derivatives at the 4-position of indole
nucleus. Heterocyclic Communications, 3, 47–50 (1997).
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(1987).
1
100ꢀC for 50 min afforded 11 in a 57% yield. The H-
NMR spectrum of 11 was identical with that reported.23)
10: 1H-NMR ꢀ (500 MHz, CDCl3): 2.35 (6H, s), 7.25
(4H, d, J ¼ 8 Hz), 7.31 (2H, t, J ¼ 8 Hz), 7.40 (2H, t,
J ¼ 8 Hz), 7.67 (2H, d, J ¼ 8 Hz), 7.82 (4H, d,
J ¼ 8 Hz), 7.82 (2H, s), 8.07 (2H, d, J ¼ 8 Hz); EI-MS
m=z: 540 (Mþ).
The reactivity of N-tosylindole 4 in the presence of
AlCl3 might be important for a better understanding of
indole chemistry. Further study of this reactivity is now
in progress.
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Efficient synthesis of indoloquinone derivative by
several oxidative derivations of 6-methylindole. Hetero-
cycles, 26, 65–68 (1987).
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