Novel and efficient synthesis of pyrroloiminoquinones using a hypervalent iodine(III) reagent

Article abstract of DOI:10.1039/a709099d

A novel and efficient route involving an intramolecular cyclization of 3-(azidoethyl)indole derivatives using a hypervalent iodine(III) reagent has been developed for the synthesis of pyrroloiminoquinones.

Full text of DOI:10.1039/a709099d

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Novel and efficient synthesis of pyrroloiminoquinones using a
hypervalent iodine(III) reagent
Yasuyuki Kita,* Hiroaki Watanabe, Masahiro Egi, Toyokazu Saiki,
Yuko Fukuoka and Hirofumi Tohma
Faculty of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, 565,
Japan
A novel and efficient route involving an intramolecular
cyclization of 3-(azidoethyl)indole derivatives using a
hypervalent iodine(III) reagent has been developed for the
synthesis of pyrroloiminoquinones.
tinuing studies on hypervalent iodine() oxidation of phenol
derivatives, we recently reported on the direct and efficient syn-
thesis of quinone imine monoacetals using a combination of
7
phenyliodine() bis(trifluoroacetate) (PIFA) and trimethylsilyl
8
trifluoromethanesulfonate (TMSOTf) (Scheme 1).
The pyrroloiminoquinone system is an essential component of
a number of recently isolated marine alkaloids such as makal-
R1
R1
N
1
2
3
uvamines, isobatzelline C and discorhabdins which possess
potent biological activities (e.g. cytotoxicity towards human
tumor cell lines and inhibition of topoisomerase II). Because of
their potent biological activities and their highly fused struc-
tures, pyrroloiminoquinone alkaloids have been challenging
targets for synthetic chemists for years.
MeO
PhI(OCOCF ) (PIFA)– MeO
3 2
TMSOTf
MeO
CF3CH2OH–MeOH
R2
R2
N3
(10:1)
MeO
MeO
R3
R3
Scheme 1
HO
Br
N
We report here a novel and efficient synthesis of pyrrolo-
iminoquinones from indoles bearing an alkyl azido side-chain
using the activated hypervalent iodine() reagent, PIFA–
TMSOTf in (CF ) CHOH–H O.
N
3
2
2
X
N
S
H
The starting indoles were prepared as follows. The treatment
N
N
O
H
9
H
of 6,7-dimethoxyindole with oxalyl chloride followed by LAH
pyrroloiminoquinone
O
reduction gave 3-(hydroxyethyl)indole (95% yield) which was
converted to 3-(azidoethyl)indole (1a) via 3-(iodoethyl)indole
in 65% yield. Other 3-(azidoethyl)indole derivatives (1b–g) were
readily prepared from 1a by standard alkylation and acylation
methods. First we examined the reaction of 1a with PIFA–
makaluvamine F
O
Br
N
N
TMSOTf. However, a complex mixture was obtained. The reac-
Cl
i
tions of 1b (R = Me) and 1c (R = SiPr ) with PIFA–TMSOTf
3
S
also gave complex mixtures due to side reactions which can
occur at the 1- or 3-positions of the indole nucleus. In fact,
several groups had already reported that 1-, 2- or 3-substituted
indole derivatives were obtained from the reaction of indoles
H2N
N
Me
N
H
N
O
H
H
O
10
isobatzelline C
discorhabdin A
with iodobenzene diacetate. Therefore we then examined the
reactions of 1-protected indoles (1d–g) with PIFA–TMSOTf in
O
the presence of H O. We found that the corresponding pyrrolo-
2
Br
Br
N
iminoquinones (2d, e) or 1-deprotected pyrroloiminoquinone
(3) could be obtained in moderate yields when the indoles
were treated with PIFA–TMSOTf in (CF ) CHOH–H O
3
2
2
(
50:1)† and when they were protected by electron-withdrawing
groups such as acetyl, benzoyl, tosyl or benzyloxycarbonyl
groups.
In conclusion, a facile and direct synthesis of pyrrolo-
iminoquinones has been developed. This work will be applied
to the syntheses of various types of quinone imine alkaloids
containing pyrroloiminoquinones.
N
H
N
H
O
discorhabdin C
So far several groups, including ours, have reported diverse
approaches for pyrroloiminoquinone derivatives: (i) intra-
molecular imine formation between the indoloquinone and the
terminal amino group of the side-chain, (ii) intramolecular
coupling reaction between the 4-amino group of the indole and
the terminal activated ester group or leaving group of the side-
chain, and (iii) formation of the pyrrole ring from 5-amino-4-
formyltetrahydroquinone. We have previously reported the
total synthesis of discorhabdin C via route (i). In our con-
4
† Typical experimental procedure is as follows; to a stirred solution of
1
(0.1 mmol) in (CF ) CHOH–H O (50:1) (2 ml), TMSOTf (0.24
3 2 2
mmol), then PIFA (0.12 mmol) as a solid were added sequentially at
ЊC. The mixture was stirred for 1 h under the same conditions. After
0
5
aqueous work-up with saturated aqueous NaHCO , purification by
3
6
preparative TLC gave pure 2 or 3. All newly isolated compounds gave
satisfactory spectroscopic data.
4a
J. Chem. Soc., Perkin Trans. 1, 1998
635

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1a: R = H
—
—
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—
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—
—
—
51
47
Paper 7/09099D
Received 19th December 1997
Accepted 19th December 1997
—
a
Complex mixture.
6
36
J. Chem. Soc., Perkin Trans. 1, 1998