One-pot construction of 3,3′-bisindolylmethanes through Bartoli indole synthesis

Article abstract of DOI:10.1021/ol401486s

A one-pot approach to 3,3′-bisindolylmethane derivatives from nitrobenzene derivatives through the Bartoli indole synthesis was developed, in which the acid used to quench the reaction markedly affected its outcome. Quenching the reaction with concd HCl produced 3,3′-bisindolylmethane in contrast to the formation of 7-substituted indole by quenching with NH ₄Cl.

Full text of DOI:10.1021/ol401486s

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3622–3625
One-Pot Construction of
3,30-Bisindolylmethanes through
Bartoli Indole Synthesis
Takumi Abe,† Shuuhei Nakamura,† Reiko Yanada,‡ Tominari Choshi,§
Satoshi Hibino,§ and Minoru Ishikura*,†
School of Pharmaceutical Sciences, Health Sciences University of Hokkaido,
Ishikari-Tobetsu, Hokkaido 061-0293, Japan, Faculty of Pharmaceutical Sciences,
Hiroshima International University, Hirokoshingai, Kure, Hiroshima 737-0112, Japan,
and Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University,
Fukuyama, Hiroshima 729-0292, Japan
ishikura@hoku-iryo-u.ac.jp
Received May 26, 2013
ABSTRACT
A one-pot approach to 3,30-bisindolylmethane derivatives from nitrobenzene derivatives through the Bartoli indole synthesis was developed, in
which the acid used to quench the reaction markedly affected its outcome. Quenching the reaction with concd HCl produced 3,30-
bisindolylmethane in contrast to the formation of 7-substituted indole by quenching with NH4Cl.
The search for natural products from terrestrial and
marine sources has led to the isolation of novel 3,30-
bisindolylmethane alkaloids with biological activities and
intriguing structures (Figure 1). For example, arundine
(1),1 isolated from the root of Arundo donax in 1994,
exhibits potent carcinogenicity, and vibrindole A (2),2
isolated from the culture medium of the marine bacterium
Vibrio parahemolyticus in 1994, shows antibacterial activ-
ity. Research has focused on developing efficient synthetic
methods3 and evaluating biological activity for 3,30-bisin-
dolylmethane derivatives.4 The majorityofsyntheticmeth-
ods depend on the condensation of indoles with carbonyl
compounds or their syntheticequivalents inthe presenceof
acid or base. Recently, metal-catalyzed processes have
been reported,5 such as the Pd-catalyzed benzylic substitution
of gramine with an indole,6 the Pt-catalyzed bisindolylation
of allene,7 and the Re-catalyzed addition of indoles to a
terminal alkyne.8
Bartoli indole synthesis is one of the shortest and most
flexible methods for accessing 7-substituted indoles.9 After
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2004, 34, 421–434. (r) Chakrabarty, M.; Sarkar, S.; Linden, A.; Stein, B. K.
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† Health Sciences University of Hokkaido.
‡ Hiroshima International University.
§ Fukuyama University.
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r
10.1021/ol401486s
Published on Web 06/28/2013
2013 American Chemical Society

1-chloro-2-nitrobenzene (8a) was treated with vinylmag-
nesium bromide (3 equiv) in THF at ꢀ40 °C for 0.5 h and
then at 0 °C for 2 h, quenching the reaction by adding
aqueous NH4Cl solution produced 7-chloroindole (9) in
60% yield (Table 1, entry 1). However, on quenching the
reaction with 10% HCl instead of NH4Cl, the reaction
mixture changed immediately from pale yellow to dark
red, and to our surprise, bisindolylmethane 10a was iso-
lated in 26% yield along with 9 in 22% yield (entry 4). An
aqueousKHSO4 solution produced10a in34% yield along
with 9 in 8% yield, whereas AcOH was virtually ineffective
for producing 10a (entries 2 and 3). Furthermore, when
concentrated HCl was used, 10a was obtained in 55% yield
without 9 (entry 5), and 10b and 10c were obtained from 8b
and 8c in 60 and 41% yields, respectively (entries 6 and 7).
Moreover, subjecting the other nitrobenzene derivatives
8d, 8e, and 8fto the samereaction conditionsprovided10d,
10e, and 10f in 50%, 20%, and 32% yields, respectively
(entries 8ꢀ10).
acetaldehyde. The first step of the Bartoli reaction is
presumed to involve the interaction of the nitro group of
8a with vinylmagnesium bromide, to produce nitroso
benzene 11 and vinyloxymagnesium bromide. Thus, the
presence of acetaldehyde can be explained by the rapid
hydrolysis of vinyloxymagnesium bromide under strongly
acidic conditions, which may support the existence of the
proposed vinyloxymagnesium bromide species in the Bar-
toli reaction. However, 10a was not observed as a product
ofthe reaction of indole9withacetaldehyde inthepresence
of concentrated HCl and MgBr2, and 7,70-dichloro-2,3-
dihydro-2,30-bisindole was isolated instead. Therefore, the
simple assumption that 9, which was derived from 12,
underwent condensation withacetaldehyde appears incon-
sistent with these observations. The details of the reaction
path are under investigation.
Table 1. Reaction of 8 with Vinylmagnesium Bromide
entry
8
acid
10 (%)a
b
1
2
3
4
5
6
7
8
9
10
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
NH4Cl
ꢀ
Figure 1. 3,30-Bisindolylmethanes.
AcOH
10a (10)c
10a (34)d
10a (26)e
10a (55)
10b (60)
10c (41)
10d (50)
10e (20)
10f (32)
KHSO4
10% HCl
concd HCl
concd HCl
concd HCl
concd HCl
concd HCl
concd HCl
Scheme 1 illustrates a plausible reaction path in accor-
dance with the usual Bartoli reaction mechanism,10 invol-
ving the in situ generation of indoline intermediate 12 from
8a and vinylmagnesium bromide. Typically, indole 9 was
produced from 12 through quenching the reaction mixture
with NH4Cl. In contrast, the production of 10a apparently
resulted from the condensation of 2 equiv of 9 with
a Isolated yield based on 8a. b 9 (60%). c 9 (35%). d 9 (8%). e 9 (22%).
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Based on these results, we expected that a one-pot
reaction containing an additional aldehyde should provide
various substituted bisindoles 10. We treated 8b with
vinylmagnesium bromide (3 equiv) in THF at ꢀ40 °C for
0.5 h and then at 0 °C for 2 h and added propanal (2 equiv)
to the reaction mixture. The mixture was then immediately
Org. Lett., Vol. 15, No. 14, 2013
3623

66 and 37% yields, respectively, whereas only 8-bromoindole
was isolated from the reaction with sterically hindered
pivalaldehyde in 70% yield (entries 7ꢀ9). In addition,
glyoxalic acid produced 10m in 55% yield (entry 10).
Aqueous KHSO4 was suitable for quenching the reaction
involving aromatic aldehydes, whereas the reaction with
concentrated HCl resulted in a complex mixture of pro-
ducts (entries 11ꢀ14).
Scheme 1. A Plausible Reaction Path
Table 2. Formation of 3,30-Bisindolylmethanes 10
quenched with concentrated HCl at 0 °C for 0.5 h. This
produced 10g in a 70% yield (Table 2, entry 1). Having
establishedaone-potprotocol fortheformation of10g, the
scope of the one-pot reaction was examined. Table 1 shows
that the yield of 10b was improved to 75% by using
additional acetaldehyde (entry 4). Compound 10j was
obtained by using paraformaldehyde or aqueous HCHO
solution (entries 5 and 6). The reaction with isovaleralde-
hyde and cyclohexanecarboxaldehyde gave 10k and 10l in
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in 70% yield.
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3624
Org. Lett., Vol. 15, No. 14, 2013

produced 3,30-bisindolylmethane 10a when the reaction
was quenched with HCl. In contrast, 7-chloroindole (9)
was formed by quenching the reaction with NH4Cl. The
production of 10a from indoline 12 was caused by the
capture of acetaldehyde, which was generated from viny-
loxymagnesium bromide during the treatment with HCl.
Moreover, various derivatives of 10 were obtained from
the one-pot reaction in the presence of an additional
aldehyde. This protocol was developed for synthesizing
several natural products. We are currently conducting
further studies to explore the scope of this reaction.
Scheme 2. Conversion of 10 to Alkaloids
Scheme 3. One-Pot Formation of 3 and 13
were derived from 10m through esterification, reduction,
debromination, and acylation (Scheme 2).
Notably, the one-pot synthesis of tris(3-indolyl)methane
(3)12,15 was achieved through the reaction of 8b with
vinylmagnesium bromide in the presence of indole-3-car-
boxaldehyde (ꢀ40 °C, for 0.5 h, 0 °C, for 2 h, then addition
of indole-3-carboxaldehyde and KHSO4). An unexpected
debromination at the 7-position of the indole ring was
observed. In addition, the reaction with isatin under the
same conditions produced trisindoline (13)16 with the same
debromination (Scheme 3).
Acknowledgment. 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. 22590010).
In summary, we have demonstrated that the Bartoli
reaction of nitrobenzene 8a with vinylmagnesium bromide
Supporting Information Available. Experimental pro-
cedures and characterization data for products and iso-
lated intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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