TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5675–5677
AuBr3-catalyzed cyclization of o-(alkynyl)nitrobenzenes.
Efficient synthesis of isatogens and anthranils
Naoki Asao,* Kenichiro Sato and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 9 April 2003; revised 19 May 2003; accepted 30 May 2003
Abstract—The cyclization of o-(arylalkynyl)nitrobenzenes was catalyzed by AuBr3 to produce the corresponding isatogens in good
to high yields together with small amounts of anthranils. On the other hand, anthranils were obtained selectively when the
AuBr3-catalyzed reaction was carried out using o-(alkylalkynyl)nitrobenzenes.
© 2003 Elsevier Ltd. All rights reserved.
2-Substituted-3-H-indol-3-one N-oxides, which are
known as isatogens, have been well investigated due to
their useful biological activities against a range of bac-
teria,1 mycobacteria2 and fungi.3 Some of them are able
to antagonize the relaxant response to adenosine-5-
triphosphate in mammals.4 Among many approaches
for the synthesis of isatogens, the intramolecular
cyclization of an ortho-substituted nitrobenzene precur-
sor is one of the most simple and convenient routes.5,6
However, this cyclization method has some drawbacks,
such as poor yields, long reaction times, and high
reaction temperatures. It seemed that an efficient and
convenient method with wide applicability for the syn-
thesis of isatogens was still needed. We previously
reported that the AuCl3-catalyzed reaction of o-
(alkynyl)benzaldehydes with alkynes produced naph-
thyl ketone derivatives in good to high yields, in which
the first step involves the coordination of the alkyne to
AuCl3 1, followed by the intramolecular attack of the
oxygen of the aldehyde to the electron deficient alkynyl
carbon, leading to benzo[c]pyrylium type zwitterionic
intermediate 2 (Eq. (1)).7
It occurred to us that if we could use, instead of an
aldehyde, a heteroatom containing functionality such as
a nitro group, we might synthesize a nitrogen contain-
ing heterocycle. In this paper, we wish to report that
gold-catalyzed cyclization of o-(alkynyl)nitrobenzene 3
affords the corresponding isatogens 4 in good to high
yields under mild conditions (Eq. (2)).
(2)
Treatment of 3a with 3 mol% of AuCl3 in 1,2-
dichloroethane at rt for 12 h gave 4a, bearing a phenyl
group at the 2-position, in 53% yield together with
3-benzoyl-2,1-benzisoxazole 5a, which is an anthranil,
in 34% yield (entry 1, Table 1). When we used AuBr3 as
the catalyst instead of AuCl3, the reaction rate was
dramatically accelerated and 4a was obtained in 67%
yield within 1.5 h (entry 2). Other more widely used
Lewis acids, such as BF3·OEt2 and TiCl4, were not
effective in the present reaction. It should be mentioned
that 4a was obtained in a moderate yield even in the
absence of a Lewis acid, although a longer reaction
time (5 days) and higher temperature (120°C) were
required (entry 3). Optimization experiments revealed
that toluene was a suitable solvent for the present
reaction (compare entries 2, 4–6). Lowering the reac-
tion temperature to 4°C increased the chemical yield of
4a up to 81% yield and decreased the yield of 5a (entry
7). We next examined the cyclization with other o-
(alkynyl)nitrobenzenes 3b–f. The reaction of 3b, bearing
a 4-anisyl group at the terminal position of the alkyne,
proceeded smoothly to give 4b in 80% yield together
(1)
Keywords: isatogen; anthranil; AuBr3; cyclization; o-(alkynyl)-
nitrobenzene.
tohoku.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01357-1