A General Synthesis of N-Hydroxyindoles

Article abstract of DOI:10.1021/jo035351l

A general method for the formation of N-hydroxyindoles is demonstrated through a lead-promoted intramolecular reductive cyclization of o-nitrobenzyl ketones and aldehydes under transfer hydrogenation conditions. The N-hydroxyindoles are isolated in high purity and excellent yield (> 90%) in an operationally simple procedure. This new method is exemplified by a two-step synthesis of the naturally occurring 1-methoxyindole-3-carboxaldehyde, which is pivotal in many alkaloid total syntheses.

Full text of DOI:10.1021/jo035351l

SCHEME 1
A Gen er a l Syn th esis of N-Hyd r oxyin d oles
Audrey Wong,* J effrey T. Kuethe, and Ian W. Davies
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
audrey_wong@merck.com
Received September 12, 2003
Abstr a ct: A general method for the formation of N-
hydroxyindoles is demonstrated through a lead-promoted
intramolecular reductive cyclization of o-nitrobenzyl ketones
and aldehydes under transfer hydrogenation conditions. The
N-hydroxyindoles are isolated in high purity and excellent
yield (>90%) in an operationally simple procedure. This new
method is exemplified by a two-step synthesis of the
naturally occurring 1-methoxyindole-3-carboxaldehyde, which
is pivotal in many alkaloid total syntheses.
cyclization of substituted o-nitrobenzyl ketones would be
an attractive method for the construction of N-hydroxy-
indoles. In this paper, we demonstrate an efficient
method for the synthesis of N-hydroxyindoles which is
mild, high yielding and tolerates a wide range of func-
tionality.
While the reduction of o-nitrobenzyl ketones or alde-
hydes has been reported to give N-hydroxyindoles in the
presence of Zn/NH4Cl,5 Pd/NaBH4,6 or Pd/H2,7 these
reactions are generally intolerable to many functional
groups, low yielding, and substrate limited. Often, further
reduction of the N-hydroxyindole to the corresponding
indole is observed. The reduction of aromatic nitro
compounds with triethylammonium formate (TEAF) in
the presence of palladium on carbon leads to the forma-
tion of anilines.8 Very recently, Gowda reported the
reduction of nitro compounds to azo compounds using Pb/
TEAF in methanol.9 Under these reaction conditions, the
initial reduction of the nitro group to a hydroxylamine
was observed, and in certain cases the hydroxylamine
was isolated in up to 30% yield. We envisioned that
reductive cyclization of a suitably substituted o-nitroben-
zyl ketone 1 mediated by Pb/TEAF might provide the
appropriate chemoselectivity to provide N-hydroxyindoles
3 via the cyclization of intermediate 2 (Scheme 1).
To examine the Pb/TEAF-promoted reductive cycliza-
tion to N-hydroxyindoles, nitroketone 410 was treated
with Pb/TEAF in MeOH at 55 °C for 12 h and gave
2-phenyl-N-hydroxyindole 5 as the sole product in 94%
isolated yield. There was no detectable amount of 2-phe-
nylindole present in the crude reaction mixture (HPLC
and 1H NMR) as evidenced by comparison with an
authentic sample. With this extremely gratifying result,
we set out to examine the scope of the reaction. The
method proved to be general and allowed access to a
diverse array of highly functionalized N-hydroxyindoles
The synthesis of N-hydroxyindoles and their deriva-
tives has received considerable attention in recent years.1
The biological role of N-hydroxyindoles is still an area of
significant investigation. A range of N-hydroxyindoles
has been shown to have antimicrobial or fungicidal
activity. In addition, biologically inactive indoles have
been rendered biologically active when the N-hydroxy-
indole analogues were prepared.1 Due to their ability to
direct lithiations at the indole 2-position and also undergo
both nucleophilic and electrophilic substitutions, N-
hydroxy- and N-alkoxyindoles have served as useful
precursors to highly functionalized indoles.1 N-Hydroxy-
indoles are also convenient precursors to isatogens which
have been shown to spin trap hydroxyl radicals2 and
exhibit a wide range of biological activities.3 The ability
to fully profile biological activity of N-hydroxyindoles has
been somewhat limited by the currently available meth-
ods which suffer from low yields and competing side
reactions. Although some of these limitations have been
addressed by the Somei “tungstate method”,4 mild syn-
thetic methods which would provide rapid assembly of
the N-hydroxyindole ring from simple precursors would
give access to an array of highly functionalized N-
hydroxyindoles would be highly desirable. Reactions
leading to increasing molecular complexity and methods
which tolerate a wide range of functionality are impor-
tant synthetic tools. It was envisioned that reductive
(1) For reviews on N-hydroxyindoles and their derivatives, see: (a)
Somei, M. Adv. Heterocycl. Chem. 2002, 82, 101. (b) Somei, M.
Heterocycles 1999, 50, 1157. (c) Acheson, R. M. Adv. Heterocycl. Chem.
1990, 51, 105. (d) Somei, M. Yuki Gosei Kogaku Kyokaishi 1991, 49,
205. (e) Acheson, R. M. In New Trends in Heterocyclic Chemistry; Mitra,
R. B., Ayyanger, N. R., Gogte, Y. N., Acheson, R. M., Cromwell, N.,
Eds.; Elsevier Science Publishers: New York, 1979; p 1.
(2) (a) Rosen, G. M.; Tsai, P.; Barth, E. D.; Dorey, G.; Casara, P.;
Spedding, M.; Halpern, H. J . J . Org. Chem. 2000, 65, 4460. (b) For
reference on the synthesis of isatogens, see: Bristow, T. H. C.; Foster,
H. E.; Hooper, M. J . Chem. Soc., Chem. Commun. 1974, 677.
(3) Adams, D. B.; Hooper, M.; Swain, C. J .; Raper, E. S.; Stoddart,
B. J . Chem. Soc., Perkin Trans. 1 1986, 1005 and references therein.
(4) (a) Somei, M.; Kawasaki, T. Heterocycles 1989, 29, 1251. (b)
Kawasaki, T.; Kodama, A.; Nishida, T.; Shimizu, K.; Somei, M.
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(5) (a) Somei, M.; Inoue, S.; Tokutake, S.; Yamada, F.; Kaneko, C.
Chem. Pharm. Bull. 1981, 29, 726. (b) Somei, M. Chem. Pharm. Bull.
1986, 34, 4109. (c) Mousseron-Canet, M.; Boca, J .-P. Bull. Soc. Chim.
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(6) Coutts, R. T.; Wibberley, D. G. J . Chem. Soc. 1962, 4610.
(7) Reboredo, F. J .; Treus, M.; Este´vez, J . C.; Castedo, L.; Este´vez,
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(8) Cortese, N. A.; Heck, R. F. J . Org. Chem. 1977, 42, 3491.
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(10) Strazzolini, P.; Giumanini, A. G.; Runcio, A.; Scuccato, M. J .
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10.1021/jo035351l CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/18/2003
J . Org. Chem. 2003, 68, 9865-9866
9865

TABLE 1. Lea d -P r om oted Red u ctive Cycliza tion
SCHEME 2
filtration through a small plug of silica gel which afforded
the products as stable crystalline solids.
Isolated from the Cruciferae family of plants,1,14 1-meth-
oxyindole-3-carboxaldehyde 22 has been utilized as a
building block for the synthesis of a number of other
natural products.15 The synthesis of 22 using the lead-
promoted reductive cyclization required only two syn-
thetic steps from commercially available 2-nitromalon-
dialdehyde 20 and occurred in 89% overall yield
(Scheme 2).
In summary, a general, high-yielding method of prepa-
ration of N-hydroxyindoles through the lead-promoted
intramolecular reductive cyclization of o-nitrobenzyl
ketones and aldehydes has been demonstrated. The
reaction conditions are mild and tolerant of a wide range
of functional groups. Increased access to o-nitrobenzyl-
carbonyl substrates through recent advances by Buch-
wald,12 Rawal,16 RajanBabu,17 and others18 and the
present sequence should allow for the generation of
previously inaccessible N-hydroxyindoles in a remarkably
straightforward manner.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O035351L
(11) (a) Bond, C. C.; Hooper, M. Synthesis 1974, 443. (b) Patterson,
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a
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(16) Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org.
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in good to excellent yield (Table 1). Rapid two-step entry
to substituted tricyclic systems of tetrahydrocyclopenta-
[b]indoles (entry 8) and tetrahydrocarbazoles (entry 9)
and the tolerance of a number of important functional
groups have been demonstrated. In all cases, isolation
of the product was achieved in a straightforward, simple
fashion. The insolubles were removed by filtration, fol-
lowed by concentration of the MeOH (or EtOH), and
9866 J . Org. Chem., Vol. 68, No. 25, 2003