One-pot synthesis of polysubstituted indoles from aliphatic nitro compounds under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2007.01.031

Polysubstituted indoles can be prepared directly from functionalized nitroalkanes under very mildly acidic conditions in a simple, one-pot, two-stage procedure.

Full text of DOI:10.1016/j.tetlet.2007.01.031

Tetrahedron Letters 48 (2007) 1809–1811
One-pot synthesis of polysubstituted indoles from aliphatic
nitro compounds under mild conditions
Christopher A. Simoneau, Alexis M. Strohl and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, United States
Received 12 December 2006; accepted 4 January 2007
Available online 10 January 2007
Abstract—Polysubstituted indoles can be prepared directly from functionalized nitroalkanes under very mildly acidic conditions in a
simple, one-pot, two-stage procedure.
Ó 2007 Elsevier Ltd. All rights reserved.
In the hierarchy of biologically privileged structures
none surpasses those containing the indole ring system,
which is prevalent in many bioactive natural products
and medicinally important synthetic compounds.1
Numerous methods have been developed for the synthe-
sis of substituted indoles and indole-containing polycy-
clic ring systems,2 which are core structural elements
in such drugs as indomethacin, vincristine and manz-
amine, as well as in drugs for the treatment of cancer,
circulatory disease, Alzheimer’s, and other neurological
disorders.3
avoids the strongly acidic conditions usually associated
with the Nef reaction.
Our findings extend the range of the Fischer indole syn-
thesis to functionalized aliphatic nitro compounds,
which can be convergently assembled from readily avail-
able building blocks by alkylation or conjugate addition
reactions involving nitro-stabilized carbanions.5
Initially, we envisioned transforming nitroalkanes via
their nitronate anions 3 (Scheme 1) either to the derived
aci-nitro species 4 or the di-protonated species 5, which
might subsequently undergo nucleophilic addition and
N/N interchange to produce arylhydrazones 6. While
the classical Nef reaction of 3 can lead to 6 in two steps
via carbonyl intermediates, it requires concentrated acid
conditions and results in numerous byproducts.6
Complex indoles are frequently synthesized by the clas-
sical Fischer method. Although historically limited to
the condensations of aldehydes or ketones with aryl-
hydrazines, the Fischer synthesis has recently been ex-
tended to the reactions of nitriles and carboxylic acids
in 3-component reactions with arylhydrazines and orga-
nometallic reagents.4 Here we describe an unexpectedly
simple and effective one-pot synthesis of substituted in-
doles 2 from aliphatic nitro compounds 1, Eq. 1, that
In searching for examples of nucleophilic additions to
species like 4 or 5 we discovered several reports of
successful condensations of primary nitroalkanes 7 with
R1
R1
R1
HO
HO
strong
acid
HO
O
O
O
acid
R1
N
N
N
R3
(1 equiv)
R2
+
+ CH3ONa
R2
R2
O2N
R2
3
5
NHNH2
4
ArNHNH
2
2
1
Nef reaction
intermediate
aci-nitro
form
R1
R2
ð1Þ
NHNH
r
R1
1. rt, CH3OH
2. H2SO4 (2 equiv)
A
R3
ArNH-N
N
H
R2
6
2
indoles
Scheme 1. Pathways for nitronate-to-imine interchange.
*
Corresponding author. Tel.: +1 607 255 7360; fax: +1 607 255
6318; e-mail: bg18@cornell.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.031

1810
C. A. Simoneau et al. / Tetrahedron Letters 48 (2007) 1809–1811
thiols (1–3 equiv) in the presence of KOCH3/CH3OH
to form thiolhydroxamate esters 9 (Scheme 2).7 Nitro-
nate 8 formed under such basic conditions might, in
principle, react with arylhydrazines to afford the corre-
sponding arylhydrazones 10. However, we were unable
to obtain 10 by replacing the thiol component with
phenylhydrazine.
tion procedure involves pouring nitronate anion 3 di-
rectly into concentrated aqueous acid, which
suppresses oxime formation via hydrolysis of 5 instead
of 4.
Another control experiment showed that when a
CH3OH solution of valerophenone oxime was heated
with phenylhydrazine (1.1 equiv) and H2SO4 (2 equiv),
indole 2a was produced in an 82% yield. Thus, our data
indicate that nitroalkanes may be converted to indoles
via the corresponding nitronates in one pot using just
mild H2SO4 treatment (2 equiv).8 Under those condi-
tions, aci-nitro, ketone and oxime intermediates are all
convergently transformed into the requisite phenylhyd-
razone, which then undergoes Fischer indole cyclization
under the same gentle conditions. The results summa-
rized in Table 1 with a variety of nitroalkanes and
substituted arylhydrazines demonstrate the scope and
generality of the method.
By contrast, when 1-nitro-1-phenylpentane 1a (R1 = n-
propyl, R2 = Ph) was combined with a solution of phen-
ylhydrazine 7 and NaOCH3 (1.1 equiv each, 1 h, rt), in
CH3OH, then acidified with sulfuric acid (2 equiv) and
heated (90 °C, 24 h), indole 2a was obtained in 68%
yield, Eq. 2.4
NO2
NaOCH3/
Ph
ð2Þ
PhNHNH2
H2SO4
N
H
Ph
2a
1a
The examples in Table 1 indicate that both primary and
secondary nitroalkanes are readily transformed into
polysubstituted indoles. The process is also successful
using ortho, meta and para-substituted arylhydrazines.
As expected, the reaction of nitrocyclohexane 1b with
m-chlorophenylhydrazine formed regioisomeric indoles
2d and 2e in roughly equal amounts.
Under these mildly acidic conditions, protonation of the
nitronate of 1a most likely formed the corresponding
aci-nitro tautomer (e.g., 4) and not the iminium species
(e.g., 5). Both valerophenone and the corresponding
oxime were detected by TLC prior to capture by phen-
ylhydrazine and conversion to indole 2a by Fischer
cyclization. A control experiment omitting phenylhydr-
azine was conducted in which 1a was treated with
NaOCH3 (1.1 equiv) in CH3OH, then with H2SO4
(2 equiv). Both valerophenone (40%) and the corre-
sponding oxime (30%) were obtained, as well as other
unidentified impurities. Such a product distribution is
common in Nef reactions that are conducted under
insufficiently acidic conditions. The standard Nef reac-
Nitroalkane 1d, which has methylene groups in the b
and b0-positions, formed two isomeric indoles 2h and
2i, with the major product 2i arising from the conju-
gated enehydrazine intermediate. Likewise, the reaction
of 1e with p-methoxyphenylhydrazine furnished iso-
meric indoles 2k and 2l in roughly equal amounts. How-
ever, PhNHNH2 reacted with 1e to furnish a single
indole product 2j. This variation in product outcomes
with 1e using different arylhydrazines, although surpris-
ing, may reflect subtle electronic effects of the p-methoxy
substituent on the hydrazone–enehydrazine equilibrium
required for Fischer cyclization.
NOH
SR2
O
O
CH3OK
CH3OH
R2SH
R1CH2NO2
R1CH
N
R1
7
8
9
In conclusion, a one-pot transformation of alphatic
nitroalkanes into polysubstituted indoles has been devel-
oped. The process capitalizes on the versatile behavior
of nitronate anions, which are efficiently protonated
and scavenged by arylhydrazines with multiplex chan-
CH3OK
CH3OH
PhNHNH2
R1CH N-NHPh
10
Scheme 2. Thiohydroxamate esters from nitroalkanes.
Table 1. One-pot synthesis of substituted indoles 2 from nitroalkanes 1
Nitroalkane
ArNHNH2
Indole9 (yield %)
1a 1-Nitro-1-phenylpentane
1b Nitrocyclohexane
PhNHNH2 7
7
2-Phenyl-3-propylindole 2a (68)
Tetrahydrocarbazole 2b (72)10
1b
1b
o-Cl-7
m-Cl-7
8-Chlorotetrahydrocarbazole 2c (66)11
7-Chlorotetrahydrocarbazole 2d (32)11
5-Chlorotetrahydrocarbazole 2e (26)11
6-Methoxytetrahydrocarbazole 2f (66)12
3-Methylindole 2g (50)
1b
1c 1-Nitropropane
1d 2-Nitro-1-phenylbutane
p-OCH3-7
7
7
2-Benzyl-3-methylindole 2h (18)13
2-Ethyl-3-phenylindole 2i (56)14
1e Methyl 4-nitrohexanoate
1e
7
3-Methylindole-2-propionic acid methyl ester 2j (70)
5-Methoxy-3-methylindole-2-propionic acid methyl ester 2k (36)
2-Ethyl-5-methoxyindole-3-acetic acid methyl ester 2l (30)15
3-Allylindole 2m (42)16
p-OCH3-7
1f 5-Nitro-1-pentene
7

C. A. Simoneau et al. / Tetrahedron Letters 48 (2007) 1809–1811
1811
6. (a) Pinnick, H. W. Org. React. 1990, 38, 655; (b) Ballini,
R.; Petrini, M. Tetrahedron 2004, 60, 1017.
neling of products into the Fischer indole reaction path-
way. It can be expected that this convergence of Nef and
Fischer methodology will further extend the utility of
aliphatic nitro compounds beyond the standard Henry,
Michael, and Knoevenagel reactions and will serve as
a practical and useful approach to the important fami-
lies of medicinally active compounds.
7. (a) Keller, T. H.; Yelland, L. J.; Benn, M. H. Can. J.
Chem. 1984, 62, 437; (b) Buchanan, J. B. U.S. Patent
3,787,470, 1974; Chem Abstr. 1974, 80, 82059; (c) Copen-
haver, J. W. U.S. Patent 2,786,865, 1957; Chem Abstr.
1957, 51, 77105.
8. Representative experimental procedure: Synthesis of tetra-
hydrocarbazole 2b: Sodium methoxide (1.0 M in CH3OH,
0.32 mL, 0.32 mmol) was added to a solution of phen-
ylhydrazine (0.32 mmol) in methanol (0.90 mL) under
argon at rt. Nitrocyclohexane (0.29 mmol) was added and
the reaction mixture stirred at rt for 2 h under argon. The
reaction mixture was cooled to 0 °C, acidified with sulfuric
acid (0.59 mmol), then heated in an oil bath at 90 °C for
3 h. After cooling the reaction to 0 °C, the bulk of
methanol was removed in vacuo and the resulting oil was
partitioned between ether (6 mL) and water (3 mL). After
separating the layers, the aqueous phase was extracted
twice more and the combined ether layers were washed
with saturated NaCl (1 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was
purified by silica gel flash column chromatography (8:1
hexanes–ethyl acetate, Rf = 0.3), to afford the known
tetrahydrocarbazole 2b as a white solid (36 mg, 72%).
9. All indoles were prepared following the procedure for 2a
except heating only 1–3 h at 90 °C.
Acknowledgements
This research was supported in part by the US National
Institutes of Health (T32 GM 08500). Support of the
Cornell NMR Facility has been provided by NSF
(CHE 7904825; PGM 8018643) and NIH (RR02002).
Supplementary data
Representative experimental procedures for the synthe-
sis of indoles described in the table, as well as supporting
spectroscopic data. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.01.031.
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Heterocycl. Chem. 1988, 25, 167.
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