Copper-catalyzed direct synthesis of 3-arylindoles

Article abstract of DOI:10.1002/ejoc.201001745

A direct method for the preparation of various 3-arylindoles from their corresponding nitrosoarenes has been developed. Various substituted nitrosoarenes and alkynes were employed to obtain substituted indoles by using a Cu^II-Cu⁰ catalytic system. This is a two-step method that involves annulation of the nitrosoarene and alkyne followed by deoxygenation to give 3-arylindoles. Copyright

Full text of DOI:10.1002/ejoc.201001745

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001745
Copper-Catalyzed Direct Synthesis of 3-Arylindoles
Siva Murru,[a] August A. Gallo,[a] and Radhey S. Srivastava*[a]
Keywords: Nitrosoarenes / Alkynes / Nitrogen heterocycles / Copper / Deoxygenation
A direct method for the preparation of various 3-arylindoles
from their corresponding nitrosoarenes has been developed.
Various substituted nitrosoarenes and alkynes were em-
ployed to obtain substituted indoles by using a CuII–Cu0
catalytic system. This is a two-step method that involves an-
nulation of the nitrosoarene and alkyne followed by deoxy-
genation to give 3-arylindoles.
Introduction
Over the past few decades the area of heterocyclic syn-
thesis has especially benefited from novel copper-facilitated
transformations, as these operations are generally tolerant
to a wide range of functionalities and are therefore appli-
cable to the synthesis of complex molecules. The high sta-
bility and low cost of copper catalysts make them a better
alternative to other expensive metal catalysts. Copper has a
high affinity for polar functional groups such as amines and
alcohols. The redox chemistry of copper has been well es-
tablished and utilized for various organic transformations.[1]
Numerous methods have been reported for the synthesis
of various nitrogen heterocycles using copper catalysts. In-
doles are the most significant heterocycles among all the
known nitrogen heterocycles, because the indole moiety is
one of the most frequently encountered subunits in phar-
macologically active compounds.[2] Various 2- and 3-aryl-
indoles display significant antimicrobial activity against the
Gram-positive microorganism Bacillus cereus.[3] Substituted
indole INF55 is a promising lead in helping a wide range
of antibiotics stay in bacterial cells.[4] Some aryl-substituted
indoles have been implicated in the inhibition of bacterial
histidine kinases.[5a] Some of the pharmaceutically impor-
tant compounds containing a 3-arylindole skeleton are
shown in Figure 1.[5b]
Figure 1. Some pharmaceutically active compounds containing the
3-arylindole skeleton.
detoxifying enzyme from the fungus Sclerotinia sclero-
tiorum.[3,5e]
The synthesis and functionalization of indoles has been
the object of research for over 100 years, and a variety of
well-established classical methods are now available.[6]
Traditional synthetic methods for 3-arylated indoles involve
the metal-catalyzed C-3 arylation or coupling reactions
using Pd catalysis.[7] However, methods for the regioselec-
tive synthesis of 3-arylated indoles are limited. Conse-
quently, there is a continued demand for the development
of general, flexible, and especially regioselective synthetic
methods for this structural moiety. Recently, a few such re-
gioselective methods starting from nitroarenes, aryl hydrox-
ylamines, and nitrosoarenes have been reported by Nicholas
et al.,[8] Ragaini et al.,[5b,9] and by us[10] using various metal
(Ru, Fe, Pd, and Au) catalysts.
Fulvastatin (i) is a member of the statin drug family and
is used for many treatments, and it is also found to exhibit
antiviral activity against hepatitis C.[5c] Substituted 3-(4-
fluorophenyl)-1H-indoles ii were found to act as serotonin
HT2 antagonists.[5d] Another example of an active com-
pound of this class is 4-fluoro-3-phenylindole (iii), which is
an inhibitor of brassinin glucosyltransferase, a phytoalexin
Results and Discussion
In connection with our ongoing research on CuI-cata-
lyzed carbon–heteroatom bond formation to access orga-
nonitrogen compounds[11] and heterocycles,[12] we have ex-
tended our methods to access valuable 3-arylindoles. By
taking cues from our previous report on Cu-catalyzed all-
ylic aminations with nitrosoarenes (Scheme 1) in which for-
mation of N-allylhydroxylamine followed by deoxygenation
[a] Department of Chemistry, University of Louisiana at Lafayette,
Lafayette, Louisiana 70504, USA
Fax: +1-337-482-5677
E-mail: rss1805@louisiana.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001745.
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S. Murru, A. A. Gallo, R. S. Srivastava
SHORT COMMUNICATION
occurs to give N-allylamine,[13] we envisaged that the forma- Table 1. Preparation of 3-aryl-substituted indoles from nitroso-
arenes and alkynes.[a]
tion of N-hydroxyindole followed by deoxygenation could
lead to 3-arylindoles (Scheme 2).
Scheme 1. Cu-catalyzed allylic amination from nitrosoarenes and
olefins.
As shown in Scheme 2, we propose the synthesis of 3-
arylindoles through ring annulation starting from the corre-
sponding arylacetylenes and nitrosoarenes followed by de-
oxygenation using our copper-catalyzed protocol developed
for allylic amination, which involves the use of catalytic
amounts of CuCl2·2H2O (0.2 equiv.) and Cu powder
(0.6 equiv.) to produce a CuI species in situ.[14]
Scheme 2. Formation of 3-arylindole by annulation and deoxygen-
ation.
We tested the initial reaction of nitrosobenzene (1 mmol)
with phenylacetylene (5 mmol) using CuCl2·2H2O
(0.2 mmol) and Cu powder (0.6 mmol) in dioxane at
100 °C. Nitrosobenzene was added slowly over a period of
4 h by using a syringe pump and the reaction was then con-
tinued. The reaction was complete in 6 h, and we observed
the formation of 3-phenylindole, which was isolated in 62%
yield. In addition to 3-phenylindole, azoxybenzene and ani-
line were formed as side products, which were identified by
GC–MS analysis.
When the solvents were surveyed at the same tempera-
ture, the reaction was found to proceed more efficiently in
1,4-dioxane than in other solvents like THF, MeCN, DME,
and toluene. Lowering the temperature led to longer reac-
tion times. With the established optimized conditions, we
next set out to determine the scope and practicality of the
method through the synthesis of substituted indoles. Ni-
trosoarenes 2–9 prepared from the corresponding anilines
by using a catalytic hydrogen peroxide oxidation method[15]
were converted smoothly into their corresponding 3-arylin-
doles 2a–9c in shorter reaction times. As shown in Table 1,
a variety of substituents are well tolerated. para-Substituted
nitrosoarenes containing electron-withdrawing groups work
[a] Reaction conditions: 1 (1 mmol), a (5 mmol), CuCl2·2H2O
(0.2 mmol), Cu powder (0.6 equiv.), dioxane (8 mL), 100 °C, 5 h.
[b] Isolated yield. [c] Reaction continued up to 20 h. [d] Com-
pounds 1d and 1dЈ were isolated as a mixture. Compound 1e could
not be isolated. [e] GC yield.
more efficiently than nitrosoarenes containing electron-do- alkynes b, d, and e either were less efficient or no reaction
nating substituents. This observation is similar to our pre- was observed. Alkyne b provided corresponding indoles 1b,
vious report on an Au-catalyzed approach.[10]
5b, and 9b in moderate yields with nitrosobenzenes 1, 5,
A range of alkynes such as phenylacetylene (a), 1-phenyl- and 9, respectively, whereas alkyne d yielded products 1d
propyne (b), 4-ethynyltoluene (c), 4-phenyl-3-butyn-2-ol (d), and 1dЈ. Formation of 1d is due to the oxidation of the
and diphenylacetylene (e) were tested with nitrosoarenes 1, secondary alcohol present in alkyne d to the corresponding
5, 8, and 9. Terminal alkynes a and c were found to react ketone. Unfortunately, the reaction of nitrosobenzene with
well, and the corresponding 3-arylindoles were isolated in diphenylacetylene (e) gave less than 5% yield, and the prod-
good yields up to 71%. reactions involving nonterminal uct was confirmed by GC–MS analysis.
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Copper-Catalyzed Direct Synthesis of 3-Arylindoles
Based on our previous reports on allylic amination and
indole formation,[10,11g] this catalytic process must be in-
volved in the formation of N-hydroxyindole, which will be
deoxygenated further to give 3-arylindole, and this same
finding was confirmed by a controlled experiment starting
from N-hydroxyindole. The in situ generated CuI species
(Scheme 3, Equation 1) from CuII and Cu0 is responsible
for deoxygenation of N-hydroxyindole (Scheme 3, Equa-
tion 2), which in turn is converted into CuII and the cyclic
process continues.
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Scheme 3. Deoxygenation of N-hydroxyindole by in situ generated
CuI species and its regeneration from the corresponding Cu0 and
CuII salts.
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species generated from the redox couple of Cu0 powder and
CuII salt. Similar deoxygenation by CuI from N-allylhydrox-
ylamine was observed and proved by Lau et al.[16]
[5]
Conclusions
[6]
In conclusion, we have developed a direct Cu-catalyzed
protocol for the synthesis of 3-arylindoles. The nitroso-
arenes afforded the corresponding indoles through annu-
lation followed by deoxygenation in good to moderate
yields. Thus, with the appropriate choice of substrates, dif-
ferently substituted indoles can be obtained.
[7]
[8]
Experimental Section
A Schlenk flask was charged with CuCl2·2H2O (0.2 equiv.), Cu
powder (0.6 equiv.), dioxane (5 mL), and phenylacetylene (a;
5 equiv.). The flask was placed in a preheated oil bath at 100 °C,
and then a solution of nitrosobenzene 1 (1 mmol) in dioxane
(5 mL) was added slowly with the help of a syringe pump over a
period of 4 h under a positive pressure of nitrogen. The reaction
mixture was cooled and filtered through Celite using diethyl ether.
The solvent was reduced under vacuum, and further purification
of the crude product was achieved by column chromatography
(hexane/ethyl acetate).
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Supporting Information (see footnote on the first page of this arti-
1
cle): H NMR spectroscopic data and copies of the spectra.
Acknowledgments
We are grateful for the financial support of the Louisiana Board
of Regents [LEQSF(2009-12)-RD-B-08]. We are also thankful for
the NMR (500 MHz) facility of the Department of Chemistry,
Louisiana State University.
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S. Murru, A. A. Gallo, R. S. Srivastava
SHORT COMMUNICATION
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Received: December 30, 2010
Published Online: March 4, 2011
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