Synthesis of Indoles by Palladium-Catalyzed Reductive Cyclization of β-Nitrostyrenes with Carbon Monoxide as the Reductant

Article abstract of DOI:10.1002/ejoc.201500933

An efficient catalytic cyclization of β-nitrostyrenes to indoles was developed. The reaction was applied to the synthesis of 3-arylindoles and 2-alkylindoles. Given that in the latter case the starting β-nitrostyrenes can be easily obtained by a Henry reaction, the present method allows indoles to be obtained in a two-step sequence starting from cheap reactants.

Full text of DOI:10.1002/ejoc.201500933

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500933
Synthesis of Indoles by Palladium-Catalyzed Reductive Cyclization of
β-Nitrostyrenes with Carbon Monoxide as the Reductant
Francesco Ferretti,[a] Mohamed A. EL-Atawy,[a,b] Stefania Muto,[a] Mohamed Hagar,[a,b]
Emma Gallo,[a] and Fabio Ragaini*[a]
Keywords: C–H activation / Carbonylation / Palladium / Nitrogen heterocycles / Nitroalkenes
An efficient catalytic cyclization of β-nitrostyrenes to indoles
was developed. The reaction was applied to the synthesis of
3-arylindoles and 2-alkylindoles. Given that in the latter case
the starting β-nitrostyrenes can be easily obtained by a
Henry reaction, the present method allows indoles to be ob-
tained in a two-step sequence starting from cheap reactants.
Introduction
The indole skeleton is central to many biologically active
pharmaceutical drugs and natural alkaloids,[1] and its syn-
thesis continues to attract the attention of many research-
ers.[2] Many syntheses of indoles are catalyzed by transition
metals, but in most cases they require substrates bearing
two suitable functional groups ortho to each other, and the
preparation of these starting materials often requires several
synthetic steps. An example relevant for this work is the
reductive cyclization of o-nitrostyrenes to indoles catalyzed
by Pd/phosphine/SnCl2,[3] Pd/phosphine,[4] and Pd/phen-
anthroline[5] systems. Several years ago, we investigated the
possibility of using β-nitrostyrenes as aminating agents for
olefins by employing a protocol previously devised for
nitroarenes[6] and based on the use of a ruthenium/bis(aryl)-
acenaphthenequinonediimine (Ar-BIAN) catalyst. The aim
was to obtain a vinylic amine that, after tautomerization,
could be easily hydrolyzed to result in the overall introduc-
tion of an NH2 group in the allylic position (Scheme 1,
path A). Despite some efforts, we never observed the forma-
tion of the allylic amine. A mixture of products was ob-
tained, among which 2-methylindole was always present
(Scheme 1, path B).
Scheme 1. Palladium- and ruthenium-catalyzed cyclization of β-
methyl-β-nitrostyrene.
consequent difficulty in its elimination from the product.
No method has been reported for the efficient deoxy-
genative cyclization of 1a or related β-nitrostyrenes lacking
additional substituents in the α position.[8] The possibility
of conducting the reaction under catalytic conditions in-
trigued us, as the use of β-nitrostyrenes as substrates in ind-
ole synthesis is very interesting. In fact, in most cases, they
can be easily prepared from an aldehyde and a nitroalkane
by the Henry reaction, which overcomes problems associ-
ated with the complex preparation of the substrates.
The indole yield was low with the use of a catalytic sys-
tem based on ruthenium, but better results were obtained
by employing [Pd(Phen)2][BF4]2 in the presence of an excess
amount of 1,10-phenanthroline (Phen). This system was
previously reported to give very good results in other carb-
onylation reactions, such as the reductive carbonylation of
nitroarenes[9] and several types of inter- and intramolecular
reductive cyclization reactions of nitroarenes.[5b,10]
The deoxygenative cyclization reaction of β-nitrostyrenes
to indoles has been reported to occur with P(OEt)3 as the
reducing agent only if the α position of the styrene bears
a substituent, most commonly a second aryl group.[7] The
reaction is only of little interest owing to the need for a
very large excess amount of the trialkylphosphite and the
[a] Dipartimento di Chimica,
Via Golgi 19, 20133 Milano, Italy
E-mail: fabio.ragaini@unimi.it
http://eng.chimica.unimi.it/
[b] Chemistry Department, Faculty of Science,
Alexandria University,
Results and Discussion
Encouraged by these preliminary results, we optimized
the reaction conditions by employing commercially avail-
P. O. 426 Ibrahemia, Alexandria 21321, Egypt
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500933.
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Synthesis of Indoles by Palladium-Catalyzed Reductive Cyclization
able trans-β-methyl-β-nitrostyrene (1a) as a model substrate
(Scheme 2, see also Table S1 in the Supporting Infor-
mation). The main results of the optimization study are the
following: (1) After an initial screening of solvents (i.e.,
DMF, THF, toluene), CH3CN was identified as the best
solvent. (2) The reaction does not need any co-catalyst to
proceed, but the addition of an organic base leads to an
enhancement in the activity of the system and to an in-
crease in indole selectivity. 1,4-Diazabicyclo[2.2.2]octane
and triethylamine were tested, and the latter gave higher
selectivities. The concentration of the base was preliminarily
optimized, and the best results were obtained with a Et3N
concentration of 0.17 m. (3) The selectivity for indole is al-
most independent of the CO pressure between 20 and
40 bar (1 bar = 100 kPa); however, the reaction is strongly
inhibited over 40 bar, whereas the indole selectivity de-
creases at pressures lower than 20 bar. (4) The selectivity is
almost constant in the range of 150 to 170 °C but decreases Scheme 3. Pathways for the formation of side products for sub-
strate 1a.
at lower temperatures. (5) Complete conversion is reached
after 2.5 h, after which only decomposition of the product
occurs. (6) The amount of phenanthroline was also opti-
tion was performed in DMF at 110 °C and 1 bar overpres-
mized, and the best results were obtained with a Phen con-
sure of CO for 3 h; excellent yields were obtained. We re-
centration of 0.012 m.[11]
produced the reaction by employing 1,1-diphenyl-2-nitro-
ethene (1b, Scheme 4) as the substrate and obtained a very
similar result (82% conversion and 92% indole selectivity
in our hands, instead of 97% yield as reported; Table S2,
entry 1).[15] However, the previously reported conditions ap-
pear to be suitable only for the very limited class of α-aryl-
Scheme 2. Palladium-catalyzed reductive cyclization of 1a by CO.
β-nitrostyrenes, and upon using 1a as the substrate under
the same experimental conditions, both the conversion and
selectivity were very poor (Table S2, entry 2; indole 2a yield
= 6.8%). By using our optimized conditions, excellent re-
With the use of the optimized conditions, we were able
to completely convert 1a into 2a with 88% selectivity (mea-
sured by gas chromatography; Table S1, entry 5) and to iso-
sults were obtained with both substrates 1a and 1b
late the product[12] with just a 2% loss with respect to the
(Table 1). The use of a different PdII precursor {Pd(OAc)2
GC yield.
or [Pd(Phen)2][BF4]2} did not affect the system perform-
ance (Table S2, entries 4 and 5).
We previously mentioned that cyclization of 1a to 2a by
using P(OEt)3 as the reductant is not known. To test if ind-
ole could be obtained by this methodology to some extent,
we heated 1a at 150 °C in neat P(OEt)3. A mixture of prod-
ucts was obtained, among which the indole was not present
(GC analysis, detection limit Ͻ1%).
During the optimization study, we were able to identify
by GC–MS some of the side products of the reaction. Un-
der the optimized conditions, their amount was very low
and it was not possible to quantify them. The likely path-
Scheme 4. Palladium-catalyzed reductive cyclization of 1b.
ways for the formation of these side products are reported
The difference in reactivity between substrates 1a and 1b
in Scheme 3. Compounds 7 and 8 may be derived from di- is due to two reasons: the higher reduction potential of β-
merization of a radical anionic intermediate;[13] the dimer substituted β-nitrostyrenes[16] relative to β-nitrostyrene (1i)
is then further reduced by carbon monoxide. The formation owing to tilting of the nitro group out the olefin plane, and
of 8 was previously reported to occur by reduction of the the presence of a more extended π system in 1b. In fact,
β-nitrostyrene with aqueous TiCl3.[13] Even if the formation given that reduction of the nitro group should involve initial
of the above-mentioned side products can be almost sup- single-electron transfer from the metal to the nitroalkene
pressed under the optimized conditions, some unidentified with the formation of a radical anion[17] (A in Scheme 5), a
high-boiling side products still form to some extent.
high degree of conjugation of the π system should favor
A few years ago, Hsieh and Dong reported a study on radical delocalization and thus the subsequent formation of
the palladium-catalyzed reductive cyclization of α-aryl-β- nitroso compound B, which is proposed to be the aminating
nitrostyrenes.[14] Pd(OAc)2 was used as the catalyst, the species, by analogy with what occurs in the cyclization of
molar ratio of cat/Phen/substrate was 1:2:50, and the reac- o-nitrostyrenes.[18] Eventually, hydroxyindole C, formed by
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F. Ragaini et al.
SHORT COMMUNICATION
Table 1. Scope of the reaction.[a]
amination, is reduced to the indole by carbon monoxide.
The formation of the radical anion allows easy rotation
around the double bond and explains why good selectivities
in indole could be obtained even upon employing trans-β-
nitrostyrenes that are selectively formed by the Henry reac-
tion. The presence of a second aryl group in 1b is expected
to favor the cyclization step, because it maximizes the
chances of proper orientation of the nitroso and phenyl
groups, in accord with the observation that 1b gave the
highest selectivity among all tested nitrostyrenes (see
above).
Scheme 5. Proposed reaction mechanism.
The scope of the reaction was then explored (Table 1).
The best results were obtained for substrate 1b owing to the
presence of the phenyl ring, as mentioned above. For other
substrates lacking an aryl group in the α position, the pres-
ence of a substituent in the β position was fundamental for
indole formation, and its absence (i.e., for 1i) resulted in
low reactivity and the formation of palladium black. In this
case, an insoluble solid derived from polymerization of the
starting β-nitrostyrene[19] was found as the main product of
the reaction, whereas 3,4-diphenylpyrrole was detected by
GC–MS as the major product in solution. Both electron-
withdrawing and electron-donating substituents can be
present in the para position of the aryl ring. However, as
expected, the presence of strongly electron-releasing groups,
such as methoxy (i.e., compound 1f) and even more dieth-
ylamino (i.e., compound 1k), led to reduced reactivity be-
cause of slower reduction of the nitro group.[10c]
It is especially notable that good results were obtained
with substrate 1e. Indeed, azaindoles are very important
molecules.[20] Cyclization of the nitroso intermediate is an
electrophilic process, and attack on the electron-poor 2- or
4-position of the pyridine ring should be disfavored. The
80% regioselectivity in 2-methyl-1H-pyrrolo[2,3-b]pyridine
(2e), the most disfavored product from an electronic point
of view, may be ascribed to partial coordination of the sub-
strate to the metal center. On the contrary, reductive cycli-
zation of chloro derivative 1h is not regioselective.
[a] Reaction conditions: [Pd(Phen)2][BF4]2 = 1.10ϫ10–2 mmol, mol
ratio substrate/Phen/[Pd(Phen)2][BF4]2 = 100:16:1, 150 °C, 20 bar
of CO, [Et3N] = 0.17 m, CH3CN (15 mL), 2.5 h. [b] Determined
by GC analysis. [c] Yield of isolated product. [d] Determined by
1H NMR spectroscopy by using anisole as an internal standard.
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Synthesis of Indoles by Palladium-Catalyzed Reductive Cyclization
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Conclusions
The reaction described herein enables the synthesis of a
wide range of indoles from easily accessible and often com-
mercially available aldehydes and nitroalkanes. Given that
nitroalkanes are much more difficult to reduce than nitro-
alkenes, it is conceivable that the Henry condensation and
the following cyclization could be performed in one pot.
Preliminary results showed that this is indeed the case, but
selectivities were poor because of difficulties in finding a
solvent mixture that was suitable for both the Henry con-
densation and the following cyclization. Further efforts will
be done in this direction in the future.
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Acknowledgments
We acknowledge the Ministero dellЈUniversità e della Ricerca
(MIUR) for financial support. F.F. thanks the University of Mil-
ano for a postdoctoral fellowship.
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Received: July 15, 2015
Published Online: August 3, 2015
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