A new one-pot synthesis of polysubstituted indoles from pyrroles and β-nitroacrylates

Article abstract of DOI:10.1002/adsc.201000965

The reaction of β-nitroacrylates with pyrroles, under solvent- and catalyst-free conditions, allows the formation of Friedel-Crafts adducts which, after in situ treatment with Amberlyst 15 in isopropyl alcohol under reflux, provide polysubstituted indoles, via a benzannulation reaction, in a one-pot process. Copyright

Full text of DOI:10.1002/adsc.201000965

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DOI: 10.1002/adsc.201000965
A New One-Pot Synthesis of Polysubstituted Indoles from
Pyrroles and b-Nitroacrylates
Alessandro Palmieri,a,* Serena Gabrielli,a Daniela Lanari,b Luigi Vaccaro,b
and Roberto Ballinia,*
a
“Green Chemistry Group,” School of Science and Technology, Chemistry Division, Universitꢀ di Camerino, via S.
Agostino 1, 62032 Camerino (MC), Italy
Fax : (+39)-0737-402-297; phone: (+39)-0737-402-270; e-mail: alessandro.palmieri@unicam.it or roberto.ballini@unicam.it
Laboratory of Green Synthetic Organic Chemistry, CEMIN – Dipartimento di Chimica, Universitꢀ di Perugia, Via Elce di
b
Sotto 8, 06123 Perugia, Italy
Received: December 22, 2010; Revised: March 21, 2011; Published online: June 16, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201000965.
Abstract: The reaction of b-nitroacrylates with pyr-
roles, under solvent- and catalyst-free conditions,
allows the formation of Friedel–Crafts adducts
which, after in situ treatment with Amberlyst 15 in
isopropyl alcohol under reflux, provide polysubsti-
tuted indoles, via a benzannulation reaction, in a
one-pot process.
stances, the development of new strategies for the
synthesis of indoles from pyrroles, via benzannulation
reactions, remains of great interest.
Recently, we have carried out a variety of studies in
which benzene derivatives have been prepared start-
ing from aliphatic nitro compounds.[5] In the mean-
time, b-nitroacrylates have demonstrated a great ver-
satility as key building blocks for the preparation of a
variety of molecular structures.[6]
Keywords: indoles; b-nitroacrylates; one-pot syn-
thesis; pyrroles; solid-supported reagents (SSR)
Based on these experiences, herein we present an
innovative, mild and efficient method for the one-pot
synthesis of polysubstituted indoles starting from pyr-
roles 1 and ketal-functionalized b-nitroacrylates 2.[7]
As reported in Scheme 1, the starting compounds 1
Indoles are the key subunits of a variety of biological- and 2 quickly react (with the exception of the reaction
ly active molecules and, probably, are the most ubiq- between 1d and 2a), under solvent- and catalyst-free
uitous heterocycles in nature.[1] Substituted indoles conditions, giving the intermediate 3 via a Friedel–
are referred to as “privileged structures” in drug dis- Crafts reaction. Then, in situ acidic treatment of the
covery because of their capacity to bind to many re- formed adduct 3, under heterogeneous conditions
ceptors with high affinity.[2] For many years, the syn- (Amberlyst 15) in refluxing 2-propanol,[8] favours the
thesis of indoles has been a major area of focus for or- aromatization of the former b-nitroacrylate moieties,
ganic chemists and numerous methods for their prep- allowing the one-pot synthesis of indoles 4 in consis-
aration have been developed.[3] In this context, the as- tent overall yields (50–74%).
sembling of the indole core starting from benzene
The generality of our procedure is demonstrated by
derivatives represents the prevalent procedure. How- the variety of indoles that can be obtained (Table 1)
ever, these approaches often show important draw- in which, by the appropriate choice of the starting
backs, such as the need for hard reaction conditions materials, several substituents can be introduced in
(very low or high temperature), very strong bases or both the indole and the phenyl rings. As evidenced in
there are the problems of regioselectivity.
Table 1, our methodology works well with 2- and 3-
Alternatively, indoles can be prepared by benzan- substituted pyrroles, as well as with 2,3-disubstituted
nulation of pyrroles but this approach has been less ones. Moreover, thanks to the mild reaction condi-
explored and, in this context, just a few elegant prepa- tions a variety of important functionalities, such as
rations have been reported.[3,4] Nevertheless, the latter ester, cyano and chlorine, can be preserved.
procedures also evidence relevant drawbacks such as
Of particular interest is the product 4cf, obtained in
limited generality, modest scalability and the need for 60% overall yield (Scheme 2), by the reaction of pyr-
toxic solvents or dry conditions. Under these circum- role 1c with methyl b-nitroacrylate 2f. In fact, 4cf was
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Alessandro Palmieri et al.
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Scheme 1. General pathway to the synthesis of indole derivatives 4.
Scheme 2. A-FABP inhibitors.
successfully used as key building block for the synthe- action E generates the bicycle intemediate F that,
sis of adipocyte fatty-acid binding protein (A-FABP) after losing a molecule of both ethylene glycol and ni-
inhibitors.[9]
trous acid, gives the target indoles 4.
A plausible mechanism for the one-pot synthesis of
In conclusion, our method represents an innovative,
4, could be rationalized (Scheme 3) by the initial Frie- chemoselective procedure for the synthesis of a varie-
del–Crafts reaction between the pyrroles 1 and b-ni- ty of polysubstituted indoles from pyrroles, since
troacrylates 2, affording the adduct 3, via the inter- these targets can be easily obtained in a one-pot way
mediate A. Then, in situ treatment of 3 with Amber- and under very mild conditions, affording consistent
lyst 15 (cationic macromolecular ion-exchange resin) overall yields of the products and tolerating the pres-
gives the protonated 1,3-dioxolane intermediate B, ence of important functionalities. Moreover, our ap-
which leads, through the intermediate C, to the oxoni- proach can be considered of interest from the eco-sus-
um cation D. Finally, a subsequent Friedel–Crafts re- tainability point of view because just an eco-friendly
solvent[8] is employed and, thanks to the nature of the
solid-supported reagents, even the classical aqueous
work-up can be avoided, since the crude product 4
Table 1. One-pot synthesis of indole derivatives 4.
1[a]
2
t1 [h] t2 [h] Yield [%][c]
of 4
can be directly charged on
column, after filtration of the Amberlyst 15, for the
final purification.
a chromatographic
R
R1
R2
1a Et H
1b H
1a Et H
2a Me
2a Me
2b Ph
2c Et
2b Ph
2c Et
2d H
0.5
2
1
1.5
5
4aa
4ba
4ab
4cc
4cb
4bc
4bd
4bb
4be
4da
4ea
60
70
59
61
50
61
68
57
74
58
53
H
0.5
0.5[b]
1[b]
2
Experimental Section
1c
1c
-(CH2)4-
-(CH2)4-
H
H
H
H
2
2
1.5
1
1b H
1b H
1b H
1b H
General Procedure for the Preparation of Indoles 4
2
A mixture of 2 (1 mmol) and 1 (from 1.2 to 2 mmol, see
Table 1), after stirring under solvent-free conditions for the
appropriate time (t1), led to the formation of the intermedi-
ate 3. Then, in situ addition of 2-propanol (12 mL) and heat-
ing at reflux, followed by addition of Amberlyst 15 (1 g) and
stirring for the needed time (t2), gave the crude compound 4
that can be directly charged on a chromatographic column,
after filtration of the Amberlyst 15, for the final purification
(cyclohexane:EtOAc=95:5).
2b Ph
3
3
2e Ph(CH2)2 5.5
G
3.5
3
3
1d H p-NCC6H4 2a Me
19[b]
3[b]
1e
H
Cl
N
[a]
1.2 mmol were used for pyrroles 1a, 1c, 1d and 1e; while
2 mmol were used for pyrrole 1b.
The reaction was performed at 508C.
[b]
[c]
Yield of pure, isolated product.
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Adv. Synth. Catal. 2011, 353, 1425 – 1428

A New One-Pot Synthesis of Polysubstituted Indoles from Pyrroles and b-Nitroacrylates
Scheme 3. Proposed reaction mechanism for the formation indole derivatives 4.
Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Spring-
Acknowledgements
er, J. Hirhfield, J. Med. Chem. 1988, 31, 2235–2246;
b) D. A. Horton, G. T. Bourne, M. L. Smythe, Chem.
Rev. 2003, 103, 893–930.
We gratefully acknowledge financial support from the
MIUR-Italy (National Project “Sintesi organiche eco-sosteni-
bili mediate da nuovi sistemi catalitici”) and FIRB National
Projects “Metodologie di nuova generazione nella forma-
zione di legami carbonio-carbonio e carbonio-eteroatomo in
condizioni eco-sostenibili” and “Metodologie di sintesi inno-
vative e sostenibili per processi di attivazione del legame C
H”. We also wish to thank the Universities of Camerino and
Perugia for financial support.
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