Bronsted acid catalyzed cascade reactions of 2-[(2-Aminophenyl) ethynyl]phenylamine derivatives with aldehydes: A new approach to the synthesis of 2,2′-disubstituted 1 H,1′ H -3,3′-biindoles

Article abstract of DOI:10.1021/ol500401p

An unusual Bronsted acid catalyzed cascade reaction of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aryl(heteroaryl)aldehydes to afford an efficient alternative entry into 2,2′-disubstituted-1H, 1′H-3,3′-biindoles under metal-free conditions is reported.

Full text of DOI:10.1021/ol500401p

Letter
pubs.acs.org/OrgLett
Brønsted Acid Catalyzed Cascade Reactions of
2‑[(2‑Aminophenyl)ethynyl]phenylamine Derivatives with
Aldehydes: A New Approach to the Synthesis of 2,2′-Disubstituted
1H,1′H‑3,3′‑Biindoles
Antonio Arcadi,*,† Marco Chiarini,‡ Gaetano D’Anniballe,§ Fabio Marinelli,† and Emanuela Pietropaolo†
†Dipartimento di Scienze Fisiche e Chimiche, Universita
̀
di L’Aquila, Via Vetoio 67010 Coppito (AQ), Italy
di Teramo,Via Lerici 1, 64023, Mosciano Sant’Angelo
‡Facolta
̀
di Bioscienze e Tecnologie Agro-alimentari e Ambientali, Universita
̀
(Te), Italy
§Research Center, Dompe
́
s.p.a., via Campo di Pile, 67100 L’Aquila, Italy
S
* Supporting Information
ABSTRACT: An unusual Brønsted acid catalyzed cascade reaction of 2-[(2-
aminophenyl)ethynyl]phenylamine derivatives with aryl(heteroaryl)aldehydes to
afford an efficient alternative entry into 2,2′-disubstituted-1H,1′H-3,3′-biindoles
under metal-free conditions is reported.
Scheme 1
he preparation of different products from the same
Tstarting materials by variation of the reaction parameters
still represents a significant challenge in organic synthesis.1
Recently, we reported a new one-pot approach to construct
11H-indolo[3,2-c]quinoline scaffolds 2 through a gold-
catalyzed reaction of 2-[(2-aminophenyl)ethynyl]phenylamine
derivatives 1 with aldehydes.2 Due to the peculiar abilities of
gold(III) and gold(I) species as π-acids for carbophilic
activation, the synthesis of indole derivatives from the already
available 2-alkynylanilines offered many advantages.3 Never-
theless, we decided to explore the behavior of the same starting
materials under Brønsted acid catalysis. It has been shown that
some reactions can be catalyzed by gold catalysts and protons.4
Conversely, another reaction was shown to be catalyzed by
protons only.5 A valuable tool for the selective activation of an
individual functional group in the cases of bi- or polyfunctional
substrates is represented by the choice of a suitable catalyst for
the desired transformation.6
Indeed, under Brønsted acid catalysis the reaction of 2-[(2-
aminophenyl)ethynyl]phenylamine derivatives 1 with alde-
hydes can achieve the rapid construction of 2,2′-disubstituted-
1H,1′H-3,3′-biindoles 3 in an easy and efficient manner
through a different sequential pathway (Scheme 1).
The synthesis of 3,3′-biindole scaffolds is of great interest
due to their presence in natural products with very promising
biological activities7 as well as in pharmaceuticals8 and
functional materials.9 A variety of syntheses of 3,3′-biindoles
have been developed.10 In particular, palladium-catalyzed
Suzuki−Miyaura cross-coupling of 3-indolyl halides with 3-
indolyl boronates emerged as an efficient tool to build up 3,3′-
biindolys.11 Moreover, the sequential Masuda borylation/
Suzuki coupling of N-protected 3-iodoindoles has successfully
been applied to the synthesis of 3,3′-biindoles of special interest
due their antifungal, antimicrobial and cytotoxic activities.12
However, great efforts have been directed to avoid the
prefunctionalization of indoles to their halides of boronic
derivatives. Then, the development of alternative approaches to
the synthesis of the target 3,3′-biindoles through sequential
reactions avoiding costly and time-consuming functionalization
processes, including purification of the intermediates or
additional steps of protection/deprotection of functional
groups, is still spurring many research activities. Gold-,13
Received: February 10, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Substrate Scope
Reaction conditions: 1 equiv of the starting alkyne 1 was reacted in CH3CN at reflux under the presence of 3 equiv of aldehyde and a catalytic
amount of HCl (a drop of HCl ACS reagent, 37%).
iron-,14 and palladium-catalyzed15 oxidative homocouplings of
indoles via direct C−H cleavage have been reported.
Furthermore, 3,3′-biindolyl products can be isolated as main
or side products in transition-metal-catalyzed cyclizative
homodimerization of 2-alkynylaniline derivatives.11,16
We wish to report herein our preliminary results on a new
alternative approach to the synthesis of valuable 3,3′-biindoles 3
through a metal-free cascade process. This new protocol makes
use of the already available 2-[(2-aminophenyl)ethynyl]-
phenylamine derivatives 1 and inexpensive aryl(heteroaryl)-
aldehydes as starting materials in the presence of a catalytic
amount of HCl.
The generality of this transformation was examined, and the
results are summarized in Table 1.
A variety of aryl aldehydes bearing both electron-donating
and electron-withdrawing substituents were successfully used to
synthesize the desired 3,3′-biindolyls in moderate to good
yields. Lower yields were observed with ortho-substituted aryl
aldehydes (Table 1, compare entries 1 and 2). It is very likely
that the increase of steric hindrance is detrimental to the
formation of the 3,3′-biindoles. The reaction also proceeded
well when the substituents were changed on the aryl rings of
the starting 2-[(2-aminophenyl)ethynyl]phenylamine 1 to give
the more challenging unsymmetrically substituted 3,3′-
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Organic Letters
Letter
biindoles 3k−o (Table 1, entries 11−15). Interestingly, the
procedure was compatible with the presence of 1H-indole-3-
carbaldehyde, which achieved the formation of the tetraindole
derivative 3p under the usual reaction conditions (Scheme 2).
promoted iminium ion−alkyne generating the corresponding
derivative 620 (path a) or by means of an intramolecular ene
reaction with inverse electron demand to give the intermediate
7 (path b).
Although benzazetine derivatives are poorly studied com-
pounds,21 their formation as unstable intermediates was
postulated.22 Intermolecular ene reactions with inverse electron
demand of alkynes with iminium salts have also been
reported.23 A control experiment was conducted to gain
more information on the reaction mechanism (Scheme 4).
Scheme 2
Scheme 4
Due to the synthetic difficulties, the synthesis of cyclic indole
tetramers has been rarely reported.17 The cyclic tetraindole
skeleton is recognized as a π-extended variant of porphyrinogen
and is an attractive scaffold for applications in the field of
material science to afford electron-conducting and optoelec-
tronic devices.
The detailed mechanism of this unprecedented cascade
process is not completely clear at this stage. On the basis of
previous studies, the intramolecular hydroamination of 1 to
give the corresponding 2-substituted indole which in turn reacts
with aldehydes leading sequentially to 11H-indolo[3,2-c]-
quinoline scaffolds 2 results only as a consequence of the π-
acid activation of the carbon−carbon triple bond. Conversely, it
was envisaged that under Brønsted acid catalysis the reaction of
1 with aldehydes should lead selectively to the formation of the
iminium ion 4 (Scheme 3).
Scheme 3
(4-Methoxyphenyl)-(2-p-tolyl-1H-indol-3-yl)methanone 9
was isolated in 30% yield after a prolonged time from the
incomplete reaction of the 2-p-tolylethynylphenylamine 8 (the
starting 2-alkynylaniline derivative 8 was recovered in 30%
yield) with p-methoxybenzaldehyde.
The formation of compound 9 could result from the
following sequential cascade process involving (a) condensa-
tion reaction of 8 with 4-methoxybenzaldehyde, (b) regiose-
lective exocyclic water-promoted iminium ion−alkyne cycliza-
tion, (c) tautomerization, and (d) aromatization. Interestingly,
the optimization of this unusual water-promoted iminium ion−
alkyne cyclization of 2-alkynylaniline derivatives promises to
accomplish a more sustainable approach to 2-aryl-3-acylin-
doles.24 The difference in the reaction outcome between
alkynes 8 and 1 shows the key role of the tethered amino
group. Disubstituted alkynes have been reported to undergo
annulation reaction with in situ generated iminium ions only
with the assistance of nucleophiles which intimately participate
in the transition state of these cyclization reactions.16 Then,
even if the intramolecular ene reaction with inverse electron
demand cannot be excluded, the smooth formation of the 3,3′-
biindole scaffolds could be supported by the free NH2 action as
an intramolecular nucleophilic promoter in the iminium ion−
alkyne cyclization. A more in-depth investigation is needed to
Iminium ion−alkyne cylization-type reactions play a pivotal
role for constructing nitrogen-containing cyclic compounds.18
Both exocyclic and endocyclic nucleophile-promoted iminium
ion−alkyne cyclization reactions have been reported.19 In our
cases, the formation of the 3,3′-biindoles under Brønsted acid
catalysis conditions rules out the endo-mode cyclization of the
in situ generated iminium ion to give the cation 5 (path c). The
formation of this latter intermediate would lead after
deprotonation/oxidative aromatization reactions to the for-
mation of the 11H-indolo[3,2-c]quinoline scaffolds under
alternative metal-free conditions. Therefore, regioselective 5-
exo-dig cyclization of 4 could occur both via nucleophile-
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Letter
(11) Duong, H. A.; Chua, A.; Huleatt, P. B.; Chai, C. L. L. J. Org.
Chem. 2008, 73, 9177−9180.
fully understand the complex mechanism involving the
formation of the 2,2′-disubstituted-1H,1′H-3,3′-biindoles 3.
In summary, a new approach to the construction of a 3,3′-
biindolyl backbone via Brønsted acid catalysis has been
developed. In this operationally simple procedure, four
chemical bonds are formed leading to the formation of two
indole rings through unprecedented sequential condensation/
annulation reactions of the readily available 2-[(2-
aminophenyl)ethynyl]phenylamine derivatives 1 and inexpen-
sive aryl(heteroaryl)aldehydes. Further applications of this
method as well as studies to elucidate more mechanistic details
are currently underway in our laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data of new
products 3b,e,j−p and 9. Copies of 1H and 13C NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) Nakamura, S.; Hiroto, S.; Shinokubo, H. Chem. Sci. 2012, 3,
524−527.
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AUTHOR INFORMATION
Corresponding Author
2010, 13, 3014−3017 and references therein.
■
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*E-mail: antonio.arcadi@univaq.it.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful for financial support from the
■
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