Microwave-assisted multicomponent domino cyclization-aromatization: An efficient approach for the synthesis of substituted quinolines

Article abstract of DOI:10.1039/c001076f

A solid acid-catalyzed microwave-assisted synthesis of substituted quinolines is described. The quinolines were synthesized by a multicomponent domino reaction of anilines, aldehydes and terminal aryl alkynes. The synthetic pathway involves the formation of an imine, followed by the intermolecular addition of an alkyne to the imine. This intermediate immediately undergoes ring closure and oxidative aromatization. The reaction is catalyzed by montmorillonite K-10, a strong, environmentally benign solid acid. The multicomponent approach yields the products with nearly 90% atom economy in excellent yields in a matter of minutes. The use of microwave activation reduces the reaction time significantly.

Full text of DOI:10.1039/c001076f

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/greenchem | Green Chemistry
Microwave-assisted multicomponent domino cyclization–aromatization: an
efficient approach for the synthesis of substituted quinolines†
Aditya Kulkarni and Be´la To¨ro¨k*
Received 18th January 2010, Accepted 26th February 2010
First published as an Advance Article on the web 1st April 2010
DOI: 10.1039/c001076f
A solid acid-catalyzed microwave-assisted synthesis of substituted quinolines is described. The
quinolines were synthesized by a multicomponent domino reaction of anilines, aldehydes and
terminal aryl alkynes. The synthetic pathway involves the formation of an imine, followed by the
intermolecular addition of an alkyne to the imine. This intermediate immediately undergoes ring
closure and oxidative aromatization. The reaction is catalyzed by montmorillonite K-10, a strong,
environmentally benign solid acid. The multicomponent approach yields the products with nearly
90% atom economy in excellent yields in a matter of minutes. The use of microwave activation
reduces the reaction time significantly.
A three-component reaction of aldehydes, anilines and termi-
Introduction
nal alkynes to give propargylamines has been widely explored.10
The quinoline moiety is present in an extensive number of
Furthermore, the synthesis of quinolines has been reported using
naturally occurring and biologically active compounds,1 and
propargylamines catalyzed by CuCl and AgOTf.11 These two
also shows interesting photochemical properties.2 Due to their
widespread biological activity, the synthesis of quinolines has
strategies were combined to synthesize quinolines by a three-
component reaction of aldehydes, anilines and alkynes via a
seen extensive research over the years. Classical examples in-
multicomponent, AuCl3/CuBr-catalyzed approach.12
clude Skraup–Doebner–Von Miller,3 Combes4 and Friedla¨nder5
However, the products were obtained in 2–12 days. Similarly,
syntheses. While very effective, these syntheses involve the use
the Cu(OTf)2-catalyzed synthesis of quinoline-2-carboxylates
of a variety of traditional Lewis and Brønsted acids, which
were reported in good yields (52–92%) using extended reac-
are not environmentally compatible, produce a large amount
tion times (16 hours).13
of waste and require long reaction times. Therefore, the design
Continuing our efforts in sustainable synthesis development,
of improved and environmentally benign approaches for their
preparation is of prime importance.
in this study, we describe a rapid and efficient synthesis of sub-
stituted quinolines via a microwave-assisted, three-component
One such way is to use multicomponent domino reactions
domino reaction of aldehydes, anilines and terminal alkynes
that can provide structurally complex molecules in a one-
catalyzed by a solid acid (Scheme 1). The catalyst of choice for
pot manner, ensuring high atom economy and good overall
this study is a commercially available, environmentally benign
yields.6 Isolation and purification of intermediates at individual
solid acid catalyst, montmorillonite K-10.8,14 With a Hammett
steps can be eliminated, thereby minimizing losses and waste
acidity constant (H0) of about -8, K-10 is a strong solid acid that
generation. Multicomponent domino reactions catalyzed by
is stable under high temperature and/or microwave conditions.15
environmentally compatible catalysts (natural or modified clays,
The three-component, four-step domino sequence includes
imine formation, nucleophilic attack by phenylacetylene on the
imine, intramolecular cyclization and aromatization.
metal oxides, zeolites and acidic ion-exchange resins, etc.) can
be considered a highly green synthesis design.7,8
Our earlier investigations have provided evidence for the
efficiency of solid acid catalysis in the synthesis and func-
tionalization of several biologically active heterocycles.7,9 Our
studies have also proved that the combination of solid acid
catalysis with microwave assisted organic synthesis (MAOS)
can lead to effective procedures for the synthesis of heterocyclic
compounds and their derivatives in excellent yields and in short
Scheme 1 The synthesis of quinolines via a microwave-assisted three-
component reaction.
reaction times.
University of Massachusetts Boston, 100 Morrissey Boulevard, Boston,
MA, USA. E-mail: bela.torok@umb.edu; Fax: +1 617-287-6030;
Tel: +1 617-287-6159
† Electronic supplementary information (ESI) available: General experi-
mental procedure, melting points, 1H NMR, 13C NMR and MS analyses
of formerly unknown compounds. See DOI: 10.1039/c001076f
Results and discussion
Initially, we selected aniline, benzaldehyde and phenylacetylene
as model substrates to optimize the conditions for our reaction.
The reactions were carried out in a CEM Discover Benchmate
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 875–878 | 875
©

View Article Online
Table 1 The synthesis of 2,4-diphenylquinoline under various experi-
Table 2 The synthesis of substituted 2,4-diphenylquinolines using
mental conditions from aniline, benzaldehyde and phenylacetylenea
benzaldehyde, phenylacetylene and substituted anilinesa
Entry Catalyst
Temp./◦C Time/min Conditions Yield (%)d
1
2
3
4
5
6
7
8
—
130
80
90
100
100
100
130
100
30
15
15
15
10
8
MWb
MWb
MWb
MWb
MWb
MWb
MWb
MWb
MWb
CHc
0
Entry
1
Aniline
Yield (%)b
96
K-10
K-10
K-10
K-10
K-10
K-10
Nafion-H
10
87
96
96
89
78
72
54
26
40
2
3
4
5
6
7
8
9
92
81
83
92
76
72
88
74
8
10
10
180
180
9
10
11
H3[PW12O40] 100
CF3SO3He
K-10
80
100
CHc
a 1.2 mmol benzaldehyde, 1.2 mmol aniline and 1 mmol phenylacetylene.
b Microwave heating. c Conventional heating. d Determined by GC,
based on phenylacetylene. e 1,2-Dichloroethane was used as a solvent.
microwave reactor using an open vessel technique. First, the
effect of temperature, catalyst and reaction time was studied.
The results are presented in Table 1.
Our preliminary investigations indicated that a small excess of
aniline and benzaldehyde (1.2 equivalent of both) with respect to
phenylacetylene were required to obtain optimum yields of the
product. The conversion was lower when equimolar amounts
of all the reactants were used. A further increase in the molar
amounts (1.5 equivalents) of aniline and benzaldehyde with
respect to phenylacetylene did not improve the yields, but rather
resulted in side reactions.
When the reaction was attempted without a catalyst, no
product formation was observed (Table 1, entry 1). We tested
several catalysts. In the presence of K-10 catalyst, the reaction
could be completed under mild conditions in a matter of minutes.
While the reaction occurred even at 80 ◦C, we obtained the
best yield and selectivity at 100 ◦C after a 10 min reaction
time (Table 1, entry 5). Longer irradiation did not increase the
yield (Table 1, entry 4). Under the same conditions, other solid
acids, such as Nafion-H or phosphotungstic acid (H3[PW12O40]),
resulted in lower yields (Table 1, entries 8 and 9). The triflic acid-
catalyzed reaction gave a much lower yield, which is in agreement
with the results of Xiao et al. (Table 1, entry 10).12 Based on
these data, we concluded that the best catalyst for the reaction is
K-10. For comparison, reactions were also carried out with K-
10 and triflic acid under conventional heating conditions in an
open vessel. As expected, conventional heating required longer
reaction times and resulted in a significantly lower yield and
selectivity (Table 1, entry 11).
The selectivity decreased in certain cases mainly due to
the formation of two by-products, though none were more
significant than a few percent (~2–5%). These by-products
were identified by mass spectrometry as N-benzylaniline and
N,N-dibenzylaniline. The formation of these by-products can
be explained by ionic hydrogenation of the intermediate N-
benzylideneaniline, and the further reaction and ionic hydro-
genation of this product by benzaldehyde.
a 1.2 mmol benzaldehyde, 1.2 mmol aniline and 1 mmol phenylacetylene.
b Determined by GC, based on phenylacetylene.
After determining the optimized conditions, we turned our
attention toward studying the scope of the method. First,
we used a broad variety of substituted anilines to synthesize
quinolines. The results are summarized in Table 2. As the data
indicate, almost all of the substituted anilines gave products
in good-to-excellent yields. Both o- and p-substituted anilines
readily underwent the reaction sequence, and only a moderate
substitution effect was observed.
To further widen the applicability of the procedure, we also
tested a variety of aldehydes. Table 3 summarizes the results for
the synthesis of quinolines using aniline, phenylacetylene and
different aldehydes. Most aldehydes gave products in good-to-
excellent yields. Substituted benzaldehydes (Table 3, entries 1–6)
reacted efficiently, again showing a moderate substitution effect.
The procedure can be extended to aliphatic aldehydes, although
the product was obtained in moderate yield (Table 3, entry 9)
compared to aromatic aldehydes.
Encouraged by these results, we further extended the scope
of our methodology with a variety of substituted anilines,
benzaldehydes and terminal phenylacetylenes. The results are
876 | Green Chem., 2010, 12, 875–878
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
Table 3 The synthesis of substituted 2,4-disubstituted quinolines using
Table 4 The synthesis of substituted 2,4-arylquinolines using substi-
tuted anilines, phenylacetylenes and aldehydesa
aniline, substituted aldehydes and phenylacetylenea
Entry
1
Aldehyde
Yield (%)b
91
Entry Aniline
1
Aldehyde
Phenylacetylene Yield (%)b
89
2
81
2
3
4
5
6
7
8
9
83
78
79
94
86
75
72
70
3
4
5
6
90
79
83
89
7
8
85
73
9
56c
a 1.2 mmol aldehyde, 1.2 mmol aniline and 1 mmol phenylacetylene.
b Determined by GC, based on phenylacetylene. c The reaction was
carried out for 15 min at 80 ◦C.
a 1.2 mmol aldehyde, 1.2 mmol aniline and 1 mmol phenylacetylene.
b Determined by GC, based on phenylacetylene.
presented in Table 4. As shown, these reactions also gave the
expected products in good yields. It is worth mentioning that
when p-methoxyphenylacetylene was used, the products were
obtained in lower yields (Table 4, entries 7–9) compared to
p-fluoro and p-methylphenylacetylenes (Table 4, entries 1–6).
Based on our earlier studies, we attribute this phenomenon to
the very strong adsorption of the methoxy group on the surface
of K-10. In general, methoxy-group containing substrates
give moderate yields in other reactions, as well when K-10
catalyst is used. Nevertheless, it appears that practically any
combination of the three components can be used to synthesize
the corresponding 2,4-diarylquinoline.
with hexane, dichloromethane, acetone and methanol to remove
organic residues. A new catalyst-reactant mixture was then
prepared using the recovered catalyst and the reaction performed
under identical conditions. This cycle was repeated five times.
The results of the catalyst recycling study are summarized in
Table 5.
As the data show, the catalyst remained very stable during
the five reactions, showing no sign of deactivation, and provided
excellent yields (92–96%).
Finally, to verify the sustainable nature of our procedure,
we carried out a series of experiments on the same catalysts.
Similarly to the optimization studies, we chose the reaction with
the simplest unsubstituted starting materials as a test reaction
for our reusability studies, carrying out the reactions under
identical conditions. Firstly, the catalyst-reactant mixture was
prepared as mentioned in the experimental. After the reaction,
the product was removed from the catalyst, which was washed
The proposed mechanism for the synthesis of 2,4-
diarylquinolines from anilines, benzaldehydes and pheny-
lacetylenes is illustrated in Scheme 2. The overall mechanism
involves the K-10-catalyzed formation of an aldimine (A), which
is attacked by phenylacetylene to give propargylamine (B), which
undergoes cyclization followed by oxidative aromatization in
presence of K-10 to give the 2,4-diarylquinoline. We propose
that the attack of acetylene on the in situ-generated imine A
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 875–878 | 877
©

View Article Online
Table 5 The synthesis of 2,4-diphenylquinoline from aniline, benzalde-
hyde and phenylacetylenea by using the same recovered K-10 catalyst in
five successive reaction cycles
terminal phenylacetylenes. The combination of solid acid cataly-
sis, a multicomponent domino reaction approach and microwave
irradiation provided the products in excellent selectivities and
yields in short reaction times. In addition to efficiency and
effective catalysis, the high atom economy, very limited energy
consumption and its waste-free nature make the process very
attractive for the environmentally benign synthesis of these
important heterocycles. The application of this solid acid-
catalyzed, microwave-assisted multicomponent approach could
most likely be extended to the synthesis of other important
medicinal scaffolds, such as pyrazoles, oxazolinones, benzodi-
azepines, quinoxalinones and possibly other heterocycles.
Reaction
Temp./◦C
Time/min
Yield (%)b
1
2
3
4
5
100
100
100
100
100
10
10
10
10
10
96
92
94
93
94
a 1.2 mmol benzaldehyde, 1.2 mmol aniline and 1 mmol phenylacetylene.
The catalyst was filtered and washed with hexane, dichloromethane,
acetone and methanol after each cycle. b Determined by GC, based on
phenylacetylene.
References
1 V. R. Solomon, W. Haq, K. Srivastava, S. K. Puri and S. B. Katti,
J. Med. Chem., 2007, 50, 394; P. M. S. Chauhan and S. K. Srivastava,
Curr. Med. Chem., 2001, 8, 1535; J. P. Michael, Nat. Prod. Rep., 2004,
21, 650; J. P. Michael, Nat. Prod. Rep., 2007, 24, 223.
2 J. I. Kim, I.-S. Shin, H. Kim and J.-K. Lee, J. Am. Chem. Soc., 2005,
127, 1614.
3 S. E. Denmark and S. Venkatraman, J. Org. Chem., 2006, 71, 1668.
4 A. Combes, Bull. Soc. Chim. Fr., 1888, 49, 89; W. S. Johnson and F. J.
Matthews, J. Am. Chem. Soc., 1944, 66, 210; J. Born, J. Org. Chem.,
1972, 37, 3952.
5 P. Friedla¨nder and C. F. Gohring, Ber., 1883, 16, 1833; J. S. Yadav,
B. V. S. Reddy, P. Sreedhar, R. S. Rao and K. Nagaiah, Synthesis,
2004, 2381; R. Mart´ınez, D. J. Ramo´n and M. Yus, Eur. J. Org. Chem.,
2007, 1599.
6 A. Do¨mling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168;
J. Zhu and H. Bienayme´, Multicomponent Reactions, Wiley-VCH,
Weinheim, 2005; L. F. Tietze, Chem. Rev., 1996, 96, 115; K. C.
Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed.,
2006, 45, 7134.
could be facilitated by a Lewis acid activation of the imine
to give propargylamine B. When the imine is formed on the
K-10 surface, it remains bound to the Lewis acid center to
further exploit the reactivity of its d+ carbonyl carbon. This
is followed by the nucleophilic attack of the ortho-position
of the aniline on the alkyne to close the ring, giving cyclic
intermediate C. This species undergoes rearrangement to give
dihydroquinoline intermediate D. In our earlier studies, we
reported the oxidizing ability of K-10, mostly under microwave-
assisted conditions.7,16 Newly formed intermediate D undergoes
oxidative aromatization in presence of K-10 to give the final
product (E).
7 A. Kulkarni, M. Abid, B. To¨ro¨k and X. Huang, Tetrahedron Lett.,
2009, 50, 1791; A. Kulkarni, P. Quang and B. To¨ro¨k, Synthesis, 2009,
4010.
8 A. Corma, Chem. Rev., 1995, 95, 559; B. C. Gates, Catalysis by
Solid Acids, in Encyclopedia of Catalysis, ed. I. Horva´th, Wiley, New
York, vol. 2, pp. 104; A. C. K. Yip, F. L. Y. Lam and X. J. Hu, Chem.
Commun., 2005, 3218; R. S. Varma, Tetrahedron, 2002, 58, 1235.
9 M. To¨ro¨k, M. Abid, S. C. Mhadgut and B. To¨ro¨k, Biochemistry,
2006, 45, 5377; M. Abid, A. Spaeth and B. To¨ro¨k, Adv. Synth. Catal.,
2006, 348, 2191.
10 N. Gommermann, C. Koradin, K. Polborn and P. Knochel, Angew.
Chem., Int. Ed., 2003, 42, 5763; C. Wei, Z. Li and C.-J. Li, Org. Lett.,
2003, 5, 4473; A. Bisai and V. K. Singh, Org. Lett., 2006, 8, 2405;
V. K.-Y. Lo, Y. Liu, M.-K. Wong and C.-M. Che, Org. Lett., 2006, 8,
1529.
11 Y. Kuninobu, Y. Inoue and K. Takai, Chem. Lett., 2007, 36, 1422.
12 F. Xiao, Y. Chen, Y. Liu and J. Wang, Tetrahedron, 2008, 64, 2755.
13 H. Huang, H. Jiang, K. Chen and H. Liu, J. Org. Chem., 2009, 74,
5476.
14 S. Dasgupta and B. To¨ro¨k, Curr. Org. Synth., 2008, 5, 321.
15 B. K. G. Theng, The Chemistry of Clay-Organic Reactions, Halsted
Press, New York, 1974; H. A. Benesi and B. H. C. Winquest, Adv.
Catal., 1979, 27, 97; M. Balogh, and P. Laszlo, Organic Chemistry
Using Clays, Springer-Verlag, Berlin, Heidelberg, 1993; A. Vaccari,
Appl. Clay Sci., 1999, 14, 161; S. Dasgupta and B. To¨ro¨k, Org. Prep.
Proced. Int., 2008, 40, 1.
Scheme 2 The proposed mechanism for the K-10-catalyzed synthesis of
2,4-diphenylquinoline from aniline, benzaldehyde and phenylacetylene.
Conclusions
In summary, we have developed an effective and direct
microwave-assisted, three-component, one-pot domino process
for the synthesis of quinolines from anilines, aldehydes and
16 O. De Paolis, L. Teixeira and B. To¨ro¨k, Tetrahedron Lett., 2009,
50, 2939; S. Landge, V. Atanassova, M. Thimmaiah and B. To¨ro¨k,
Tetrahedron Lett., 2007, 48, 5161.
878 | Green Chem., 2010, 12, 875–878
This journal is
The Royal Society of Chemistry 2010
©