Microwave-assisted and Yb(OTf)3-promoted one-pot multicomponent synthesis of substituted quinolines in ionic liquid

Article abstract of DOI:10.1055/s-0030-1261200

A straightforward and efficient method has been developed for the synthesis of quinolines by Yb(OTf)catalyzed three-component reaction of aldehydes, alkynes, and amines under microwave irradiation in ionic liquid. A series of 2,4-disubstituted quinolines was synthesized in excellent yield (69-93%) under mild reaction condition and the catalyst was recycled for four cycles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1261200

LETTER
2157
Microwave-Assisted and Yb(OTf)3-Promoted One-Pot Multicomponent
Synthesis of Substituted Quinolines in Ionic Liquid
Multicomponent
S
n
ynthesis of
Q
i
uinolin
l
es in Ionic
L
K
iquid umar,* V. Kameshwara Rao
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
Fax +91(1596)244183; E-mail: anilkumar@bits-pilani.ac.in
Received 13 April 2011
Microwave-assisted reactions are of great interest because
of their simplicity in operation, enhanced reaction rates,
and greater selectivity.10 Combination of Lewis acids with
microwave irradiation has become a powerful synthetic
Abstract: A straightforward and efficient method has been devel-
oped for the synthesis of quinolines by Yb(OTf)3 catalyzed three-
component reaction of aldehydes, alkynes, and amines under micro-
wave irradiation in ionic liquid. A series of 2,4-disubstituted quino-
lines was synthesized in excellent yield (69–93%) under mild tool for the rapid synthesis of a variety of biologically ac-
reaction condition and the catalyst was recycled for four cycles.
tive compounds. Ionic liquids have excellent microwave
coupling capability due to their ionic character and, in par-
ticular, those based on imidazolium salts have been used
as excellent reaction media for microwave-assisted organ-
ic synthesis.11 Ionic liquids have been utilized for the
Friedländer synthesis of quinolines under mild reaction
conditions.12 We envisaged that synergies arising from the
combined use of microwave and ionic liquids could lead
to an efficient method for the synthesis of quinolines. In
continuation of our efforts to develop novel reaction
methodologies using Yb(OTf)3 and ionic liquid,13 we re-
port herein a straightforward and practical microwave-as-
sisted and Yb(OTf)3-promoted one-pot three-component
method for efficient synthesis of substituted quinolines in
ionic liquid. To the best of our knowledge, this is the first
report on synthesis of quinolines using Yb(OTf)3 as cata-
lyst.
Key words: microwave assisted, ytterbium triflate, one-pot , multi-
component, quinolines, ionic liquid
Quinoline is a common heterocyclic scaffold in many nat-
ural and synthetic compounds of medicinal and biological
significance.1 Antimalarial drugs containing quinoline are
mainstays of chemotherapy against malaria.2 Quinoline-
based compounds show a broad range of biological activ-
ities like anti-HIV,3 antituberculosis,4 antimicrobial, anti-
fungal,5 and anticancer.6 Due to their great application as
synthetic intermediates and their unique biological activi-
ties, there has been growing interest in development of
synthetic methods for these molecules.7 Although these
methods are effective, they suffer from some disadvantag-
es such as harsh reaction conditions, extended reaction
times, limited availability of starting materials, tedious
workup procedures or use of environmentally harmful
solvents. Keeping in view the importance of the quinoline
scaffold in pharmaceutical and synthetic chemistry, the
development of more convenient and efficient methods is
still desirable.
R3
NH2
Yb(OTf)3
[bmim][BF4]
R1CHO
+
R3
+
MW (80 W, 5.5 bar)
N
R1
R2
R2
4a–u
1
2
3
In recent years multicomponent reactions (MCR) have
emerged as a powerful tool for diversity-oriented organic
synthesis.8 These reactions can provide druglike mole-
cules with several degrees of structural diversity in a one-
pot operation and offer significant advantages over con-
ventional linear-type syntheses such as high atom econo-
my and E-factors, low cost, reduction in overall reaction
time, and operational simplicity. Recently, a three-com-
ponent reaction of aldehydes, anilines, and alkynes has
been developed for the synthesis of quinolines.9 However,
the yields of quinolines were moderate to good, and the
reaction required extended times. From an environmental
and efficiency point of view lanthanide triflates have be-
come highly attractive Lewis acid catalysts for various
chemical reactions.
Scheme 1 Synthesis of quinolines using Yb(OTf)3 under micro-
wave irradiation in [bmim][BF4]
Firstly, we selected the reaction of benzaldehyde, phenyl-
acetylene, and aniline to give the corresponding quinoline
4a as a model reaction to find the optimum conditions
(Table 1, Scheme 1). When the model reaction was car-
ried out using Yb(OTf)3 (10 mol%) as catalyst under ther-
mal heating at 120 °C (oil bath) in an open vessel it took
10 hours to give 4a in only 60% yield (Table 1, entry 16).
However, when the reaction was carried out in a CEM
Discover® Benchmate microwave reactor using a closed
vessel the rate of reaction and yield were markedly en-
hanced (Table 1 entry 4).
Next, we screened different metal triflates and solvents
for the model reaction, and it was found that under micro-
wave conditions other metal triflates resulted in lower
yield of 4a (Table 1, entries 11–15). The yield of 4a was
also best in [bmim][BF4] among all the solvents screened
SYNLETT 2011, No. 15, pp 2157–2162
x
x
.x
x
.2
0
1
1
Advanced online publication: 31.08.2011
DOI: 10.1055/s-0030-1261200; Art ID: D11711ST
© Georg Thieme Verlag Stuttgart · New York

2158
A. Kumar, V. Kameshwara Rao
LETTER
with Yb(OTf)3 as catalyst (Table 1, entries 6–10). The The optimum catalyst loading was found to be 10 mol%
role of Yb(OTf)3 and [bmim][BF4] was confirmed by the and increasing the amount of Yb(OTf)3 did not improve
fact that only 33% and 45% yield was observed for 4a in the yield; whereas decreasing the amount of Yb(OTf)3 re-
the absence of Yb(OTf)3 and [bmim][BF4], respectively, duced the yield of 4a (Table 1, entries 3–5). The optimal
under similar reaction conditions (Table 1, entries 1 and reaction conditions for the model reaction were found to
2).
be 10 mol% Yb(OTf)3 and 80 W irradiation power for
three minutes.
Table 1 Optimization of the Reaction Conditionsa
After determining the optimized reaction conditions, we
next studied the substrate scope by varying aldehydes,
alkynes, and amines for the synthesis of various substitut-
ed quinolines. The results are summarized in Table 2.14 A
wide range of structurally diverse aldehydes gave the cor-
responding quinolines in good to excellent yields
(Table 2). Aromatic aldehydes with both electron-donat-
ing and electron-withdrawing groups reacted to afford the
corresponding products in almost equally high yields. The
present method is equally effective for aromatic amines
with both electron-donating and electron-withdrawing
substituents affording the desired quinolines in almost
equally high yields (Table 2, entry 9–19). We also studied
the scope of alkynes, and it was found that substituted
phenylacetylenes were good substrates. The structure of
Entry
Solvent
Catalyst
Cat.
Time Yield
(mol%) (min) (%)b
1
2
[bmim][BF4]
–
–
–
3
3
33
45
74
90
88
65
25
45
40
45
62
58
60
55
50
60c
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Ag(OTf)
Cu(OTf)2
Sc(OTf)3
Ce(OTf)3
Sc(OTf)3
Yb(OTf)3
10
5
3
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][PF6]
[PyBu][Br]
PEG
3
4
10
20
10
10
10
10
10
10
10
10
10
10
10
3
5
3
6
3
7
3
8
3
1
all the synthesized compounds was confirmed by H
NMR and 13C NMR spectroscopy and mass spectrometry.
In general, different functional groups such as F, Cl, Br,
CN, NO2 and alkoxy are tolerated, reactions are clean,
yields are excellent, and reaction complete in three min-
utes.
9
EtOH
3
10
11
12
13
14
15
16
MeCN
3
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
[bmim][BF4]
3
3
The reaction is proposed to proceed through a four-step
domino sequence as shown in Scheme 2. The first step is
believed to be formation of the imine which undergoes
nucleophilic attack by phenylacetylene to give a propar-
gylamine derivative which further undergoes intramolec-
ular cyclization and aromatization to give the quinoline.
Yb(OTf)3 may be playing a role in activating the triple
bond to promote this intramolecular cyclization to give
the dihydroquinoline intermediate which further aroma-
tizes to give quinoline. Formation of quinolines from pro-
pargyl amine derivatives has been observed using other
3
3
3
600
a Reaction conditions: benzaldehyde (1 mmol), phenylacetylene (1
mmol), aniline (1 mmol), MW irradiation at 80 W, 80 °C, 5.5 bar.
b Isolated yield.
c Thermal heating at 120 °C, [PyBu][Br]: butylpyridinium bromide.
δ–
Yb(OTf)3
δ–
δ+
O
H
Yb(OTf)3
O
••
HN
R1
NH2
H
R1
NH2
δ+
N
R1
+
R1CHO
R2
imine formation
nucleophilic addition
aromatization
– H2
HN
R1
N
N
HN
R1
(TfO)3Yb
intramolecular
cyclization
R1
R2
R1
R2
R2
R2
Scheme 2 Proposed mechanism for the synthesis of quinolines by three-component reaction
Synlett 2011, No. 15, 2157–2162 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of Quinolines in Ionic Liquid
2159
Lewis acid catalysts such as AuCl3 and K-10 Montmoril- mation of imine by the activation of the aldehyde carbonyl
lonite clay.9 The role of the ionic liquid is not clear but it through hydrogen bonding.15
is expected that the acidic nature of C-2 proton
(pKa = 22.7 in DMSO) of imidazolium facilitates the for-
Table 2 Synthesis of Substituted Quinolines Using Yb(OTf)3 in Ionic Liquid under MW Irradiationa
Entry R1
R2
R3
Productb
Yield (%)c Mp (°C)
Ph
1
2
Ph
Ph
Ph
4a
4b
90d
108–110
N
Ph
Ph
3,4,5-(MeO)3C6H3
Ph
Ph
88
113–115
OMe
OMe
N
OMe
Ph
3
4
5
3,4-(MeO)2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
4c
4d
4e
77
76
82
142–144
106–108
117–119
OMe
OMe
N
Ph
F
2-FPh
N
Ph
4-(BnO)C6H4
N
OBn
Ph
6
7
8
4-(C3H5O)C6H4
Ph
Ph
Ph
Ph
Ph
Ph
4f
83
69
89
114–116
N
O
Ph
viscous
liquid
4g
4h
S
S
N
Ph
4-O2NC6H4
162–164
108–110
N
NO2
Ph
9
4-MeC6H4
Ph
Ph
4i
92
N
Synlett 2011, No. 15, 2157–2162 © Thieme Stuttgart · New York

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A. Kumar, V. Kameshwara Rao
LETTER
Table 2 Synthesis of Substituted Quinolines Using Yb(OTf)3 in Ionic Liquid under MW Irradiationa (continued)
Entry R1
R2
R3
Ph
Productb
Yield (%)c Mp (°C)
Ph
Br
10
Ph
4-BrC6H4
4j
96
153–155
N
Ph
Br
Br
11
12
13
14
4-(C3H5O)C6H4
4-MeC6H4
Ph
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-O2NC6H4
Ph
Ph
Ph
Ph
4k
4l
91
90
87
89
150–152
120–122
127–129
218–220
N
O
Ph
N
Ph
Cl
O2N
I
4m
4n
N
Ph
3-ClC6H4
Cl
N
Ph
N
15
16
4-NCC6H4
4-NCC6H4
4-IC6H4
Ph
4o
4p
86
88
225–227
171–173
CN
N
Ph
4-MeC6H4
NC
Br
N
17
18
3,4,5-(MeO)3C6H3
4-BrC6H4
4-MeC6H4
4q
91
93
124–126
194–196
MeO
MeO
OMe
Br
N
3,4,5-(MeO)3C6H3
4-O2NC6H4
4-MeC6H4
4r
MeO
MeO
NO2
OMe
Synlett 2011, No. 15, 2157–2162 © Thieme Stuttgart · New York

LETTER
Multicomponent Synthesis of Quinolines in Ionic Liquid
2161
Table 2 Synthesis of Substituted Quinolines Using Yb(OTf)3 in Ionic Liquid under MW Irradiationa (continued)
Entry R1
R2
R3
Productb
Yield (%)c Mp (°C)
Br
N
19
4-NCC6H4
4-BrC6H4
4-MeC6H4
4s
90
220–222
NC
a Reaction conditions: aldehyde (1 mmol), alkyne (1 mmol), aniline (1 mmol), MW irradiation at 80 W, 80 °C, 5.5 bar, 3 min.
b All compounds showed satisfactory 1H NMR, 13C NMR, and mass data.
c Isolated yield.
d Yields for four cycles were 90%, 88%, 85%, and 86%, respectively.
Niedbala, H.; Podeszwa, B.; Palka, A.; Majerz-Maniecka,
K.; Oleksyn, B.; Polanski, J. Bioorg. Med. Chem. 2006, 15,
3592.
We subsequently investigated the possibility of recycling
of the catalyst. After a first cycle of the model reaction the
product was extracted with ethyl acetate–hexane, and the
ionic liquid containing Yb(OTf)3 was dried under reduced
pressure. The ionic liquid thus recovered was charged
with fresh benzaldehyde, phenylacetylene, and aniline, ir-
radiated under the same conditions, and the product ex-
tracted. The above sequence was repeated four times to
give 4a in good yields (90%, 88%, 85%, and 86%) with-
out significant loss in catalytic activity of the Yb(OTf)3.
(6) (a) Heiniger, B.; Gakhar, G.; Prasain, K.; Hua, D. H.;
Nguyen, T. A. Anticancer Res. 2010, 30, 3927.
(b) Fujimoto, S. Biol. Pharm. Bull. 2007, 1923.
(7) (a) Korivi, R. P.; Cheng, C.-H. J. Org. Chem. 2006, 71,
7079. (b) Sarma, R.; Prajapati, D. Synlett 2008, 3001.
(c) Lekhok, K. C.; Prajapati, D.; Boruah, R. C. Synlett 2008,
655. (d) Zhang, Z.; Tang, J.; Wang, Z. Org. Lett. 2008, 10,
173. (e) Sandelier, M. J.; DeShong, P. Org. Lett. 2007, 9,
3209.
In summary, we have developed a straightforward and ef-
ficient method for the synthesis of quinolines by the
Yb(OTf)3-catalyzed three-component reaction of alde-
hydes, alkynes, and amines under microwave irradiation
in ionic liquid. A series of 2,4-disubstituted quinolines has
been synthesized in excellent yield (69–93%). The cata-
lyst can be recycled up to four cycles without significant
decrease in catalytic activity. Short reaction times, an en-
vironment friendly catalyst, and excellent yields are the
advantages of the method which will make it a practical
method for synthesis of substituted quinolines over exist-
ing methods.
(8) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Dömling, A. Chem. Rev. 2006, 106, 17.
(c) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15,
1300. (d) Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed.
2005, 44, 1602.
(9) (a) Cao, K.; Zhang, F.; Tu, Y. Q.; Zhuo, X.; Fan, C. A. Chem.
Eur. J. 2009, 15, 6332. (b) Xiao, F.; Chen, Y.; Liu, Y.;
Wang, J. B. Tetrahedron 2008, 64, 2755. (c) Huang, H.;
Jiang, H.; Chen, K.; Liu, H. J. Org. Chem. 2009, 74, 5476.
(d) Guchhait, S.; Jadeja, K.; Madaan, C. Tetrahedron Lett.
2009, 50, 6861. (e) Gaddam, V.; Ramesh, S.; Nagarajan, R.
Tetrahedron 2010, 66, 4218. (f) Li, X.; Mao, Z.; Wang, Y.;
Chen, W.; Lin, X. Tetrahedron 2011, 3858.
(10) (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563.
(b) Martínez-Palou, R. Mol. Diversity 2006, 10, 435.
(c) Polshettiwar, V.; Nadagouda, M. N.; Varma, R. S. Aust.
J. Chem. 2009, 62, 16.
Acknowledgment
(11) (a) Forsyth, S. A.; Pringle, J. M.; MacFarlane, D. R. Aust. J.
Chem. 2004, 57, 113. (b) Leadbeater, N. E.; Torenius, H. M.
J. Org. Chem. 2002, 67, 3145. (c) Hoffmann, J.; Nüchter,
M.; Ondruschka, B.; Wasserscheid, P. Green Chem. 2003, 5,
296.
(12) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. J. Org. Chem. 2003, 68, 9373.
(13) (a) Kumar, A.; Rao, M. S.; Rao, V. K. Aust. J. Chem. 2010,
63, 135. (b) Kumar, A.; Rao, M. S.; Rao Ahmad, I.;
Khungar, B. Aus. J. Chem. 2009, 62, 322. (c) Kumar, A.;
Ahmad, I.; Rao, M. S. J. Sulfur Chem. 2009, 30, 570.
(d) Kumar, A.; Ahmed, I.; Rao, M. S. Can. J. Chem. 2008,
86, 899. (e) Kumar, A.; Jain, N.; Rana, S.; Chauhan, S. M. S.
Synlett 2004, 2785.
(14) Synthesis of 2,4-Diphenylquinoline (4a)
A mixture of benzaldehyde (106 mg, 1 mmol), aniline (93
mg, 1 mmol), phenylacetylene (102 mg, 1 mmol), and
Yb(OTf)3 (62 mg, 10 mol%) was taken in a tube containing
2 mL of [bmim][BF4] and placed under MW irradiation in a
CEM Discover BenchMate® reactor. The reaction
parameters were set to 80 W, 80 °C for 3 min under stirring.
After completion of the reaction, the reaction mixture was
We thank the Department of Science and Technology, New Delhi
for a grant to purchase a focused microwave under the FIST pro-
gramme. VKR is thankful to BITS Pilani for a Research Fellowship.
References and Notes
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
(2) (a) Foley, M.; Tilley, L. Int. J. Parasitol. 1997, 27, 231.
(b) Egan, T. J. Expert Opin. Ther. Pat. 2001, 11, 185.
(3) McCormick, J. L.; McKee, T. C.; Cardellina, J. H. II.; Boyd,
M. R. J. Nat. Prod. 1996, 59, 469.
(4) (a) Eswaran, S.; Adhikari, A. V.; Chowdhury, I. H.; Pal, N.
K.; Thomas, K. D. Eur. J. Med. Chem. 2010, 3374. (b) de
Souza, M. V.; Pais, K. C.; Kaiser, C. R.; Peralta, M. A.;
de L Ferreira, M.; Lourenço, M. C. Bioorg. Med. Chem.
2009, 17, 1474. (c) Vangapandu, S.; Jain, M.; Jain, R.; Kaur,
S.; Singh, P. P. Bioorg. Med. Chem. 2004, 12, 2501.
(5) (a) Eswaran, S.; Adhikari, A. V.; Shetty, N. S. Eur. J. Med.
Chem. 2009, 4637. (b) Musiol, R.; Serda, M.; Hensel-
Bielowka, S.; Polanski, J. Curr. Med. Chem. 2010, 17,
1960. (c) Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.;
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A. Kumar, V. Kameshwara Rao
LETTER
extracted with EtOAc–hexane (1:1, 3 × 10 mL). Evaporation
of solvent gave the crude product which was purified by
passing through a silica column to give pure 4a (253 mg,
90%) as an off-white solid; mp 108–110 °C (lit.16 109–
111 °C).
(15) (a) Kim, Y.-J.; Streitwieser, A. J. Am. Chem. Soc. 2002, 124,
5757. (b) Chakraborti, A. K.; Roy, S. R. J. Am. Chem. Soc.
2009, 131, 6902. (c) Chakraborti, A. K.; Roy, S. R.; Kumar,
D.; Chopra, P. Green Chem. 2008, 10, 1111.
(16) Nishio, T.; Omote, Y. J. Chem. Soc., Perkin Trans. 1 1983,
1773.
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