Synthesis of quinolines by a solid acid-catalyzed microwave-assisted domino cyclization-aromatization approach

Article abstract of DOI:10.1016/j.tetlet.2009.03.208

A microwave-assisted solid acid-catalyzed synthesis of quinolines from anilines and cinnamaldehydes is described. Use of montmorillonite K-10 results in a one-pot process; the cyclization and oxidation steps readily take place in a domino approach. Reactions were completed in a matter of minutes and provided excellent yields. The efficient and ecofriendly catalyst and the convenience of the product isolation make this process an attractive alternative for the synthesis of these important heterocycles.

Full text of DOI:10.1016/j.tetlet.2009.03.208

Tetrahedron Letters 50 (2009) 2939–2942
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of quinolines by a solid acid-catalyzed microwave-assisted
domino cyclization–aromatization approach
*
Omar De Paolis, Liliana Teixeira, Béla Török
Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd. Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave-assisted solid acid-catalyzed synthesis of quinolines from anilines and cinnamaldehydes is
described. Use of montmorillonite K-10 results in a one-pot process; the cyclization and oxidation steps
readily take place in a domino approach. Reactions were completed in a matter of minutes and provided
excellent yields. The efficient and ecofriendly catalyst and the convenience of the product isolation make
this process an attractive alternative for the synthesis of these important heterocycles.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 March 2009
Revised 30 March 2009
Accepted 30 March 2009
Available online 5 April 2009
Keywords:
Microwave irradiation
Montmorillonite K-10
Anilines
Cinnamaldehydes
Quinolines
1. Introduction
includes an additional advantage; reactions can be carried out with
minimum solvent use.
The quinoline skeleton is a common structural motif in a broad
range of biologically active compounds,1 including many natural
products.2 Quinoline derivatives are utilized as antimalarial,3 anti-
tumor,4 and antibacterial agents.5
Based on our recent studies,11 we have chosen montmorillonite
K-10 as the catalyst. It is a commercially available, stable, inexpen-
sive, strong solid acid, active under microwave conditions, and can
be used without any pretreatment. Its features and synthetic appli-
cations have been the topic of many reviews.12 The combination of
K-10 and microwave irradiation provided an extensive number of
successful processes.13,14
Herein, we describe an environmentally benign one-pot domino
approach for the synthesis of quinolines. The major benefits of the
microwave-assisted heterogeneous catalytic process are the fast
reactions, solvent-free environment, and improved yields.14
In the reaction, the catalyst has a dual role. It ensures an effec-
tive condensation and cyclization of anilines with cinnamaldehy-
des and promotes the aromatization to the final product. The
approach is summarized in Scheme 1.
Due to their importance, the synthesis of quinolines attracted
widespread attention. Several methods were developed which pro-
vide quinoline derivatives efficiently, but do so in multiple steps
and using harmful reagents and harsh conditions. These proce-
dures, including the Skraup and Doebner–Miller syntheses,6 in-
volve the use of a variety of Lewis7 and Brønsted8 acids. These
traditional acids are corrosive, produce significant amount of
waste, and rely on long reaction times, which do not conform to re-
cent environmental standards. Therefore, the design of improved
and environmentally benign approaches for their preparation is
in great demand.
Solid acids can replace traditional mineral acids as safer alterna-
tives. Clays, zeolites, metal oxides, and acidic ion-exchange resins
have become the catalysts of choice in research laboratories and
industrial processes.9 They are also widely used in microwave-as-
sisted organic synthesis (MAOS).9 These catalysts are stable, easy
to store and handle, and do not produce hazardous waste. Besides
the potential for sustainability and improved safety, the applica-
tion of heterogeneous catalysts10 under microwave conditions
O
R1
R4
R1
R2
R4
R3
K-10, MW
90 o
+
R2
NH2
R3
C
N
R1 = H, CH3, CH3CH2, F, Cl, Br, CH3O
R2 = H, CH3, Cl
R3 = C6H5, 2-NO2-C6H4, 2-CH3O-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4
R4 = H, CH3
* Corresponding author. Tel.: +1 617 287 6159; fax: +1 617 287 6030.
E-mail address: bela.torok@umb.edu (B. Török).
Scheme 1. Synthesis of substituted quinolines from anilines and cinnamaldehydes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.208

2940
O. De Paolis et al. / Tetrahedron Letters 50 (2009) 2939–2942
Table 2
2. Results and discussion
Microwave-assisted K-10-catalyzed synthesis of quinolines from cinnamaldehyde
and substituted anilinesa
To develop our new approach, we have chosen the cyclization of
aniline with cinnamaldehyde as a probe reaction. We have observed
that the catalyst yielded quinoline in a one-pot cyclization-aromati-
zationdomino sequence. Theformation of dihydroquinoline was not
detected. In contrast, HCl, a traditional liquid acid, while providing
the intermediate dihydroquinoline, did not yield the aromatic prod-
uct. In order to optimize the reaction parameters, we carried out
several test reactions and studied the effect of temperature, reactant
ratio, and time. Our results (Table 1) indicated that the amount of the
nucleophile had a significant effect on the yield of the product. An in-
crease in the amount of aniline from 1 to 1.5 equiv appeared to be
beneficial. Further increase in the quantity of the nucleophile did
not result in notable improvement. We also found that the reactions
could be completed at a relatively mild temperature (90 °C) in a mat-
ter of minutes (6 min), while at higher temperatures and prolonged
irradiation product decomposition and secondary reactions
occurred.
O
R1
R1
R2
K-10, MW
90 oC
+
R2
NH2
R1
Ph
N
Ph
Entry
R2
Time (min)
Yieldc (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
Cl
CH3
6
6
6
6
6
8
6
4
6
95
90
40
90
60
70
55
65
90
CH3
CH3O
CH3CH2
Fb
Clb
Brb
H
H
a
Reactant ratio: aniline (1.5 mmol), cinnamaldehyde (1 mmol).
Reactant ratio: aniline (2.0 mmol), cinnamaldehyde (1 mmol).
Determined by GC.
b
c
For comparison, we carried out the probe reaction in a pressure
vessel using conventional heating in the absence of a solvent (en-
tries 10 and 11). The formation of the aromatic product took place
very slowly. As expected, conductive heating resulted in a reaction
time that was 15 times longer and provided a lower yield (entry
11). After optimization of the reaction conditions, we obtained
quinoline in excellent yield and high selectivity in a short reaction
time (entry 9).
marized in Table 3. As the data demonstrate, in each case the
reactions took place efficiently showing a moderate substituent ef-
fect. Cinnamaldehydes readily underwent cyclization to form quin-
olines in moderate to excellent yields. It appears that the steric
hindrance in the
a-position (entry 1) and the presence of a meth-
oxy substituent on the aromatic ring of the substrate result in
To explore the scope of our methodology we used a variety of
substituted anilines to synthesize quinolines. The results are sum-
marized in Table 2.
moderate yields.
Overall, the reaction accommodates a variety of substituents on
both rings. The reaction does not proceed with acrolein and meth-
acrolein due to immediate polymerization of the starting materials
under microwave irradiation.
As the data indicate, almost all substituted anilines gave good to
excellent yields. A minor reaction time adjustment was necessary
for a couple of substrates (entries 6 and 8) to ensure the highest
possible yield. In the case of the m-substituted anilines, a regiose-
lective para cyclization occurred, yielding one product exclusively.
The reactions were fast and selective with a few exceptions (en-
tries 3, 5, and 7) when a certain amount of byproduct formed. It
is worth mentioning that substrates with strong electron-with-
drawing groups showed diminished reactivity, which had a nega-
tive effect on yields. Trifluoromethyl-, cyano-, and nitroaniline
did not afford satisfactory yields (<20%).
The mechanism for the reaction of an a,b-unsaturated aldehyde
or ketone with aniline has long been a subject of a debate. Presum-
ably, the reaction proceeds with a Michael addition of aniline with
subsequent cyclization and aromatization under the catalytic con-
ditions.15 Other claims suggest that the first step is a traditional
condensation leading to the formation of an imine, followed by a
conjugate addition of a second molecule of aniline (Scheme 2,
pathway (a)).16 A recent work proposed a fragmentation-recombi-
nation mechanism in which the intermediate formed from an ini-
tial conjugate addition undergoes fragmentation (Scheme 2,
pathway (b)).17 A corresponding ketone or aldehyde, along with
an imine, is obtained before recombining to yield quinoline. Inter-
To further widen the applicability of the procedure, we have se-
lected several substituted cinnamaldehydes. The results are sum-
Table 1
Effect of activation method, temperature, time, and initial reactant molar ratio on the
microwave-assisted K-10-catalyzed reaction of cinnamaldehyde (CN) with aniline
(AN)
Table 3
Microwave-assisted, K-10-catalyzed synthesis of quinolines from substituted cinn-
amaldehydes and substituted anilinesa
O
K-10
O
+
R1
R4
R1
R4
R3
NH2
Δ
K-10, MW
90 o
Ph
N
Ph
+
NH2
R3
R4
C
N
Entry
Methoda
T (°C)
Time (min)
CN:AN
Yieldb (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
MW
MW
MW
MW
MW
MW
MW
MW
MW
CH
80
80
80
80
90
90
80
90
90
80
90
2
4
6
10
2
4
6
4
6
150
90
1:1
1:1
1:1
1:1
1:1
1:1
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
25
45
60
85
35
60
60
75
95
80
70
Entry
R3
C6H5
2-NO2C6H4
2-NO2C6H4
R1
Time (min)
1
2
3
4
5
6
7
8
9
CH3
H
H
H
H
H
H
H
H
H
H
CH3
CH3CH2
H
CH3
CH3CH2
H
H
6
6
6
6
6
6
6
6
6
70
95
95
95
65
55
60
65
95
2-NO2C6H4
2-(CH3O)C6H4
4-(CH3O)C6H4
4-(CH3O)C6H4
4-(CH3O)C6H4
4-NO2C6H4
10
11
CH
a
a
Reactant ratio: aniline (1.5 mmol), cinnamaldehyde (1 mmol).
Determined by GC.
MW—microwave heating, CH—conventional heating.
Determined by GC; based on cinnamaldehyde.
b
b

O. De Paolis et al. / Tetrahedron Letters 50 (2009) 2939–2942
2941
addition of K-10 (500 mg). After 5 min stirring, the solvent was
evaporated to obtain a dry mixture which was transferred into a
glass reaction vessel and irradiated in the microwave reactor
(CEM Discover Benchmate, 90 °C). During the optimization process,
the progress of the reaction was monitored by TLC and GC. After
completion of the reaction, CH2Cl2 was added to the mixture, and
the product was separated from the catalyst by filtration. The prod-
ucts were isolated and purified by flash chromatography. All prod-
ucts showed satisfactory spectral data (MS, 1H, and 13C NMR). Here,
the full spectral characterization is given for only the previously
unknown products. Such data for the known compounds synthe-
sized in this study are available from the authors.
O
+
NH2
Ph
conventional
heating
microwave
heating
pathway (a)
pathway (b)
O
Ph
N
Ph
Ph
NH
PhNH2
Ph
A
N
Ph
NH
B
Ph
O
N
Ph
+
Ph
Ph
-PhNH2
4.1.1. 6-Ethyl-2-phenylquinoline (Table 2, entry 4)
Mp 40–42 °C; 1H NMR (300 MHz, CDCl3), d (ppm) 8.13 (m, 4H),
7.83 (d, J = 7.2 Hz, 1H), 7.59 (m, 2H), 7.49 (m, 3H), 2.84 (q,
J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H).
H
N
Ph
Ph
O
13C NMR (75.474 MHz, CDCl3), d (ppm) 156.5, 146.9, 142.4,
139.7, 136.3, 130.9, 129.4, 129.1, 128.8, 127.5, 127.2, 124.9,
118.9, 28.8, 15.4.
N
Ph
Scheme 2. Proposed mechanistic pathways for the K-10-catalyzed synthesis of
MS-C17H15N (233), m/z (%): 233 (M+, 71), 218 (100), 204 (15).
quinolines.
4.1.2. 6-Ethyl-2-(2-nitrophenyl)quinoline (Table 3, entry 4)
Mp 75–77 °C; 1H NMR (300 MHz, CDCl3), d (ppm) 8.16 (d,
J = 8.4 Hz, 1H), 7.98 (m, 2H), 7.70 (m, 2H), 7.58 (m, 3H), 7.48 (d,
J = 8.4 Hz, 1H), 2.85 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H).
13C NMR (75.474 MHz, CDCl3), d (ppm) 154.6, 146.7, 143.2,
136.3, 135.9, 132.6, 131.6, 131.2, 129.4, 129.2, 127.2, 125.1,
124.4, 120.4, 28.9, 15.4.
estingly, we have observed, under different conditions, the forma-
tion of these distinct intermediates suggested in the two major
pathways. While intermediate A was observed when the reaction
was carried out with conventional heating, intermediate B formed
under microwave-assisted conditions (Scheme 2).
While the reason is not clear as yet, it seems that either one of
the two distinct pathways may become a major route for the reac-
tion under different conditions. Microwave irradiation, as com-
pared to conventional heating, initiated different pathways in
reactions, even yielding different products.18a Local temperatures
in such reactions can be significantly higher than the observed
temperature of the bulk reaction mixture.18b Thus, it appears rea-
sonable to propose that pathway (b) requires higher activation en-
ergy, which is available under microwave conditions.
MS-C17H14N2O2 (278), m/z (%): 278 (M+, 100), 263 (19), 248
(71), 233 (42), 216 (39), 207 (67).
4.1.3. 6-Methyl-2-(4-methoxyphenyl)quinoline (Table 3, entry 6)
Mp 131–133 °C; 1H NMR (300 MHz, CDCl3), d (ppm) 8.10 (m,
4H), 7.79 (m, 1H), 7.55 (m, 2H), 7.05 (m, 2H), 3.88 (s, 3H), 2.53
(s, 3H).
13C NMR (75.474 MHz, CDCl3), d (ppm) 160.6, 156.1, 146.8,
135.9, 131.8, 129.8, 129.2, 128.7, 127.9, 126.3, 118.5, 114.1,
112.8, 55.4, 21.5.
MS-C17H15NO (249), m/z (%): 249 (M+, 100), 234 (38), 206 (29),
191 (22).
3. Conclusion
In conclusion, a novel, solid acid-catalyzed synthesis of substi-
tuted quinolines is described. This method provides the products
in good to excellent yields and selectivities in very short reaction
times from commercially available and inexpensive starting mate-
rials. In addition to efficiency, the solvent-free reaction, the limited
energy consumption, and waste-free nature make the process an
attractive green synthesis of the target compounds.
4.1.4. 6-Ethyl-2-(4-methoxyphenyl)quinoline (Table 3, entry 7)
Mp 101–103 °C; 1H NMR (300 MHz, CDCl3), d (ppm) 8.11 (m,
3H), 7.78 (m, 2H), 7.56 (m, 2H), 7.03 (m, 2H), 3.86 (s, 3H), 2.82
(q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H).
13C NMR (75.474 MHz, CDCl3), d (ppm) 160.1, 155.9, 149.8,
136.8, 131.5, 129.7, 129.2, 128.1, 127.5, 126.1, 119.5, 114.2,
113.6, 55.4, 28.8, 15.3.
MS-C17H17NO (263), m/z (%): 263 (M+, 100), 248 (95), 204 (25).
4. General procedure
All reactants and the catalyst montmorillonite K-10 were pur-
chased from Aldrich and used without further purification. The
1H and 13C NMR spectra were recorded on a 300 MHz Varian
NMR spectrometer, in CDCl3. Tetramethylsilane or the residual sol-
vent signal was used as reference. The mass spectrometric identi-
fication of the products was carried out on an Agilent 6850 GC-
5973 MS system (70 eV EI ionization) using a 30 m long DB-5 col-
umn (J&W Scientific). The melting points were uncorrected and
were recorded on a MEL-TEMP apparatus.
Acknowledgment
Financial support provided by the University of Massachusetts
Boston is gratefully acknowledged.
References and notes
1. (a) Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001,
44, 2374; (b) Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem. 2001, 8, 1535;
(c) Balasubramanian, M.; Keay, J. G.. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: New York, NY, 1996; Vol. 5, p 245.
2. (a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650; (b) Michael, J. P. Nat. Prod. Rep.
2007, 24, 223.
3. (a) Samosorn, S.; Bremner, J. B.; Ball, A.; Lewis, K. Bioorg. Med. Chem. 2006, 14,
857; (b) Foley, M.; Tilley, L. Pharmacol. Ther. 1998, 79, 55.
4. (a) Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. J. Am. Chem.
Soc. 1997, 119, 6072; (b) Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org.
4.1. One-pot microwave-assisted synthesis of quinolines—
general procedure
Aniline (1.5 mmol) and cinnamaldehyde (1.0 mmol) were dis-
solved in 3 mL of CH2Cl2 in a round-bottomed flask, followed by

2942
O. De Paolis et al. / Tetrahedron Letters 50 (2009) 2939–2942
Chem. 1994, 59, 5120; (c) Shen, W.; Coburn, C. A.; Bornmann, W. G.;
Danishefsky, S. J. J. Org. Chem. 1993, 58, 611.
10. (a) Augustine, R. L. Heterogeneous Catalysis for the Synthetic Chemists; Marcel
Dekker: New York, 1996; (b) Smith, G. V.; Notheisz, F. Heterogeneous Catalysis
in Organic Chemistry; Academic Press: San Diego, 1999.
11. (a) Abid, M.; Landge, S. M.; Török, B. Org. Prep. Proced. Int. 2006, 35, 495; (b)
Abid, M.; Spaeth, A.; Török, B. Adv. Synth. Catal. 2006, 348, 2191; (c) Landge, S.
M.; Atanassova, V.; Thimmaiah, M.; Török, B. Tetrahedron Lett. 2007, 48, 5161.
12. (a) Benesi, H. A.; Winquest, B. H. C. Adv. Catal. 1978, 27, 97; (b) Vaccari, A. Appl.
Clay Sci. 1999, 14, 161; (c) Nikalje, M. D.; Phukan, P.; Sudalai, A. Org. Prep.
Proced. Int. 2000, 32, 1; (d) Varma, R. S. Tetrahedron 2002, 58, 1235; (e)
Dasgupta, S.; Török, B. Org. Prep. Proced. Int. 2008, 40, 1.
13. (a) Varma, R. S.; Saini, R. K. Synlett 1997, 7, 857; (b) Varma, R. S.; Kumar, D.
Tetrahedron Lett. 1999, 40, 7665; (c) Vass, A.; Dudas, J.; Varma, R. S. Tetrahedron
Lett. 1999, 40, 4951.
14. (a) Abid, M.; De Paolis, O.; Török, B. Synlett 2008, 410; (b) Landge, S. M.;
Berryman, M.; Török, B. Tetrahedron Lett. 2008, 49, 4505; (c) Landge, S. M.;
Schmidt, A.; Outerbridge, V.; Török, B. Synlett 2007, 10, 1600.
5. Yearick, K.; Ekoue-Kovi, K.; Iwaniuk, D. P.; Natarajan, J. K.; Alumasa, J.; de Dios,
A. C.; Roepe, P. D.; Wolf, C. J. Med. Chem. 2008, 51, 1995.
6. (a) Skraup, Z. H. Monatsh. Chem. 1881, 2, 139; (b) Skraup, Z. H. Ber. Dtsh. Chem.
Ges. 1882, 15, 897; (c) Doebner, O.; Miller, W. v. Ber. Dtsh. Chem. Ges. 1881, 14,
2812; (d) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl. Compd. 2006, 42,
701.
7. (a) Korivi, R. P.; Cheng, C.-H. J. Org. Chem. 2006, 71, 7079; (b) Taguchi, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539; (c) Wang, X.; Zhang, Y.
Synth. Commun. 2002, 32, 3617; (d) Cho, C. S.; Kim, B. T.; Choi, H.-J.; Kim, T.-J.;
Shim, S. C. Tetrahedron 2003, 59, 7997.
8. (a) Heinrich, M. R.; Steglich, W. Tetrahedron 2003, 59, 9231; (b) Matsugi, M.;
Tabusa, F.; Minamikawa, J. Tetrahedron Lett. 2000, 41, 8523; (c) Li, X.-G.; Cheng,
X.; Zhou, Q.-L. Synth. Commun. 2002, 32, 2477.
9. (a) Gates, B. C. Catalysis by Solid Acids. In Encyclopedia of Catalysis; Horváth, I.,
Ed.; Wiley: New York, 2003; Vol. 2, p 104; (b) Molnár, Á. Curr. Org. Chem. 2008,
12, 159; (c) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629; (d)
Dasgupta, S.; Török, B. Curr. Org. Synth. 2008, 5, 321; (e) Loupy, A. Microwaves in
Organic Synthesis; Wiley-VCH, 2005; (f) Kappe, C. O.; Stadler, A. Microwaves in
Organic and Medicinal Chemistry; Wiley-VCH, 2005; (g) Kappe, C. O.; Dallinger,
D. Nat. Rev. 2006, 5, 51.
15. Badger, G. M.; Ennis, B. C.; Matthews, W. E. Aust J. Chem. 1963, 16, 828.
16. Tung, C. C. Tetrahedron 1963, 19, 1685.
17. Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71, 1668.
18. (a) Linders, J. T. M.; Kokje, J. P.; Overhand, M.; Lie, T. S.; Maat, L. Recl. Trav. Chim.
Pays-Bas 1988, 107, 449; (b) Herrero, M. A.; Kremsner, J. M.; Kappe, C. O. J. Org.
Chem. 2008, 73, 36.