Commercial ZrO2 as a new, efficient, and reusable catalyst for the one-step synthesis of quinolines in solvent-free conditions

Article abstract of DOI:10.1139/V09-069

Commercially available zirconia (ZrO₂) is reported as an extremely efficient catalyst for the synthesis of quinolines. A one-step reaction of 2-aminoarylketones and a carbonyl compound (Friedlander reaction) took place under solvent-free condit

Full text of DOI:10.1139/V09-069

1122
Commercial ZrO2 as a new, efficient, and
reusable catalyst for the one-step synthesis of
quinolines in solvent-free conditions
Mona Hosseini-Sarvari
Abstract: Commercially available zirconia (ZrO2) is reported as an extremely efficient catalyst for the synthesis of quino-
lines. A one-step reaction of 2-aminoarylketones and a carbonyl compound (Friedlander reaction) took place under sol-
vent-free conditions to afford the corresponding quinolines in good-to-high yields in the presence of ZrO2. Furthermore,
the catalyst is reused several times without any significant loss of its catalytic activity.
Key words: ZrO2, Quinoline, Friedlander reaction, solvent-free, 2-aminoarylketones.
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Resume : On a observe que la zircone commercialement disponible est un catalyseur extremement efficace pour la syn-
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these des quinoleines. En presence de ZrO2, la reaction de Friedlander, une reaction en une etape entre une 2-aminoarylce-
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tones et un compose carbonyle, se produit dans des conditions sans solvant pour conduire aux quinoleines correspondantes
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avec des rendements allant de bons a excellents. De plus, on peut reutiliser le catalyseur a plusieurs reprises sans perte si-
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gnificative de son activite catalytique.
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Mots-cles : ZrO2, reaction de Friedlander, sans solvant, 2-aminoarylcetones.
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[Traduit par la Redaction]
Introduction
Today, active surfaces, such as metal oxides, play an ever
growing role in organic synthesis and are widely employed
not only for preparative organic reactions but also in the in-
dustry. Such reactions normally proceed under mild condi-
tions, with high chemo-, regio-, and stereo-selectivities,
securing simpler isolation procedures compared with similar
reactions in solution.7,8
Quinolines are well-known for a wide range of medicinal
properties and for being used as antimalarial, antiasthmatic,
antihypertensive, antibacterial, and tyrosine-kinase-inhibiting
agents.1 They also undergo hierarchical self-assembly into a
variety of nano- and meso-structures with enhanced elec-
tronic and photonic functions.2 Thus, a great deal of effort
has been drawn to develop new and efficient synthetic
routes to quinoline derivatives. Among several routes to qui-
noline synthesis, an acid- or base-catalyzed condensation
followed by a cyclodehydration between a 2-aminoarylke-
tone and a carbonyl compound containing a reactive a-meth-
ylene group, namely the Friedlander reaction, is one of the
simplest and straightforward methods.3 This classical
method is still not fully satisfactory with regard to the rela-
tively low yield, harsh reaction conditions, side reactions,
and also under base-catalyzed conditions. In addition, o-ami-
nobenzophenone fails to react with simple ketones such as
cyclohexanone and b-ketoesters.4 Recently, modified meth-
ods employing ZnCl2, SnCl2, Bi(OTf)3, AuCl3, CeCl3, and
so forth5,6 have been reported for the synthesis of quinolines.
In these methods, the catalyst is destroyed during the work-
up and cannot be recovered. However, development of a
new catalyst, which can be reused, commercially available,
new, and simplest for the synthesis of this important class
of heterocyclic compounds is of demand.
Results and discussion
Herein, I have studied the reaction of ethylacetoacetate
with 2-aminoacetophenone in the presence of metal oxides
as a model reaction in solvent-free conditions (Table 1).
1
The progress of the reaction was monitored by TLC and H
NMR spectra from the reaction mixture.
For the first time, it is shown (Table 1) that certain metal
oxides are active catalysts for the interaction studied, partic-
ularly ZrO2, TiO2, and both acidic and basic types of Al2O3.
So, by considering the reaction time and yield, ZrO2 was
found to be the most effective in comparison with other
metal oxides that were chosen. Subsequently, a series of
substituted quinolines were synthesized following the same
method using this catalyst (Scheme 1, Table 2). Interest-
ingly, cyclic ketones, such as cyclohexanone and cyclopen-
tanone, reacted with 2-arylketones to afford the respective
tricyclic quinolines. The reaction is fairly general, clean,
and efficient. The experimental procedure is very simple.
The good-to-high yield transformation did not form any sig-
nificant amounts of undesirable side products.
Received 12 January 2009. Accepted 18 March 2009. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
28 July 2009.
The condensation of 2-aminoarylketones (2) (R3 = Me,
Ph; R4 = H, Cl) with unsymmetrical 1,3-diones (1) gave ex-
clusively the regioisomer 3 if the two carbonyl groups
present in 1 had dissimilar reactivity with regard to enamine
M. Hosseini-Sarvari. Department of Chemistry, Shiraz
University, Shiraz 71454, I.R. Iran. (e-mail:
hossaini@susc.ac.ir).
Can. J. Chem. 87: 1122–1126 (2009)
doi:10.1139/V09-069
Published by NRC Research Press

Hosseini-Sarvari
1123
1
Table 1. H NMR spectroscopic monitoring of the reaction of
Scheme 1.
ethylacetoacetate (1a, 1.5 mmol) with 2-aminoacetophenone
(2a, 1 mmol) at 100 8C under solvent-free condition.
formation. However, the condensation of 2-aminoarylketones
(2) with ethyl-4,4,4-trifluoro-3-oxobutanoate led to regioiso-
meric mixtures of quinolines 3 and 4, respectively (Table 2,
entries 3 and 12). This can be discussed by the similar
activity of the two carbonyl groups present in ethyl-4,4,4-
trifluoro-3-oxobutanoate, where the actual mechanism seems
to be that the enamine formation may proceed in the con-
densation step; however, in this case, it is rather an imi-
noether (4c, 4l).
Entry
Active surfacea
MgO
TiO2
CaO
Time (h)
24
8
24
11
6
Yield (%)
1
2
3
4
5
6
7
40
90
73
90
82
80
98
ZnO
Al2O3 (acidic type)
Al2O3 (basic type)
ZrO2
9
4
From an environmental point of view, it is desirable to
minimize the amount of waste for organic transformation. In
this context, the catalyst was recycled for subsequent runs.
The recyclability of the catalyst was investigated using a
model reaction of the synthesis of quinoline 3a in the pres-
ence of 10 mol% of the catalyst in solvent-free conditions.
After the completion of the reaction (monitored by TLC),
EtOAc was added to the reaction mixture and then filtered to
separate the catalyst. The recycled catalyst was used for fur-
ther runs, and it was found that its activity does not show any
significant decrease even after six runs. It should be noted
that although no solvents are used in the reaction itself, but
to separate the catalyst and for the isolation and purification
of the products, quantitative amounts of solvent are used.
In summary, the present protocol is the first example of
ZrO2-catalyzed synthesis of quinolines in benign conditions.
The advantages of this method are the use of a cheap and
commercially available catalyst. No toxic reagents, solvents,
or byproducts were involved, and no laborious purifications
were necessary. These conditions are also environment-
friendly, cost-effective, and possess high generality to make
our methodology industrialized as a valid contribution to the
existing methodologies in the field of quinoline synthesis.
a10 mol% of the metal oxide was used as catalyst.
1
known and were characterized by H NMR, IR, and mass
spectral data, which were found to be identical to those de-
scribed in the literature, and for the new compounds, com-
plete spectroscopic data are described below.
Compound (3c)
Light yellow solid. H NMR (250 MHz, CDCl3) dH: 7.23–
1
7.33 (4H, m, ArH), 3.95–4.03 (2H, m, –OCH2CH3), 2.33
(3H, s, ArCH3), 1.13 (3H, t, J =7.05 Hz, –OCH2CH3). 13C
NMR (62.9 MHz, CDCl3) dC: 15.3, 17.2, 64.7, 108.1, 115.2,
122.3, 128.9 (–CF3), 119.2, 124.5, 124.8, 128.8, 131.3, 134.6,
145.3, 147.6, 148.9, 171.3. MS (ESI) m/z: 283 (M+ + H). HR-
MS calcd. for C14H12F3NO2 (M+ + H): 283.2490, found:
283.2489. Anal. calcd. for C14H12F3NO2: C, 59.37; H,
4.27%. Found: C, 59.12; H, 4.00.
Compound (4c)
Light yellow solid. H NMR (250 MHz, CDCl3) dH: 7.50–
1
7.93 (4H, m, ArH), 4.39 (2H, m, –OCH2CH3), 2.60 (3H, s,
ArCH3), 1.31 (3H, t, J = 7.05 Hz, –OCH2CH3). 13C NMR
(62.9 MHz, CDCl3) dC: 15.4, 17.5, 65.1, 107.5, 115.1, 122.5,
129.2 (–CF3), 100.2, 162.5, 124.8, 128.9, 130.4, 130.9,
132.7, 141.7, 151.4, 185.0. MS (ESI) m/z: 283 (M+ + H).
HR-MS calcd. for C14H12F3NO2 (M+ + H): 283.2490, found:
283.2489. Anal. calcd. for C14H12F3NO2: C, 59.37; H,
4.27%. Found: C, 59.20; H, 4.03.
Experimental
Chemicals were purchased from Fluka, Merck, BDH, and
Aldrich Chemical Companies. Progress of the reactions was
followed by TLC using silica gel polygrams SIL G/UV 254
plates. NMR spectra were recorded on a Bruker DPX
250 MHz instrument. Microanalyses were performed on a
PerkinElmer 240-B microanalyzer.
Compound (3l)
Light yellow solid. H NMR (250 MHz, CDCl3) dH: 7.40–
1
General procedure
8.50 (9H, m, ArH), 5.25 (2H, m, –OCH2CH3), 1.96 (3H, t,
J =7.06 Hz, –OCH2CH3). 13C NMR (62.9 MHz, CDCl3) dC:
31.2, 65.8, 107.1, 119.2, 122.3, 128.8 (–CF3), 116.0, 122.5,
126.4, 126.9, 127.7, 127.8, 128.1, 128.2, 128.5, 128.7,
130.9, 137.5, 148.0, 161.2. MS (ESI) m/z: 345 (M+ + H).
HR-MS calcd. for C19H14F3NO2 (M+ + H): 345.3190, found:
345.3189. Anal. calcd. for C19H14F3NO2: C, 66.09; H,
4.09%. Found: C, 66.02; H, 4.00.
To a mixture of 2-aminoaryl ketone (1 mmol) and a meth-
ylene carbonyl compound (1.5 mmol) ZrO2 (0.12 g,
10 mol%) was added. The mixture was heated in an oil
bath at 100–120 8C, and the reaction was monitored by
TLC. After the reaction was complete, EtOAc was added to
the reaction mixture, which was filtered to separate the cata-
lyst. The organic solvent was removed under reduced pres-
sure. After purification by chromatography on silica gel (n-
hexane/ethyl acetate, 70:30), the product was obtained. The
Compound (4l)
Light yellow solid. H NMR (250 MHz, CDCl3) dH: 7.13–
1
1
structures of the products were confirmed by H NMR, IR,
and comparison with authentic samples obtained commer-
cially or prepared by reported methods. All products are
7.28 (9H, m, ArH), 4.00 (2H, m, –OCH2CH3), 1.08 (3H, t,
J = 7.06 Hz, –OCH2CH3). 13C NMR (62.9 MHz, CDCl3)
Published by NRC Research Press

1124
Can. J. Chem. Vol. 87, 2009
Table 2. Quinolines synthesis using ZrO2 (10 mol%) as catalyst under solvent-free conditions.
Published by NRC Research Press

Hosseini-Sarvari
1125
Table 2. Concluded.
Published by NRC Research Press

1126
Can. J. Chem. Vol. 87, 2009
A. J. Mol. Catal. A 2007, 274 (1-2), 148–152. doi:10.1016/j.
molcata.2007.04.034.; (k) Jia, C.-S.; Zhang, Z.; Tu, S.-J.;
Wang, G.-W. Org. Biomol. Chem. 2006, 4 (1), 104–110.
doi:10.1039/b513721g. PMID:16358003.; (l) Bose, D. S.; Ku-
mar, R. K. Tetrahedron Lett. 2006, 47 (5), 813–816. doi:10.
1016/j.tetlet.2005.11.075.; (m) Wang, G.-W.; Jia, C.-S.;
Dong, Y.-W. Tetrahedron Lett. 2006, 47 (7), 1059–1063.
doi:10.1016/j.tetlet.2005.12.053.;
dC: 49.5, 66.9, 108.2, 121.1, 123.5, 129.0 (–CF3), 119.3,
126.0, 126.6, 127.1, 127.8, 127.9, 128.2, 128.4, 128.8,
129.1, 133.3, 137.8, 149.3, 201.5. MS (ESI) m/z: 345 (M+ +
H). HR-MS calcd. for C19H14F3NO2 (M+ + H): 345.3190,
found: 345.3189. Anal. calcd. for C19H14F3NO2: C, 66.09;
H, 4.09%. Found: C, 66.00; H, 4.05.
Acknowledgement
(6) (a) Yadav, J. S.; Purushothama Rao, P.; Sreenu, D.; Rao, R.
S.; Naveen Kumar, V.; Nagaiah, K.; Prasad, A. R. Tetrahe-
dron Lett. 2005, 46 (42), 7249–7253. doi:10.1016/j.tetlet.
2005.08.042.; (b) Yadav, J. S.; Subba Reddy, B. V.; Sunitha,
V.; Srinivasa Reddy, K.; Ramakrishna, K. V. S. Tetrahedron
Lett. 2004, 45 (42), 7947–7950. doi:10.1016/j.tetlet.2004.08.
128.; (c) Ghassamipour, S.; Sardarian, A. R. Tetrahedron
Lett. 2009, 50 (5), 514–519. doi:10.1016/j.tetlet.2008.09.097.;
(d) Muscia, G. C.; Bollini, M.; Carnevale, J. P.; Bruno, A. M.;
Asis, S. E. Tetrahedron Lett. 2006, 47 (50), 8811–8815.
doi:10.1016/j.tetlet.2006.10.073.
(7) (a) Banerjee, A. K.; Laya, M. S.; Vera, W. J. Russ.
Chem. Rev. 2001, 70 (11), 971–990. doi:10.1070/
RC2001v070n11ABEH000642.; (b) Sharghi, H.; Hosseini-Sar-
vari, M. J. Chem. Res. 2000, 24.; (c) Sharghi, H.; Hosseini, M.
Synthesis 2002, 2002 (08), 1057–1060. doi:10.1055/s-2002-
31964.; (d) Sharghi, H.; Hosseini-Sarvari, M. Tetrahedron
2002, 58 (52), 10323–10328. doi:10.1016/S0040-4020(02)
01417-5.; (e) Sharghi, H.; Hosseini-Sarvari, M. J. Chem. Res.
(s) 2003, 3, 176; (f) Sarvari, M. H.; Sharghi, H. J. Org. Chem.
2004, 69 (20), 6953–6956. doi:10.1021/jo0494477. PMID:
15387635.; (g) Hosseini-Sarvari, M. Synthesis 2005, 2005
(05), 787–790. doi:10.1055/s-2005-861826.; (h) Hosseini-Sar-
vari, M.; Sharghi, H. Tetrahedron 2005, 61 (46), 10903–
10907. doi:10.1016/j.tet.2005.09.002.; (i) Hosseini-Sarvari,
M.; Sharghi, H. J. Org. Chem. 2006, 71 (17), 6652–6654.
doi:10.1021/jo060847z. PMID:16901164.; (j) Hosseini-Sar-
vari, M.; Sharghi, H.; Etemad, S. Chin. J. Chem. 2007, 25
(10), 1563–1567. doi:10.1002/cjoc.200790288.; (k) Hosseini-
Sarvari, M. Acta Chim. Slov. 2007, 54, 345; (l) Hosseini-Sar-
vari, M.; Sharghi, H. Phos. Silicon. Sulf. 2007, 182 (9), 2125–
2130. doi:10.1080/10426500701372355.; (m) Hosseini-Sar-
vari, M. Synth. Commun. 2008, 38 (6), 832–840. doi:10.1080/
00397910701845274.;
The support of this work by the Shiraz University Re-
search Council is gratefully acknowledged.
References
(1) (a) Sinden, R. E.; Morris, H. R.; Billker, O.; Lindo, V.; Pa-
nico, M.; Etienne, A. E.; Paxton, T.; Dell, A.; Rogers, M. Nat-
ure 1998, 392 (6673), 289–292. doi:10.1038/32667. PMID:
9521324.; (b) Roma, G.; Di Braccio, M.; Grossi, G.; Mattioli,
F.; Ghia, M. Eur. J. Med. Chem. 2000, 35 (11), 1021–1035.
doi:10.1016/S0223-5234(00)01175-2. PMID:11137230.; (c)
Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-
C. J. Med. Chem. 2001, 44 (14), 2374–2377. doi:10.1021/
jm0100335.
(2) (a) Agrawal, A. K.; Jenekhe, S. A. Macromolecules 1991, 24
(25), 6806–6808. doi:10.1021/ma00025a044.; (b) Zhang, X.;
Shetty, A. S.; Jenekhe, S. A. Macromolecules 1999, 32 (22),
7422–7429. doi:10.1021/ma990960+.; (c) Jenekhe, S. A.; Lu,
L.; Alam, M. M. Macromolecules 2001, 34 (21), 7315–7324.
doi:10.1021/ma0100448.
(3) (a) Friedlander, P. Chem. Ber. 1882, 15, 2572; (b) Cheng, C.
C.; Yan, S. J. Org. React. 1982, 28, 37.
(4) Fehnel, E. A. J. Heterocycl. Chem. 1967, 4 (4), 565–570.
doi:10.1002/jhet.5570040417.
(5) (a) Strekowski, L.; Czamy, A. J. Fluor. Chem. 2000, 104 (2),
281–284. doi:10.1016/S0022-1139(00)00252-9.; (b) Hu, Y. Z.;
Zhang, G.; Thummel, R. P. Org. Lett. 2003, 5 (13), 2251–
2253. doi:10.1021/ol034559q. PMID:12816421.; (c) Arcadi,
A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F. Synlett 2003,
(2): 0203–0206. doi:10.1055/s-2003-36798.; (d) McNaughton,
B. R.; Miller, B. L. Org. Lett. 2003, 5 (23), 4257–4259.
doi:10.1021/ol035333q. PMID:14601974.; (e) Yadav, J. S.;
Reddy, B. V.; Premalatha, K. Synlett 2004, (6): 963–966.
doi:10.1055/s-2004-822898.; (f) Yadav, J. S.; Reddy, B. V.;
Sreedhar, P.; Rao, R. S.; Nagaiah, K. Synthesis 2004, 2004
(14), 2381–2385. doi:10.1055/s-2004-831185.; (g) Mogilaiah,
K.; Reddy, C. S. Synth. Commun. 2003, 33 (18), 3131–3134.
doi:10.1081/SCC-120023427.; (h) Desai, U. V.; Mitragotri, S.
D.; Thopate, T. S.; Pore, D. M.; Wadganokar, P. P. ARKIVOK
2006, xv, 198; (i) Atechian, S.; Nock, N.; Norcross, R. D.;
Ratni, H.; Thomas, A. W.; Verron, J.; Masciadri, R. Tetrahe-
dron 2007, 63 (13), 2811–2823. doi:10.1016/j.tet.2007.01.
050.; (j) Das, B.; Damodar, K.; Chowdhury, N.; Kumar, R.
(8) (a) Hosseini-Sarvari, M. Can. J. Chem. 2008, 86 (1), 65–71.
doi:10.1139/V07-135.; (b) Hosseini-Sarvari, M. Tetrahedron
2008, 64 (23), 5459–5466. doi:10.1016/j.tet.2008.04.016.; (c)
Hosseini-Sarvari, M.; Etemad, S. Tetrahedron 2008, 64 (23),
5519–5523. doi:10.1016/j.tet.2008.03.095.; (d) Hosseini-Sar-
vari, M. Act. Chim. Slov. 2008, 440; (e) Hosseini-Sarvari, M.;
Sharghi, H.; Etemad, S. Helv. Chim. Acta 2008, 91 (4), 715–
724. doi:10.1002/hlca.200890072.
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