Efficient synthesis of 2,3,4-trisubstituted quinolines via friedl?nder annulation with nanoporous cage-type aluminosilicate AlKIT-5 catalyst

Article abstract of DOI:10.1055/s-0030-1258575

2-Aminoaryl ketones undergo smooth Friedl?nder condensation/annulation with α-methyleneketones on the surface of nanoporous aluminosilicate catalyst to afford the corresponding quinoline derivatives in good yields with high selectivity due to its high sur

Full text of DOI:10.1055/s-0030-1258575

LETTER
2597
Efficient Synthesis of 2,3,4-Trisubstituted Quinolines via Friedländer
Annulation with Nanoporous Cage-Type Aluminosilicate AlKIT-5 Catalyst
Synthesis of
2.
C
ituted Quinolineshauhan,a R. Chakravarti,a S. M. J. Zaidi,b Salem S. Al-Deyab,c B. V. Subba Reddy,*a,d A. Vinu*a,d
a
International Center for Materials Nanoarchitectonics, WPI Research Center, National Institute for Materials Science,
1-1 Namiki, Tsukuba, 305-0044, Japan
Fax +81(29)8604706; E-mail: vinu.ajayan@nims.go.jp
Department of Chemical Engineering, King Fahd University of Petroleum & Minerals, Dhahran-31261, Saudi Arabia
Department of Chemistry, Petrochemicals Research Chair, Faculty of Science, King Saud University,
P.O. Box 2455, Riyadh 11451, Saudi Arabia
b
c
d
NIMS-IICT Materials Research Center, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 July 2010
from satisfactory due to the occurrence of several side re-
actions. Therefore, new catalytic systems are being con-
tinuously explored in search of improved efficiencies and
cost effectiveness.10 Since quinoline derivatives are in-
Abstract: 2-Aminoaryl ketones undergo smooth Friedländer con-
densation/annulation with a-methyleneketones on the surface of na-
noporous aluminosilicate catalyst to afford the corresponding
quinoline derivatives in good yields with high selectivity due to its
high surface area, large pore volume, and high acidity. The use of creasingly useful and important in drugs and pharmaceu-
highly acidic and reusable AlKIT-5 catalyst makes the Friedländer
ticals, the development of simple, convenient, and high-
annulation simple, convenient, and practical.
yielding protocols is desirable.
Key words: o-aminoaryl ketones, nanoporous catalysts, domino
Following our interest on the use of nanoporous alumino-
reactions, quinolines
silicate catalyst with 3D cage-type porous structure for the
synthesis of biologically active heterocycles,11 we herein
report an efficient and straightforward approach for the
Quinoline scaffolds are important heterocycles in medici-
synthesis of highly substituted quinolines using highly
nal chemistry and are found to possess a broad spectrum
acidic nanoporous AlKIT-5 as a heterogeneous solid-acid
of biological activities such as antimalarial, antibacterial,
catalyst.12,13 In a model reaction, 2-aminobenzophenone
anti-asthmatic, antihypertensive, and anti-inflammatory
(1) was treated with ethyl acetoacetate (2) in the presence
behavior.1,2 The substituted quinoline are found to exhibit
of AlKIT-5. Initially the reaction was carried out with Al-
tyrokinase PDGF-RTK inhibiting properties.3 In addition
KIT-5 catalyst with different Al content. It was found that
to pharmaceutical applications, polyquinolines derived
the amount of Al in the catalyst plays a significant role in
from quinolines are found to undergo hierarchical self-as-
controlling the activity of the catalyst. The catalytic activ-
sembly into a variety of nanostructures and mesostruc-
ity increases with increasing the amount of Al in the cata-
tures with enhanced electronic and photonic functions.4
lyst. Among the catalysts studied, AlKIT-5(10) where the
Consequently, several methods such as Skraup, Doebner–
number in the parenthesis indicates the Si/Al molar ratio
von Miller, Friedländer, and Combes have been reported
in the final product, was found to be the best, affording the
for the synthesis of quinoline derivatives.5,6 Among these
product in high yield. This was mainly due to the fact that
methods, the Friedländer annulation is found to be the best
the acidity, surface area, and the specific pore volume of
approach for the synthesis of substituted quinolines.6b
AlKIT-5(10) are much higher than that of the other Al-
Generally, these annulation reactions are carried out either
KIT-5 catalysts.11 Thus, AlKIT-5(10) was used for the
in the presence of a base catalyst or under thermal condi-
rest of the study. To start with, we have investigated the
tions ranging from 150–220 °C without a catalyst.7 How-
reaction with different weight of the AlKIT-5(10) cata-
lyst. To our surprise, we noticed that 50 mg catalyst was
sufficient for the reaction of 2-aminobenzophenone with
ever, o-aminobenzophenone fails to react with simple
ketones such as cyclohexanone, deoxybenzoin, and b-
keto esters either under thermal or base catalysis.8 Subse-
ethyl acetoacetate in ethanol at 80 °C for obtaining the fi-
quently, acid catalysts were proved to be more effective
nal product ethyl 2-methyl-4-phenyl-quinoline-3-carbox-
ylate (3a) with a yield of 92% (Scheme 1).
than base catalysts for Friedländer annulation.8 Acid cata-
lysts such as hydrochloric acid, sulfuric acid, p-toluene-
In order to investigate the scope and limitation of this
sulfonic acid, and phosphoric acid have been used for this
transformation using the AlKIT-5, we turned our attention
to various b-keto esters and ketones. Notably, various b-
keto esters including methyl acetoacetate and ethyl ben-
zoylacetate participated effectively in this annulation re-
action (entries 2, 3, 8, and 9, Table 1). We also found that
the reaction gave excellent yield with 1,3-diketones such
as acetyl acetone and 1,3-cyclohexanedione (entries 4, 7,
and 10, Table 1). This transformation was also extended
transformation.7,9 However, many of these classical meth-
ods require high temperatures, prolonged reaction times,
drastic conditions, and the conversions reported are far
SYNLETT 2010, No. x, pp 2597–2600
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Advanced online publication: 23.09.2010
DOI: 10.1055/s-0030-1258575; Art ID: U07010ST
© Georg Thieme Verlag Stuttgart · New York

2598
S. Chauhan et al.
LETTER
to the reaction of cyclic ketones and 2-aminoketones.
Both cyclohexanone and cyclopentanone (entries 5, 6, 11,
and 12, Table 1) reacted well with 2-aminoketones under
the influence of AlKIT-5 to furnish the corresponding an-
nulated quinoline derivatives in a 86–91% yield
(Scheme 2). Mechanistically, the reaction proceeds via
the activation of 1,3-diketone by AlKIT-5 to give the cor-
responding enamine. Thus formed enamine subsequently
reacts with keto group to undergo cyclodehydration re-
sulting in the formation of quinoline as depicted in
Scheme 3.
Table 1 AlKIT-5-Catalyzed Synthesis of Quinolines via
Friedländer Annulation
Entry 2-Amino-
ketone
1,3-Diketone Quinolinea
Time Yield
(h) (%)b
Ph
Ph
O
O
O
O
O
O
1
2.5 92
3.0 90
2.5 89
3.5 90
3.0 91
2.5 86
3.0 88
O
O
OEt
OEt
OMe
OEt
NH2
O
N
Ph
Ph
2
3
4
5
6
7
OMe
OEt
Ph
O
Ph
O
NH2
Ph
N
O
O
O
O
OEt
Ph
OEt
AlKIT-5
+
EtOH, reflux
NH2
O
O
N
1
2
3a
NH2
Ph
Ph
O
N
Ph
O
Scheme 1 Friedländer condensation of 2-aminobenzophenone with
b-keto ester
Ph
O
NH2
Ph
R
N
N
R
O
Ph
O
O
AlKIT-5
O
EtOH, reflux
n
+
O
NH2
n
NH2
Ph
N
Scheme 2 Friedländer annulation of cyclic ketones
Ph
O
Notably, no reaction was observed at room temperature or
reflux conditions in the absence of a catalyst. However,
our catalyst was highly active and effective for both cyclic
and acyclic ketones in ethanol under reflux conditions.
Several examples illustrating the scope and generality of
this process with respect to various a-methylene ketones
and 2-aminoaryl ketones, and the results are summarized
in Table 1. The structures of the products were determined
from their spectral data (NMR, IR, and MS) and also by
comparison with authentic samples.7 These data confirm
that the present method is clean and free from side reac-
tions such as self-condensation of ketones which is nor-
mally observed under basic conditions. Interestingly, the
catalyst showed excellent recyclable capability. The cata-
lyst was easily separated by filtration and reused after ac-
tivation at 500 °C for three to four hours. The efficiency
of the recovered catalyst was verified in the coupling of
2-aminobenzophenone with ethyl acetoacetate (entry 1,
Table 1). Using the fresh catalyst, the yield of product 3a
was 92%, while the recovered catalyst gave the yield of
92%, 89%, and 86% over three cycles, respectively.
NH2
Ph
N
O
Ph
O
O
O
O
O
NH2
N
N
N
O
O
O
O
O
O
O
8
9
3.0 89
3.0 86
4.0 90
2.5 90
3.0 91
O
OEt
OEt
OMe
OEt
NH2
O
OMe
NH2
10
11
12
O
NH2
N
N
O
O
O
In summary, we have demonstrated for the first time the
Friedländer annulation using a highly acidic 3D nanopo-
rous aluminosilicate nanocage catalyst for the synthesis of
substituted quinolines. The heterogeneous nature, high
surface area, large pore volume, high acidity, and reus-
ability of the catalyst make the Friedländer annulation
simple, convenient, and practical. This method avoids the
use of hazardous acids or bases and harsh reaction condi-
tions.
NH2
O
NH2
N
a All products were characterized by NMR, IR and mass spectroscopy.
b Yield refers to pure products after column chromatography.
Synlett 2010, No. x, 2597–2600 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,3,4-Trisubstituted Quinolines
2599
R
O
R
R
O
Al
O
O
O
O
OMe
O
OMe
+
– H2O
..
OMe
NH2
..
N
H
N
R
N
O
H
HO
R
O
OMe
OMe
– H2O
N
Scheme 3 A plausible reaction mechanism
(10) (a) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5,
4257. (b) Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P.; Rao,
R. S.; Nagaiah, K. Synthesis 2004, 2381. (c) Arcadi, A.;
Chiarini, M.; Di Giuseppe, S.; Marinelli, F. Synlett 2003,
203. (d) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti,
R. J.; Srinivasan, K. V. J. Org. Chem. 2003, 68, 9371.
(e) Wu, J.; Xia, H.-G.; Gao, K. Org. Biomol. Chem. 2006, 4,
126. (f) Varala, R.; Enugala, R.; Adapa, S. R. Synthesis
2006, 3825.
Acknowledgment
This work was financially supported by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) under the Strate-
gic Program for Building an Asian Science and Technology Com-
munity Scheme and World Premier International Research Center
(WPI) Initiative on Materials Nanoarchitectonics, MEXT, Japan.
B.V.S. thanks CSIR, New Delhi, for the award of fellowships. S.
Chauhan thanks M. Bello for the preparation of the catalyst.
(11) (a) Chakravarti, R.; Kalita, P.; Selvan, S. T.; Oveisi, H.;
Balasubramanian, V. V.; Kantam, M. L.; Vinu, A. Green
Chem. 2010, 12, 49. (b) Shobha, D.; Chari, M. A.; Mano,
A.; Selvan, S. T.; Mukkanti, K.; Vinu, A. Tetrahedron 2009,
65, 10608. (c) Vinu, A.; Kalita, P.; Balasubramanian, V. V.;
Oveisi, H.; Selvan, S. T.; Mano, A.; Chari, M. A.; Reddy,
B. V. S. Tetrahedron Lett. 2009, 50, 7132. (d) Chari, M. A.;
Karthikeyan, G.; Pandurangan, A.; Naidu, T. S.;
Sathyaseelan, B.; Zaidi, S. M. J.; Vinu, A. Tetrahedron Lett.
2010, 51, 2629.
References and Notes
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Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N.
Bioorg. Med. Chem. Lett. 1998, 8, 1255.
(12) General Procedure
A mixture of 2-aminoaryl ketone (1.0 mmol), a-methylene
ketone (1.0 mmol), and AlKIT-5 (50 mg) in EtOH (5 mL)
was stirred at 80 °C for the specified time (see Table 1).
After completion of the reaction, as monitored by TLC, the
catalyst was separated by filtration, and the residue was
washed with EtOH (10 mL). The combined organic layers
were concentrated under reduced pressure, and the crude
product was purified by silica gel column chromatography
using EtOAc–n-hexane (1:9) as eluent to afford the pure
quinoline derivative.
(3) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
Zilberstein, A. J. Med. Chem. 1994, 37, 2129.
(4) (a) Zhang, X.; Shetty, A. S.; Jenekhe, S. A. Macromolecules
1999, 32, 7422. (b) Zhang, X.; Jenekhe, S. A.
Macromolecules 2000, 33, 2069. (c) Jenekhe, S. A.; Lu, L.;
Alam, M. M. Macromolecules 2001, 34, 7315.
(5) (a) Cho, C. S.; Oh, B. H.; Kim, T.-J.; Shim, S. C. Chem.
Commun. 2000, 1885. (b) Jiang, B.; Si, Y.-G. J. Org. Chem.
2002, 67, 9449.
(6) (a) Skraup, Z. H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086.
(b) Friedländer, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.
(c) Manske, R. H. F.; Kulka, M. Org. React. 1953, 7, 59.
(d) Linderman, R. J.; Kirollos, S. K. Tetrahedron Lett. 1990,
31, 2689. (e) Theoclitou, M.-E.; Robinson, L. A.
Tetrahedron Lett. 2002, 43, 3907.
(7) (a) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37.
(b) Thummel, R. P. Synlett 1992, 1. (c) Eckert, H. Angew.
Chem., Int. Ed. Engl. 1981, 20, 208. (d) Gladiali, S.;
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R. P. J. Org. Chem. 2001, 66, 400.
(8) Fehnel, E. A. J. Heterocycl. Chem. 1966, 31, 2899.
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281. (b) Hu, Y.-Z.; Zang, G.; Thummel, R. P. Org. Lett.
2003, 5, 2251. (c) Jia, C.-S.; Zhang, Z.; Tu, S.-J.; Wang,
G.-W. Org. Biomol. Chem. 2006, 4, 104.
Spectral Data for Selected Products
Ethyl 2-Methyl-4-phenylquinoline-3-carboxylate (3a)
Solid, mp 98 °C. IR (KBr): n = 3030, 2960, 1700, 1605,
1568, 1482, 905 cm–1. 1H NMR (200 MHz, CDCl3): d = 0.95
(t, J = 7.0 Hz, 3 H), 2.80 (s, 3 H), 4.05 (q, J = 7.0 Hz, 2 H),
7.35–7.50 (m, 6 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.70 (t, J = 7.9
Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H). MS (EI): m/z = 291 [M]+,
85, 263, 246, 218, 176, 150.
3-Acetyl-2-methyl-4-phenylquinoline (3d)
Solid, mp 115 °C. IR (KBr): n = 3027, 2960, 1705, 1610,
1569, 1485, 705 cm–1. 1H NMR (200 MHz, CDCl3): d = 1.95
(s, 3 H), 2.60 (s, 3 H), 7.25–7.30 (m, 2 H), 7.35 (t, J = 8.0 Hz,
1 H), 7.40–7.50 (m, 3 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.65 (t,
J = 8.0 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H). MS (EI): m/z =
261 [M]+, 246, 218, 176, 150, 43.
9-Phenyl-1,2,3,4-tetrahydroacridine (3e)
Solid, mp 137 °C. IR (KBr): n = 3057, 2945, 1609, 1575,
1480, 1210, 708 cm–1. 1H NMR (200 MHz, CDCl3): d =
1.75–1.85 (m, 2 H), 1.95–2.05 (m, 2 H), 2.60 (t, J = 6.7 Hz,
2 H), 3.20 (t, J = 6.9 Hz, 2 H), 7.20–7.32 (m, 3 H), 7.40–7.60
Synlett 2010, No. x, 2597–2600 © Thieme Stuttgart · New York

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S. Chauhan et al.
LETTER
mixture was stirred for 24 h at 45 °C. Subsequently, the
(m, 5 H), 8.00 (d, J = 8.2 Hz, 1 H). MS (EI): m/z = 259 [M]+,
230, 182, 176, 57.
(13) Syntheses of AlKIT-5 Catalyst with Different nSi/nAl
Ratio
reaction mixture was heated for 24 h at 100 °C under static
conditions for hydrothermal treatment. After hydrothermal
treatment, the final solid product was filtered off and then
dried at 100 °C without washing. The product was calcined
at 540 °C for 10 h. The samples are denoted as AlKIT-5
(x)where x denotes the nSi/nAl ratio in the final product.
The molar gel composition of the reaction mixture was
SiO2/Al2O3/F127/HCl/H2O = 1.0:0.041–
The AlKIT-5 materials with different nSi/nAl ratios were
synthesized using Pluronic F127 as the template in an acidic
medium. In a typical synthesis, 5.0 g of F127 was dissolved
in 3 g of HCl (35 wt%) and 240 g of distilled H2O. To this
mixture, 24.0 g of TEOS and the required amount of the
aluminium isopropoxide were added, and the resulting
0.071:0.0035:0.25:116.6.
Synlett 2010, No. x, 2597–2600 © Thieme Stuttgart · New York

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