Bi(OTf)3-catalyzed Friedl?nder hetero-annulation: A rapid synthesis of 2,3,4-trisubstituted quinolines

Article abstract of DOI:10.1055/s-2004-822898

Polysubstituted quinolines are readily prepared in high yields under extremely mild conditions through a sequential condensation/annulation reaction of 2-aminoaryl ketones and α-methylene ketones using a catalytic amount of bismuth triflate.

Full text of DOI:10.1055/s-2004-822898

LETTER
963
Bi(OTf)3-Catalyzed Friedländer Hetero-Annulation: A Rapid Synthesis of
2,3,4-Trisubstituted Quinolines
B
i(OTf) -C
.
atalyze
d
Fr
S
iedländer
H
ete
.
ro-Annulatio
Y
n
adav,* B. V. S. Reddy, K. Premalatha
3
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)27160512; E-mail: yadav@iict.ap.nic.in
Received 4 December 2004
development of simple, convenient and high yielding pro-
tocols is desirable.
Abstract: Polysubstituted quinolines are readily prepared in high
yields under extremely mild conditions through a sequential con-
densation/annulation reaction of 2-aminoaryl ketones and a-meth-
ylene ketones using a catalytic amount of bismuth triflate.
Recently, bismuth(III) triflate has attracted the attention
of synthetic organic chemists because it is inexpensive
Key words: o-aminoaryl ketones, bismuth catalysis, domino reac- and it can be readily prepared on a multi-gram scale in the
tions, quinolines
laboratory from commercially available bismuth(III) ox-
ide and triflic acid.12 Owing to its unique catalytic proper-
ties, bismuth(III) triflate has been extensively used for a
plethora of organic transformations.13 However, there
Quinolines are found to possess a wide spectrum of bio-
have been no reports on the use of bismuth triflate for
Friedlander quinoline synthesis.
logical activities such as antimalarial, antibacterial, anti-
asthmatic, antihypertensive and antiinflammatory
behavior.1,2 Aryl substituted quinolines are found to ex-
hibit tyrokinase PDGF-RTK inhibiting properties.3 In ad-
dition to medicinal applications, polyquinolines derived
from quinolines, are found to undergo hierarchical self-as-
sembly into a variety of nanostructures and mesostruc-
tures with enhanced electronic and photonic functions.4
Consequently, various methods such as Skraup, Doebner
von Miller, Friedländer and Combes methods have been
developed for the preparation of quinoline derivatives.5,6
Among them, Friedländer annulation is one of the most
simple and straightforward approaches for the synthesis
of polysubstituted quinolines.6b Friedländer reactions are
generally carried out either by refluxing an aqueous or al-
coholic solution of reactants in the presence of base or by
heating a mixture of the reactants at high temperatures
ranging from 150–220 °C in the absence of catalyst.7 Un-
der thermal or base catalysis conditions, o-aminoben-
zophenone fails to react with simple ketones such as
cyclohexanone, deoxybenzoin and b-keto esters.8 Subse-
quent work showed that acid catalysts are more effective
than base catalysts for the Friedländer annulation.8 Acid
catalysts such as hydrochloric acid, sulfuric acid, p-tolue-
nesulfonic acid and phosphoric acids are widely used for
this conversion.7a,9 However, many of these classical
methods require high temperatures, prolonged reaction
times and drastic conditions and the yields reported are far
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 As a result, Lewis acids such as
ZnCl2, and AuCl3·3H2O are found to be effective for this
conversion.11 Since quinoline derivatives are increasingly
useful and important in drugs and pharmaceuticals, the
In this article, we wish to report a mild and efficient ver-
sion of the Friedländer annulation for the synthesis of
polysubstituted quinolines using a catalytic amount of
Bi(OTf)3. Accordingly, treatment of 2-aminobenzophe-
none (1) with acetyl acetone (2) in the presence of 5 mol%
of Bi(OTf)3 resulted in the formation of 3-acetyl-2-meth-
yl-4-phenylquinoline (3a) in 91% yield (Scheme 1).
Scheme 1
Similarly, various 1,3-diketones such as 1,3-cyclohex-
anedione and 5,5-dimethylcyclohexanedione (dimedone)
and acyclic ketones including 2-butanone and 3-pen-
tanone reacted efficiently with 2-aminobenzophenone to
give the corresponding substituted quinolines. Interest-
ingly, cyclic ketones such as cyclopentanone and cyclo-
hexanone also underwent smooth condensation with 2-
aminoaryl ketones to afford the respective tricyclic quin-
olines (Scheme 2).
Scheme 2
This method is equally effective for both cyclic and acy-
clic ketones. Various substituted 2-aminoaryl ketones
such as 2-aminoacetophenone, 2-aminobenzophenone, 2-
amino-5-chloro-benzophenone and 2-amino-5-chloro-2¢-
fluoro-benzophenone reacted smoothly with a-methylene
SYNLETT 2004, No. 6, pp 0963–0966
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-822898; Art ID: D29003ST
© Georg Thieme Verlag Stuttgart · New York

964
J. S. Yadav et al.
LETTER
ketones to produce a range of quinoline derivatives. In all Ce(OTf)3 studied for this transformation, bismuth(III) tri-
cases, the reactions proceeded rapidly at room tempera- flate was found to be the most effective in terms of con-
ture with high efficiency. As solvent, EtOH appeared to version and reaction rates. Similar yields and selectivity
give the best results. The products were characterized by were also obtained using 5 mol% of scandium(III) triflate
1H, 13C NMR, IR and mass spectroscopic data and also by under identical conditions. In the absence of catalyst, the
comparison with authentic samples.7a This method is reaction did not yield any product even after long reaction
clean and free from side reactions such as self-condensa- times (8–12 h). The scope and generality of this process is
tion of ketones which are normally observed under basic illustrated with respect to various 2-aminoaryl ketones
conditions. Unlike reported methods, the present protocol and a wide array of a-methylene ketones and the results
does not require high temperature or drastic conditions to are summerized in the Table 1.14
produce quinoline derivatives. Among the various metal
triflates such as Cu(OTf)2, Yb(OTf)3, In(OTf)3 and
Table 1 Bi(OTf)3-Catalyzed Synthesis of Quinolines and Polycyclic Quinolines
Entry
a
2-Aminoketone
1
Ketone
2
Quinolinea
3
Mp (°C)
Time (h)
4.0
Yield (%)b
91
115 (113–114)c
b
c
d
e
f
98 (99–100)c
96
3.5
5.0
6.0
4.0
3.5
5.0
6.0
3.0
86
80
75
90
86
81
84
82
147
130 (132–134)c
138 (140–142)c
155 (156–157)c
195 (190–192)c
Liquid
g
h
i
j
78 (78–79)c
4.5
5.5
85
80
k
150 (151–152)c
l
110
131
5.0
5.5
77
85
m
Synlett 2004, No. 6, 963–966 © Thieme Stuttgart · New York

LETTER
Bi(OTf)3-Catalyzed Friedländer Hetero-Annulation
965
Table 1 Bi(OTf)3-Catalyzed Synthesis of Quinolines and Polycyclic Quinolines (continued)
Entry
n
2-Aminoketone
1
Ketone
2
Quinolinea
3
Mp (°C)
114
Time (h)
6.0
Yield (%)b
72
o
p
138
112
5.0
6.5
80
75
a All products were characterized by 1H NMR, IR, and mass spectroscopy.
b Yield refers to pure products after chromatography.
c Melting points indicated in parenthesis refer to literature values.7
(6) (a) Skraup, H. Chem. Ber. 1880, 13, 2086. (b) Friedländer,
P. Ber. 1882, 15, 2572. (c) Mansake, 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.;
Chelucci, G.; Mudadu, M. S.; Gastaut, M. A.; Thummel, R.
P. J. Org. Chem. 2001, 66, 400.
In conclusion, we describe a mild and efficient version of
the Friedländer annulation for the synthesis of quinolines
and polycyclic quinolines using bismuth(III) triflate as a
novel catalyst. This method not only offers substantial
improvements in reaction rates and yields but also avoids
the use of hazardous acids or bases and harsh reaction
conditions.
Acknowledgment
(8) Fehnel, E. A. J. Heterocycl. Chem. 1966, 31, 2899.
(9) (a) Strekowski, L.; Czamy, A. J. Fluor. Chem. 2000, 104,
281. (b) Hu, Y.-Z.; Zang, G.; Thummel, R. P. Org. Lett.
2003, 5, 2251.
B.V.S. and K.P.L thank CSIR, New Delhi for the award of
fellowships.
(10) (a) Kwon, T. W.; Song, S. J.; Cho, S. J. Tetrahedron Lett.
2003, 44, 255. (b) Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.;
Kumar, V. N.; Nagaiah, K. Synthesis 2003, 1610. (c) Cho,
S. C.; Oh, B. O.; Shin, S. C. Tetrahedron Lett. 1999, 40,
1499.
(11) (a) Arcadi, A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F.
Synlett 2003, 203. (b) McNaughton, B. R.; Miller, B. L.
Org. Lett. 2003, 5, 4257. (c) Walser, A.; Flyll, T.; Fryer, R.
I. J. Heterocycl. Chem. 1975, 12, 737.
(12) Repichet, S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 2002, 43, 993.
(13) Leonard, M. N.; Wieland, L. C.; Mohan, R. S. Tetrahedron
2002, 58, 8373.
(14) General Procedure: A mixture of the 2-aminoaryl ketone
(1.0 mmol), a-methylene ketone (1.2 mmol) and Bi(OTf)3 or
Sc(OTf)3 (5 mol%) in EtOH (10 mL) was stirred at r.t. for the
specified time (see Table 1). After completion of the
reaction as indicated by TLC, the reaction mixture was
quenched with water (15 mL) and extracted with EtOAc (2
× 10 mL). Evaporation of the solvent followed by
purification on silica gel (Merck, 100–200 mesh, EtOAc–
hexane, 0.5:9.5) afforded pure quinoline. Spectral data for
selected products: 3a: 3-Acetyl-2-methyl-4-phenyl-
quinoline: Solid; mp 115 °C. IR (KBr): 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), 8.0 (d, J = 8.2 Hz, 1 H). EIMS: m/
z (%) = 261 (75) [M+], 246 (100), 218 (80), 176 (50), 150
(20), 43 (30). 3b: Ethyl 2-methyl-4-phenyl-quinoline-3-
References
(1) (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.;
Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.;
Gauthier, J. Y.; Xiang, Y. B.; Zamboni, R. J. J. Org. Chem.
1996, 61, 3398. (b) Chen, Y. L.; Fang, K. C.; Sheu, J.-Y.;
Hsu, S. L.; Tzeng, C. C. J. Med. Chem. 2001, 44, 2374.
(c) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia,
M. Eur. J. Med. Chem. 2000, 35, 1021.
(2) (a) Kalluraya, B.; Sreenivasa, S. Farmaco 1998, 53, 399.
(b) Doube, D.; Blouin, M.; Brideau, C.; Chan, C.;
Desmarais, S.; Eithier, D.; Falgueyret, J. P.; Friesen, R. W.;
Girard, M.; Girard, Y.; Guay, J.; Tagari, P.; Young, R. N.
Bioorg. Med. Chem. Lett. 1998, 8, 1255.
(3) Maguire, M. P.; Sheets, K. R.; McVety, K.; Spada, A. P.;
Zilberstein, A. J. Med. Chem. 1994, 37, 2129.
(4) (a) Agarwal, A. K.; Jenekhe, S. A. Macromolecules 1991,
24, 6806. (b) Zhang, X.; Shetty, A. S.; Jenekhe, S. A.
Macromolecules 1999, 32, 7422. (c) Zhang, X.; Shetty, A.
S.; Jenekhe, S. A. Macromolecules 2000, 33, 2069.
(d) Jenekhe, S. A.; Lu, L.; Alam, M. M. Macromolecules
2001, 34, 7315.
(5) (a) Jones, G. In Comprehensive Heterocyclic Chemistry II,
Vol. 5; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
New York, 1996, 167. (b) Cho, C. S.; Oh, B. H.; Kim, T. J.;
Shim, S. C. Chem. Commun. 2000, 1885; and references
therein. (c) Jiang, B.; Si, Y.-C. J. Org. Chem. 2002, 67,
9449.
Synlett 2004, No. 6, 963–966 © Thieme Stuttgart · New York

966
J. S. Yadav et al.
LETTER
carboxylate : Solid; mp 98 °C. IR (KBr): 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). EIMS: m/z (%) =
291 (85) [M+], 263 (10), 246 (100), 218 (60), 176 (40), 150
(20). 3f: 9-Phenyl-1,2,3,4-tetrahydroacridine: Solid; mp
137 °C. IR (KBr): 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 (m, 5 H), 8.0 (d, J
= 8.2 Hz, 1 H). EIMS: m/z (%) = 259 (100) [M+], 230 (30),
182 (10), 176 (12), 57 (25). 3h: 3,3-Dimethyl-9-phenyl-
1,2,3,4-tetrahydro-1-acridinone: Solid; mp 197 °C. IR
(KBr): 3060, 2958, 1710, 1601, 1575, 1208, 735 cm–1. 1H
NMR (200 MHz, CDCl3): d = 1.20 (s, 6 H), 2.55 (s, 2 H),
3.30 (s, 2 H), 7.10–7.20 (m, 2 H), 7.35–7.50 (m, 5 H), 7.75
(t, J = 7.9 Hz, 1 H), 8.05 (d, J = 8.1 Hz,1 H). EIMS: m/z (%)
= 301 (100) [M+], 272 (70), 246 (60), 218 (45), 190 (10). 3k:
6-Chloro-3-acetyl-2-methyl-4-phenyl-quinoline: Solid;
mp 150 °C. IR (KBr): 3028, 2960, 1703, 1609, 1570, 1485,
901 cm–1. 1H NMR (200 MHz, CDCl3): d = 2.0 (s, 3 H), 2.60
(s, 3 H), 7.35–7.40 (m, 2 H), 7.60–7.70 (m, 3 H), 8.20 (d, J
= 8.0 Hz, 1 H), 8.45–8.55 (m, 2 H). EIMS: m/z (%) = 295
(65) [M+], 280 (100), 252 (30), 217 (40), 189 (20), 176 (50),
109 (10). 3n: Ethyl 6-chloro-4-(2-fluorophenyl)-2-
methyl-3-quinolinecarboxylate: Solid; mp 114 °C. IR
(KBr): 3029, 2960, 1702, 1601, 1570, 1483, 900 cm–1. 1H
NMR (200 MHz, CDCl3): d = 0.98 (t, J = 7.0 Hz, 3 H), 2.80
(s, 3 H), 4.06 (q, J = 7.0 Hz, 2 H), 7.20–7.30 (m, 3 H), 7.38–
7.70 (m, 3 H), 8.05 (d, J = 8.2 Hz, 1 H). EIMS: m/z (%) =
342 (100) [M+], 298 (90), 270 (45), 236 (40), 194 (40), 177
(10), 71 (10), 57 (38).
Synlett 2004, No. 6, 963–966 © Thieme Stuttgart · New York