Molecular iodine: A highly efficient catalyst in the synthesis of quinolines via Friedlaender annulation

Article abstract of DOI:10.1039/b514635f

A mild and efficient route for the synthesis of quinolines and polycyclic quinolines via Friedlaender annulation, utilizing molecular iodine (1 mol%) as a new catalyst, is described. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b514635f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Molecular iodine: a highly efficient catalyst in the synthesis of quinolines via
¨
Friedlander annulation
Jie Wu,* Hong-Guang Xia and Ke Gao
Received 17th October 2005, Accepted 3rd November 2005
First published as an Advance Article on the web 28th November 2005
DOI: 10.1039/b514635f
A mild and efficient route for the synthesis of quinolines and polycyclic quinolines via Friedla¨nder
annulation, utilizing molecular iodine (1 mol%) as a new catalyst, is described.
o-aminobenzophenone fails to react with simple ketones such
Introduction
as cyclohexanone and b-keto esters.9 Recently, Lewis acids such
as FeCl3, Mg(ClO4)2, ZnCl2, SnCl2, Bi(OTf)3, Sc(OTf)3, silver
phosphotungstate, sodium fluoride, and NaAuCl4·2H2O have been
reported to be effective for the synthesis of quinolines.10 However,
many of these procedures also suffered from harsh reaction
conditions, low yields, difficulties in work-up, and the use of
stoichiometric and/or relatively expensive reagents. And in some
cases, high catalyst loading had to be employed in order to obtain
respectable yields. Since quinoline derivatives are increasingly
useful and important in pharmaceuticals and industry, the devel-
opment of a simple, eco-benign, low cost protocol is still desirable.
Inspired by reports of continuation of interest in catalytic
applications of elemental iodine for organic transformation,1,2
we considered employing molecular iodine as a catalyst for
Friedla¨nder quinoline synthesis since most of the iodine-catalyzed
transformations are acid-induced processes. As Friedla¨nder an-
nulations are among the most important acid-mediated reactions,
development of a reaction that uses catalytic amounts of low toxic,
economic, readily available iodine should greatly contribute to the
creation of environmentally benign processes.
Recently, molecular iodine has received considerable attention as
an inexpensive, nontoxic, readily available catalyst for various
organic transformations, affording the corresponding products
in excellent yields with high selectivity. The mild Lewis acidity
associated with iodine enhanced its usage in organic synthesis to
realize several organic transformations using stoichiometric levels
to catalytic amounts. Owing to numerous advantages associated
with this eco-friendly element, iodine has been explored as
a powerful catalyst for various organic transformations.1,2 For
instance, it shows high efficiency in the Hantzsch reaction1a as well
as the cyanation of imines.1b,1o Recently, we found that it was also
efficient as a catalyst in the synthesis of quinolines and polycyclic
quinolines via Friedla¨nder annulation, which is disclosed herein.
As a privileged fragment, quinoline is a ubiquitous subunit
in many quinoline-containing natural products with remark-
able biological activities.3 Members of this family have wide
applications in medicinal chemistry, being used as antimalarial,
antiinflammatory, antiasthmatic, antibacterial, antihypertensive,
and tyrosine kinase inhibiting agents.3 In addition, quinolines
are valuable synthons, used for the preparation of nano- and
mesostructures with enhanced electronic and photonic properties.4
Because of their importance as substructures in a broad range of
natural and designed products, significant effort continues to be
directed into the development of new quinoline-based structures5
and new methods for their construction.6
As part of a continuing effort in our laboratory toward the
development of new methods for the expeditious synthesis of bio-
logically relevant heterocyclic compounds,7 we became interested
in the possibility of developing a novel and efficient method to
construct the quinoline scaffold. Though some methods such as
the Skraup, Doebner–von Miller, and Combes reactions8 are avail-
able, the protocol reported by Friedla¨nder is one of the most simple
and straightforward methods for the synthesis of polysubstituted
quinolines. The Friedla¨nder annulation, that is, a condensation fol-
lowed by a cyclodehydration between 2-aminoaryl ketones and a-
methylene ketones, is catalyzed by both acids and bases. Brønsted
acids like sulfamic acid, hydrochloric acid, sulfuric acid, p-toluene
sulfonic acid and phosphoric acid were widely used as catalysts.9
However, many of these methods require harsh reaction conditions
and lead to several side reactions. Under base catalysis conditions,
Results and discussion
An initial study was performed by the treatment of 2-
aminobenzophenone 1a with ethyl acetoacetate 2a in EtOH in
the presence of a catalytic amount of I2 (10 mol%) at room
temperature. To our delight, we observed the formation of ethyl-2-
methyl-4-phenylquinoline-3-carboxylate 3a. Complete conversion
and 96% isolated yield were obtained after 16 hours. Further
studies established that 1 mol% of catalyst was also efficient in this
reaction (1 mol%: 16 hours, 96% yield). Moreover, it is noteworthy
that this reaction could be run under air without loss of efficiency
(Scheme 1).
Scheme 1 Reaction of 1a and 2a catalyzed by I2 (1 mol%) in EtOH at
room temperature.
Among the solvents (EtOH, THF, H2O, CH3CN, toluene)
screened, EtOH was demonstrated as the best solvent. Under
solvent-free conditions, the reaction also proceeded smoothly to
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai,
200433, China. E-mail: jie_wu@fudan.edu.cn; Fax: 86 21 6510 2412;
Tel: 86 21 5566 4619
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Table 1 Molecular iodine-catalyzed Friedla¨nder synthesis of quinolinesa
Entry
1
2-Aminoaryl ketone 1
Ketone 2
Product 3
Yield (%)b
96
2
3
4
5
90
73
88
68
6
7
53
98
8
9
93
71
83
10
11
12
76
61
a Reaction conditions: 2-aminoaryl ketone 1 (0.5 mmol), a-methylene ketone 2 (0.6 mmol, 1.2 equiv.), iodine (1 mol%), EtOH (1.0 mL), r.t. b Isolated
yield based on 2-aminoaryl ketone 1.
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afford the corresponding product although the yield was slightly
lower (89%). To demonstrate the generality of this method, we next
investigated the scope of this reaction under the optimized condi-
tions (EtOH, 1 mol% of iodine, r.t.) and the results are summarized
in Table 1. As shown in Table 1, this method is equally effective for
both cyclic and acyclic ketones. Various substituted 2-aminoaryl
ketones 1 such as 2-aminobenzophenone, 2-aminoacetophenone,
and 2-amino-5-chlorobenzophenone reacted smoothly with a-
methylene ketones 2 to produce a range of quinoline derivatives.
Complete conversion and good to excellent isolated yields were
observed for all substrates employed. This reaction is very clean
and free from side reactions, such as self-condensation of ketones,
which are normally observed under basic conditions. Unlike
reported methods, the present protocol does not require high
temperature or drastic conditions to produce quinoline derivatives.
In the absence of a catalyst, the reaction did not yield any product
even after long reaction times. Interestingly, cyclic ketones such
as cyclopentanone and cyclohexadione also underwent smooth
condensation with 2-aminoaryl ketones to afford the respective
tricyclic quinolines (for example: Table 1, entries 3 and 4).
3d: 9-phenyl-3,4-dihydroacridin-1(2H)-one. 1H NMR (400 MHz,
CDCl3): d (ppm) 2.24–2.27 (m, 2H), 2.69 (t, J = 6.6 Hz, 2H), 3.36
(t, J = 6.4 Hz, 2H), 7.17–7.19 (m, 2H), 7.40–7.46 (m, 6H), 8.05 (d,
J = 8.7 Hz, 1H).
3e: ethyl-2,4-dimethylquinoline-3-carboxylate. 1H NMR
(500 MHz, CDCl3): d (ppm) 1.41 (t, J = 7.1 Hz, 3H), 2.61 (s, 3H),
2.71 (s, 3H), 4.45–4.49 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.66 (t,
J = 7.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz,
1H).
3f: 1-(2,4-dimethylquinolin-3-yl)ethanone. 1H NMR (500 MHz,
CDCl3): d (ppm) 2.54 (d, J = 12.3 Hz, 6H), 2.62 (s, 3H), 7.49 (t,
J = 7.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.91 (d, J = 8.3 Hz,
1H), 7.99 (d, J = 8.4 Hz, 1H).
3g: ethyl-6-chloro-2-methyl-4-phenylquinoline-3-carboxylate. 1H
NMR (500 MHz, CDCl3): d (ppm) 0.94 (t, J = 7.1 Hz, 3H), 2.77
(s, 3H), 4.04–4.09 (m, 2H), 7.34–7.66 (m, 7H), 8.00 (d, J = 9.0 Hz,
1H).
3h: 1-(6-chloro-2-methyl-4-phenylquinolin-3-yl)ethanone. 1H
NMR (500 MHz, CDCl3): d (ppm) 2.00 (s, 3H), 2.68 (s, 3H),
7.33–7.35 (m, 2H), 7.53–7.66 (m, 5H), 8.00 (d, J = 8.9 Hz, 1H).
3i: 7-chloro-9-phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline. 1H
NMR (400 MHz, CDCl3): d (ppm) 2.14–2.18 (m, 2H), 2.89 (t, J =
7.3 Hz, 2H), 3.21 (t, J = 7.8 Hz, 2H), 7.32–7.34 (m, 2H), 7.52–7.53
(m, 5H), 7.98 (d, J = 9.2 Hz, 1H).
3j: 7-chloro-9-phenyl-3,4-dihydroacridin-1(2H)-one. 1H NMR
(400 MHz, CDCl3): d (ppm) 2.22–2.27 (m, 2H), 2.69–2.72 (m, 2H),
3.34–3.37 (m, 2H), 7.15–8.00 (m, 8H).
Conclusions
In conclusion, we describe a mild and efficient route for the
synthesis of quinolines and polycyclic quinolines utilizing molec-
ular iodine as a novel catalyst via Friedla¨nder annulation. This
method not only provides an excellent complement to quinoline
synthesis via Friedla¨nder annulation, but also avoids the use of
hazardous acids or bases and harsh reaction conditions. The
advantages of this method include good substrate generality, the
use of inexpensive reagents and catalyst under mild conditions,
and experimental operational ease. Reactions employing iodine as
a catalyst for other organic transformations are currently under
investigation in our research group, and will be reported in due
course.
3k: ethyl 6-chloro-4-(2-chlorophenyl)-2-methylquinoline-3-car-
boxylate. 1H NMR (400 MHz, CDCl3): d (ppm) 0.95–0.98 (m,
3H), 2.81 (s, 3H), 4.06–4.08 (m, 2H), 7.27–7.55 (m, 6H), 8.02 (d,
J = 9.3 Hz, 1H).
3l: 1-(6-chloro-4-(2-chlorophenyl)-2-methylquinolin-3-yl)etha-
none. 1H NMR (400 MHz, CDCl3): d (ppm) 2.15 (s, 3H), 2.71
(s, 3H), 7.23–7.28 (m, 2H), 7.40–7.67 (m, 4H), 8.01 (d, J = 9.2 Hz,
1H).
Experimental
General procedure
A mixture of the 2-aminoaryl ketone 1 (0.5 mmol), the a-methylene
ketone 2 (0.6 mmol, 1.2 equiv.) and I2 (1 mol%) in EtOH (1.0 mL)
was stirred at r.t. 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 afforded pure quinoline.
(All the products are known compounds. The characterizations
of these compounds are identical with the literature reports.10)
References
1 (a) S. Ko, M. N. V. Sastry, C. Lin and C.-F. Yao, Tetrahedron Lett., 2005,
46, 5771; (b) J. S. Yadav, B. V. S. Reddy, M. Srinivas and K. Sathaiah,
Tetrahedron Lett., 2005, 46, 3489; (c) C.-M. Chu, S. Gao, M. N. V.
Sastry and C.-F. Yao, Tetrahedron Lett., 2005, 46, 4971; (d) W.-Y. Chen
and J. Lu, Synlett, 2005, 1337; (e) B. S. Lee, S. Mahajan and K. D. Janda,
Synlett, 2005, 1325; (f) M. C. Bagley, C. Glover and D. Chevis, Synlett,
2005, 649; (g) B. K. Banik, M. Fernandez and C. Alvarez, Tetrahedron
Lett., 2005, 46, 2479; (h) B. K. Banik, M. Chapa, J. Marquez and M.
Cardona, Tetrahedron Lett., 2005, 46, 2341; (i) P. D. Lokhande, S. S.
Sakate, K. N. Taksande and B. Navghare, Tetrahedron Lett., 2005, 46,
1573; (j) P. Gogoi, P. Hazarika and D. Konwar, J. Org. Chem., 2005,
70, 1934; (k) J. Sun, Y. Dong, L. Cao, X. Wang, S. Wang and Y. Hu,
J. Org. Chem., 2004, 69, 8932; (l) K. V. N. S. Srinivas and B. Das,
Synthesis, 2004, 2091; (m) R. S. Bhosale, S. V. Bhosale, T. Wang and
P. K. Zubaidha, Tetrahedron Lett., 2004, 45, 7187; (n) B. P. Bandgar
and S. V. Bettigeri, J. Chem. Res., 2004, 389; (o) L. Royer, S. K. De and
R. A. Gibbs, Tetrahedron Lett., 2005, 46, 4595.
3a: ethyl-2-methyl-4-phenylquinoline-3-carboxylate. 1H NMR
(500 MHz, CDCl3): d (ppm) 0.94 (t, J = 7.1 Hz, 3H), 2.79 (s, 3H),
4.04–4.09 (m, 2H), 7.36–7.72 (m, 8H), 8.07 (d, J = 8.4 Hz, 1H).
3b: 1-(2-methyl-4-phenylquinolin-3-yl)ethanone. 1H NMR
(400 MHz, CDCl3): d (ppm) 2.00 (s, 3H), 2.71 (s, 3H), 7.36–8.11
(m, 9H).
2 (a) K. K. Rana, C. Guin, B. Banerjee and S. C. Roy, J. Indian Chem.
Soc., 2003, 80, 1005; (b) J. S. Yadav, B. V. S. Reddy, K. V. Rao, K. S.
Raj, P. P. Rao, A. R. Prasad and D. Gunasekar, Tetrahedron Lett.,
2004, 45, 6505; (c) P. Phukan, J. Org. Chem., 2004, 69, 4005; (d) B. P.
Bandgar, S. V. Bettigeri and N. S. Joshi, Synth. Commun., 2004, 34,
3c: 9-phenyl-2,3-dihydro-1H-cyclopenta[b]quinoline. 1H NMR
(400 MHz, CDCl3): d (ppm) 2.16–2.19 (m, 2H), 2.91 (t, J = 7.3 Hz,
2H), 3.25 (t, J = 7.6 Hz, 2H), 7.36–8.10 (m, 9H).
1 2 8 | Org. Biomol. Chem., 2006, 4, 126–129
This journal is
The Royal Society of Chemistry 2006
©

View Online
1447; (e) X. Gang, Y. Zhu, H. Birch, H. A. Hjuler and N. J. Bjerrum,
Appl. Catal., A, 2004, 261, 91; (f) P. Phukan, Synth. Commun., 2004,
34, 1065; (g) J. S. Yadav, B. V. S. Reddy and M. S. Reddy, Synlett, 2003,
1722; (h) B. Karimi and D. Zareyee, Synthesis, 2003, 1875; (i) C.-S.
Liu, C.-F. Zhao and G.-X. Luo, Hecheng Huaxue, 2003, 11, 254; (j) R.
Saeeng, U. Sirion, P. Sahakitpichan and M. Isobe, Tetrahedron Lett.,
2003, 44, 6211; (k) J. S. Yadav, B. V. S. Reddy, C. V. Rao and M. S. Reddy,
Synthesis, 2003, 247; (l) B. P. Bandgar and K. A. Shaikh, Tetrahedron
Lett., 2003, 44, 1959; (m) J. S. Yadav, B. V. S. Reddy, M. S. Reddy and
A. R. Prasad, Tetrahedron Lett., 2002, 43, 9703; (n) J. S. Yadav, B. V. S.
Reddy, K. Sadasiv and G. Satheesh, Tetrahedron Lett., 2002, 43, 9695;
(o) J. S. Yadav, B. V. S. Reddy, C. V. Rao and K. V. Rao, J. Chem. Soc.,
Perkin Trans. 1, 2002, 1401; (p) B. Karimi and B. Golshani, Synthesis,
2002, 784; (q) J. S. Yadav, P. K. Chand and S. Anjaneyulu, Tetrahedron
Lett., 2002, 43, 3783; (r) M. K. Basu, S. Samajdar, F. F. Becker and
B. K. Banik, Synlett, 2002, 319; (s) J. S. Yadav, B. V. S. Reddy, C. V. Rao,
P. K. Chand and A. R. Prasad, Synlett, 2001, 1638; (t) S. Samajdar,
M. K. Basu, F. F. Becker and B. K. Banik, Tetrahedron Lett., 2001, 42,
4425; (u) C. Mukhopadhyay, F. F. Becker and B. K. Banik, J. Chem.
Res., Synop., 2001, 28; (v) N. Deka and J. C. Sarma, J. Org. Chem.,
2001, 66, 1947; (w) H. M. S. Kumar, B. V. S. Reddy, E. J. Reddy and
J. S. Yadav, Chem. Lett., 1999, 857; (x) K. M. Kim, D. J. Jeon and E. K.
Ryu, Synthesis, 1998, 835; (y) N. Deka, D. J. Kalita, R. Borah and J. C.
Sarma, J. Org. Chem., 1997, 62, 1563.
3 (a) R. D. Larsen, E. G. Corley, A. O. King, J. D. Carrol, P. Davis, T. R.
Verhoeven, P. J. Reider, M. Labelle, J. Y. Gauthier, Y. B. Xiang and R.
Zamboni, J. Org. Chem., 1996, 61, 3398; (b) Y. L. Chen, K. C. Fang,
J. Y. Sheu, S. L. Hsu and C. C. Tzeng, J. Med. Chem., 2001, 44, 2374;
(c) G. Roma, M. D. Braccio, G. Grossi and M. Chia, Eur. J. Med.
Chem., 2000, 35, 1021; (d) D. Doube, M. Bloun, C. Brideau, C. Chan,
S. Desmarais, D. Eithier, J. P. Falgueyeret, R. W. Friesen, M. Girad, Y.
Girad, J. Guay, P. Tagari and R. N. Yong, Bioorg. Med. Chem. Lett.,
1998, 8, 1255; (e) M. P. Maguire, K. R. Sheets, K. Mcvety, A. P. Spada
and A. Zilberstein, J. Med. Chem., 1994, 37, 2129; (f) O. Bilker, V.
Lindo, M. Panico, A. E. Etiene, T. Paxton, A. Dell, M. Rogers, R. E.
Sinden and H. R. Morris, Nature, 1998, 289.
4 (a) A. K. Aggarwal and S. A. Jenekhe, Macromolecules, 1991, 24, 6806;
(b) X. Zhang, A. S. Shetty and S. A. Jenekhe, Macromolecules, 1999,
32, 7422; (c) S. A. Jenekhe, L. Lu and M. M. Alam, Macromolecules,
2001, 34, 7315.
5 M. Z. Hoemann, G. Kumaravel, R. L. Xie, R. F. Rossi, S. Meyer, A.
Sidhu, G. D. Cuny and J. R. Hauske, Bioorg. Med. Chem. Lett., 2000,
10, 2675.
6 A subset of recent work in this area includes: (a) W. Du and D. P. Curran,
Org. Lett., 2003, 5, 1765; (b) D. M. Lindsay, W. Dohle, A. E. Jensen,
F. Kopp and P. Knochel, Org. Lett., 2002, 4, 1819; (c) M. Matsugi, F.
Tabusa and J. Minamikawa, Tetrahedron Lett., 2000, 41, 8523; (d) P. G.
Dormer, K. K. Eng, R. N. Farr, G. R. Humphrey, J. C. McWilliams,
P. J. Reider, J. W. Sager and R. P. Volante, J. Org. Chem., 2003, 68,
467.
7 (a) J. Wu, L. Zhang and X. Sun, Chem. Lett., 2005, 34, 796; (b) J. Wu,
X. Sun and L. Zhang, Chem. Lett., 2005, 34, 550.
8 (a) C. S. Cho, B. H. Oh, J. S. Kim, T.-J. Kim and S. C. Shim, Chem.
Commun., 2000, 1885; (b) B. Jiang and Y. C. Si, J. Org. Chem., 2002,
67, 9449; (c) H. Skraup, Chem. Ber., 1880, 13, 2086; (d) P. Friedla¨nder,
Chem. Ber., 1882, 15, 2572; (e) R. H. Mansake and M. Kulka, Org.
React., 1953, 7, 59; (f) R. J. Linderman and S. K. Kirollos, Tetrahedron
Lett., 1990, 31, 2689; (g) M. E. Theclitou and L. A. Robinson,
Tetrahedron Lett., 2002, 43, 3907.
9 E. A. Fehnel, J. Heterocycl. Chem., 1966, 31, 2899.
10 (a) L. Strekowski and A. Czamy, J. Fluorine Chem., 2000, 104, 281;
(b) Y. Z. Hu, G. Zang and R. P. Thummel, Org. Lett., 2003, 5, 2251;
(c) A. Arcadi, M. Chiarini, S. Di Giuseppe and F. Marinelli, Synlett,
2003, 203; (d) B. R. McNaughton and B. L. Miller, Org. Lett., 2003,
5, 4257; (e) J. S. Yadav, B. V. S. Reddy and K. Premlatha, Synlett,
2004, 963; (f) J. S. Yadav, B. V. S. Reddy, P. Sreedhar, R. S. Rao and
K. Nagaiah, Synthesis, 2004, 2381; (g) K. Mogilaih and C. S. Reddy,
Synth. Commun., 2003, 3131; (h) A. Walser, T. Flyll and R. I. Fryer,
J. Heterocycl. Chem., 1975, 12, 737; (i) S. K. De and R. A. Gibbs,
Tetrahedron Lett., 2005, 46, 1647; (j) P. Arumugam, G. Karthikeyan,
R. Atchudan, D. Muralidharan and P. T. Perumal, Chem. Lett., 2005,
34, 314; (k) J. Wu, L. Zhang and T.-N. Diao, Synlett, 2005, 2653.
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