Indium(III) trifluoromethanesulfonate: An efficient reusable catalyst for the alkynylation-cyclization of 2-aminoaryl ketones and synthesis of 2,4-disubstituted quinolines

Article abstract of DOI:10.1055/s-2008-1042800

An environmentally friendly and highly efficient procedure for the preparation of 2,4-disubstituted quinoline derivatives has been developed by a simple alkynylation-cyclization reaction of 2-aminoaryl ketones with phenylacetylenes in the presence of indi

Full text of DOI:10.1055/s-2008-1042800

LETTER
655
Indium(III) Trifluoromethanesulfonate: An Efficient Reusable Catalyst
for the Alkynylation–Cyclization of 2-Aminoaryl Ketones and Synthesis of
2,4-Disubstituted Quinolines
Catalyst for the
Al
u
kynylation–C
s
yclization
h
of 2-Amino
a
aryl
K
eton
l
es C. Lekhok, Dipak Prajapati,* Ramesh C. Boruah
Department of Medicinal Chemistry, North East Institute of Science & Technology, Jorhat 785 006, Assam, India
Fax +91(376)2370011; E-mail: dr_dprajapati2003@yahoo.co.uk
Received 3 October 2007
Ar
N
Ar
Abstract: An environmentally friendly and highly efficient proce-
In(OTf)3
dure for the preparation of 2,4-disubstituted quinoline derivatives
has been developed by a simple alkynylation–cyclization reaction
of 2-aminoaryl ketones with phenylacetylenes in the presence of in-
dium(III) trifluoromethanesulfonate In(OTf)3 under microwave ir-
radiation and solvent-free conditions. This catalyst can be recovered
after the reaction and reused efficiently in subsequent runs.
O
PhC
CH
+
R
solvent-free
MW
NH2
R
Ph
3
1
2
Ar
Ph
R
a
H
b
c
d
e
f
g
6-Cl
6-Cl
6-NO2
8-NO2
6-Cl
Ph
2'-ClC6H4
Ph
Ph
2'-FC6H4
Key words: 2,4-disubstituted quinolines, solvent-free conditions,
microwave irradiations, indium triflate
2'-FC6H4
Me
H
H
Quinolines and their derivatives are important scaffolds
because of their wide spectrum of biological activities1
and formation of conjugated molecules and polymers that
combine enhanced electronic, optoelectronic, or nonlinear
optical properties with excellent medicinal properties.2 In
addition to medicinal applications, quinoline derivatives
have been employed in the study of bioorganic and bioor-
ganometallic processes.3 In spite of their importance from
industrial, pharmacological, and synthetic points of view,
relatively few methods of their preparation have been re-
ported. Although other methods such as Skraup, Doeb-
ner–von Miller, Friedländer, Combes reactions have been
developed for the preparation of quinolines,4 but due to
their importance as substructures in a broad range of nat-
ural and designed products, significant effort continues to
be directed into the development of new quinoline-based
structures5 and new methods for their constructions.6
Amongst methodologies reported for the preparation of
quinolines, Friedländer annulation is the most straightfor-
ward protocol, but the harsh reaction conditions can lead
to several side reactions.7 Under thermal or base-catalysis
conditions, 2-aminobenzophenone fails to react with sim-
ple ketones such as cyclohexanone and b-keto esters.8 Re-
cently, Rh(I)-complex-catalyzed coupling cyclization of
N-aryl trifluoroacetylimidoyl chloride with alkynes9 and
InBr3-promoted dimerization of 2-ethynylaniline10 to give
polysubstituted quinoline have been reported. However,
most of the reported protocols for the synthesis of quino-
lines suffer from the use of harmful organic solvents, high
reaction temperatures, prolonged reaction times, low
yields, tedious workup procedures and the use of stoi-
h
Scheme 1
Ar
Ar
HO
In(OTf)3
O
R
NH2
Ph
Ph
NH2
1
2
3'
Ar
Ar
N
Meyer–Schuster
rearrangement
O
NH2
Ph
Ph
R
3
Scheme 2
chiometric and/or relatively expensive reagents. Conse-
quently, there is great current interest in assembling
quinoline systems from acyclic precursors11 and an ever-
increasing demand for selective and low-cost protocols
for their synthesis.12
In recent years indium salts have received increasing at-
tention both as reagents and catalysts for organic reac-
tions.13 We have studied the application and catalytic
effect of indium trifluoromethanesulfonate and indium
chloride in various carbon–carbon bond-forming reac-
tions.14
To overcome the problems arising from the addition of
stoichiometric amounts of the Brønsted and Lewis acidic
or basic reagents, and in continuation to our studies on
metal catalysts,14 we report herein an efficient synthesis of
2,4-disubstituted quinolines using catalytic amount of
In(OTf)3, under microwave irradiation and solvent-free
conditions. Accordingly, treatment of 5-chloro-2-ami-
SYNLETT 2008, No. 5, pp 0655–0658
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042800; Art ID: D31408ST
© Georg Thieme Verlag Stuttgart · New York

656
K. C. Lekhok et al.
LETTER
Table 1 In(OTf)3-Catalyzed Synthesis of Quinolines 3
Entry
2-Aminoaryl ketones 1
Quinolines 1
Reaction time [min,
In(OTf)3]
Yield
[%,In(OTf)3]
O
Cl
1
Cl
4.5
5.0
4.5
93
NH2
N
Ph
3a
Ph
Ph
O
2
3
9020
N
Ph
NH2
3b
O
Cl
Cl
Cl
96
Cl
NH2
N
Ph
3c
O
O2N
4
5
6
5.0
4.5
3.5
87
86
92
O2N
NH2
N
Ph
3d
O
NH2
N
NO2
Ph
NO2
3e
O
F
F
Cl
Cl
NH2
N
Ph
3f
O
F
F
7
8
4.0
5.0
90
NH2
Me
N
Ph
3g
Me
9020
O
N
Ph
NH2
3h
Synlett 2008, No. 5, 655–658 © Thieme Stuttgart · New York

LETTER
Catalyst for the Alkynylation–Cyclization of 2-Aminoaryl Ketones
657
nobenzophenone (1a, R = 5-Cl, Ar = Ph) with phenyl- synthesis, but also avoids the use of hazardous acids or
acetylene (2) in the presence of 1 mol% In(OTf)3 under bases and harsh reaction conditions. The yields obtained
microwave irradiation and solvent-free conditions, result- by this method are superior to the corresponding
ed in the formation of 6-chloro-2,4-diphenylquinoline Friedländer synthesis, which uses o-acylanilines and ke-
(3a) in 93% yield (Scheme 1). The reaction was carried tones.19 In addition to its simplicity and selectivity, this re-
out in a Synthwave 402 Monomod reactor from Prolabo action shows the ability to tolerate a variety functional
and the automatic mode stirrer helps in mixing and uni- groups (nitro, chloro, fluoro, and amino) and will consti-
form heating of the reactants. The reaction proceeds effi- tute a useful alternative to the commonly utilized proce-
ciently in excellent yields within a few minutes at 110 °C dures.
and at 2450 MHz frequency. Complete conversion and
93% isolated yield was obtained after 4.5 minutes of mi-
crowave irradiations. Rate enhancement of the reaction
Acknowledgment
We thank the Department of Science and Technology (DST), New
Delhi for financial support and Director, North East Institute of Sci-
ence & Technology (NEIST), Jorhat for his keen interest and con-
stant encouragement.
was observed when 5 mol% or 10 mol% of In(OTf)3 were
used but relatively lower yields (85% or 80%) were ob-
tained due to decomposition of the starting material.
Moreover, use of a lesser amount 0.5 mol% of In(OTf)3
led to lower yields (60–70%) in longer reaction times. In
view of our current interest in environmentally benign cat- References and Notes
alytic processes, we decided to extend the scope of the re-
(1) (a) Larsen, R. D.; Corley, E. G.; King, A. O.; Carrol, J. D.;
action using only 1 mol% of the catalyst (1 mol%, 4.5
min, 93% yield). It is noteworthy that this reaction can be
run without an inert atmosphere without loss of efficien-
cy. Similarly, various 2-aminoaryl ketones 1b–h were re-
acted with phenylacetylene in the presence of 1 mol%
In(OTf)3 and the corresponding 2,4-disubstituted quino-
lines 3b–h were obtained in excellent yields. The reac-
tions are generally clean and no side products such as
dihydroquinolines could be detected in the NMR spectra
of the crude products. To be conclusive and for direct
comparison, parallel reactions have also been investigated
under conventional heating at 85 °C in solvent-free condi-
tions. The reaction proceeded, but not so effectively, re-
quiring several hours and the corresponding quinoline
derivatives were obtained in 75–83% yields. To demon-
strate the generality of this reaction, we next studied the
scope of this reaction under the optimized conditions and
the results are summarized in Table 1 (Scheme 2).15 In the
absence of a catalyst, the reaction did not yield any prod-
uct even after 10 minutes of microwave irradiation. Fur-
ther increase of reaction time led only to decomposition of
starting materials. The advantage of In(OTf)3 as a Lewis
acid catalyst is that it can be quantitatively recovered after
the reaction and the recovered catalyst is effective in sub-
sequent experiments.
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, 1021. (d) Kalluraya, B.;
Sreenivasa, S. Farmaco 1998, 53, 399. (e) Dube, D.;
Blouin, M.; Brideau, C.; Chan, C. C.; Desmarais, S.; Ethier,
D.; Falgueyret, J. P.; Friesen, R. W.; Girard, M.; Girard, Y.;
Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N. Bioorg.
Med Chem. Lett. 1998, 8, 1255.
(2) (a) Stille, J. K. Macromolecules 1981, 14, 870.
(b) Agrawal, A. K.; Jenekhe, S. A. Macromolecules 1991,
24, 6806. (c) Agrawal, A. K.; Jenekhe, S. A. Chem. Mater.
1992, 4, 95. (d) Agrawal, A. K.; Jenekhe, A. K.; Jenekhe, S.
A. Chem. Mater. 1993, 28, 895. (e) Agrawal, A. K.;
Jenekhe, S. A. Chem. Mater. 1993, 5, 633. (f) Jenekhe, S.
A.; Lu, L.; Alam, M. M. Macromolecules 2001, 34, 7315.
(g) Agrawal, A. K.; Jenekhe, S. A.; Vanherzeele, H.; Meth,
J. S. J. Phys. Chem. 1992, 96, 2837. (h) Jegou, G.; Jenekhe,
S. A. Macromolecules 2001, 34, 7926. (i) Lu, L.; Jenekhe,
S. A. Macromolecules 2001, 34, 6249. (j) Agrawal, A. K.;
Jenekhe, S. A. Chem. Mater. 1996, 8, 579. (k) Jenekhe, S.
A.; Zhang, X.; Chen, X. L.; Choong, V. E.; Gao, Y.; Hsieh,
B. R. Chem. Mater. 1997, 9, 409. (l) Zhang, X.; Shetty, A.
S.; Jenekhe, S. A. Macromolecules 1999, 32, 7422.
(m) Zhang, X.; Shetty, A. S.; Jenekhe, S. A. Macromolecules
2000, 33, 2069.
(3) (a) Saito, I.; Sando, S.; Nakatani, K. Bioorg. Med. Chem.
2001, 9, 2381. (b) He, C.; Lippard, S. J. J. Am. Chem. Soc.
2001, 40, 1414.
It should be noted that the yields in second and even third
runs are comparable to that of the first run. As shown in
the Table 1 the method appears to be quite general and the
reaction conditions are tolerant of nitro groups.16 Al-
though the detailed mechanism of the reaction is not clear
at this stage, it seems likely that the reaction is preceded
by initial alkynylation of the 2-aminoaryl ketone 1 with
phenyl acetylene 2 to form the propargylic alcohol 3¢ fol-
lowed by Meyer–Schuster rearrangement17 to the enone
and cyclization.
(4) (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.;
Kim, T. J.; Shim, S. C. Chem. Commun. 2000, 1885.
(c) Jiang, B.; Si, Y. G. J. Org. Chem. 2002, 67, 9449.
(d) Skraup, H. Ber. Dtsch. Chem. Ges. 1880, 13, 2086.
(e) Friedlander, P. Ber. Dtsch. Chem. Ges. 1882, 15, 2572.
(f) Mansake, R. H.; Kulka, M. Org. React. 1953, 7, 59.
(g) Linderman, R. J.; Kirollos, K. S. Tetrahedron Lett. 1990,
31, 2689. (h) Theoclitou, M. E.; Robinson, L. A.
In conclusion, we describe a mild and efficient route for
the synthesis of 2,4-disubstituted quinolines18 utilizing in-
dium triflate as a new catalyst. This method not only pro-
vides an excellent complement to substituted quinoline
Tetrahedron Lett. 2002, 43, 3907.
(5) Hoemann, M. Z.; Kumaravel, G.; Xie, R. L.; Rossi, R. F.;
Meyer, S.; Sidhu, A.; Cuny, G. D.; Hauske, J. R. Bioorg.
Med. Chem. Lett. 2000, 10, 2675.
Synlett 2008, No. 5, 655–658 © Thieme Stuttgart · New York

658
K. C. Lekhok et al.
LETTER
2,4-diphenylquinoline was isolated in 90% yield.
(6) (a) Du, W.; Curran, D. P. Org. Lett. 2003, 5, 1765.
(b) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.;
McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P.
J. Org. Chem. 2003, 68, 467. (c) Matsugi, M.; Tabusa, F.;
Minamikawa, J. Tetrahedron Lett. 2000, 41, 8523.
(d) Lindsay, D. M.; Dohle, W.; Jensen, A. E.; Kopp, F.;
Knochel, P. Org. Lett. 2002, 4, 1819.
(7) Arcadi, A.; Chiarini, M.; Giuseppe, S. D.; Marinelli, F.
Synlett 2003, 203; and references therein.
(8) Fehnel, E. A. J. Org. Chem. 1966, 31, 2899.
(9) Amii, H.; Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3,
1109.
6-Chloro-2,4-diphenylquinoline (3a): mp 98 °C. IR (KBr):
1610, 1375, 1270, 1160, 1125 cm–1. 1H NMR (CDCl3): d =
7.10–7.23 (m, 8 H), 7.65 (m, 1 H), 7.95 (m, 1 H), 8.10–8.25
(m, 4 H). Anal. Calcd for C21H14ClN: C, 80.00; H, 4.44; N,
4.44. Found: C, 80.11; H, 4.52; N, 4.36. MS: m/z = 315 [M+].
2,4-Diphenyl-quinoline (3b): mp 107 °C. IR (KBr): 1610,
1375, 1270, 1160, 1125 cm–1. 1H NMR (CDCl3): d = 7.10–
7.23 (m, 9 H), 7.65 (m, 1 H), 7.95 (m, 1 H), 8.10–8.25 (m, 4
H). Anal. Calcd for C21H15N: C, 89.69; H, 5.34; N, 4.98.
Found: C, 89.75; H, 5.42; N, 4.88. MS: m/z = 281 [M+].
2-Phenyl-4-(2¢-chlorophenyl)-6-chloroquinoline (3c): mp
112 °C. IR (KBr): 1610, 1375, 1270, 1160, 1125 cm–1. 1H
NMR (CDCl3): d = 7.27 (s, 1 H), 7.39–7.84 (m, 7 H), 8.18
(s, 1 H), 8.19–8.21 (m, 4 H). Anal. Calcd for C21H13Cl2N: C,
72.21; H, 3.72, N, 4.01. Found: C, 72.13; H, 3.82; N, 4.12.
MS: m/z = 349 [M+].
2,4-Diphenyl-6-nitroquinoline (3d): mp 264 °C. IR (KBr):
1625, 1370, 1240, 1150, 1035 cm–1. 1H NMR (CDCl3): d =
7.30–7.65 (m, 8 H), 7.80 (m, 1 H), 8.10–8.15 (m, 5 H). Anal.
Calcd for C21H14N2O2: C, 77.30; H, 4.29; N, 8.59. Found: C,
77.39; H, 4.19; N, 8.66. MS: m/z = 326 [M+].
2,4-Diphenyl-8-nitroquinoline (3e): mp 264 °C. IR (KBr):
1630, 1375, 1235, 1150, 1030 cm–1. 1H NMR (CDCl3): d =
7.25–7.60 (m, 8 H), 7.75 (m, 1 H), 8.12–8.20 (m, 5 H). Anal.
Calcd for C21H14N2O2: C, 77.30; H, 4.29; N, 8.59. Found: C,
77.42; H, 4.35; N, 8.48. MS: m/z = 326 [M+].
(10) Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006,
71, 3653.
(11) (a) Li, A. H.; Ahmed, E.; Chen, X.; Cox, M.; Crew, A. P.;
Dong, H. Q.; Jin, M. Z.; Ma, I. F.; Panicker, B.; Siu, K. W.;
Steing, A. G.; Stolz, K. M.; Tavares, P. A. R.; Volk, B.;
Weng, Q. H.; Werner, D.; Mulyihill, M. Org. Biomol. Chem.
2007, 5, 61. (b) Janza, B.; Studer, A. Org. Lett. 2006, 3,
1875. (c) Jia, C. S.; Wang, G. W. Lett. Org. Chem. 2006, 3,
289.
(12) (a) Zolfigol, M. A.; Salehi, P.; Ghaderi, A.; Shiri, M.;
Tanbakouchian, Z. J. Mol. Catal. A: Chem. 2006, 259, 253.
(b) Li, Y. S.; Wu, C. L.; Huang, J. L.; Su, W. K. Synth.
Commun. 2006, 36, 3065. (c) Selvam, N. P.; Saravan, C.;
Muralidharan, D.; Perumal, P. T. J. Heterocycl. Chem. 2006,
43, 1379.
(13) For selected reviews and papers on reactions mediated by
indium, see: (a) Gregg, B. T.; Golden, K. C.; Quinn, J. F. J.
Org. Chem. 2007, 72, 5890. (b) Ranu, B. C.; Hajra, A.; Jana,
U. Tetrahedron Lett. 2000, 41, 531. (c) Marshall, J. A.;
Hinkle, K. W. J. Org. Chem. 1995, 60, 1920. (d) Ranu, B.
C. Eur. J. Org. Chem. 2000, 3347. (e) Yasuda, M.; Onishi,
Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66,
7741. (f) Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara,
T. Tetrahedron 2005, 61, 9298.
(14) (a) Prajapati, D.; Laskar, D. D.; Sandhu, J. S. Tetrahedron
Lett. 2000, 41, 8639. (b) Barman, D. C.; Gohain, M.;
Prajapati, D.; Sandhu, J. S. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 2002, 41, 154. (c) Barman, D. C.;
Thakur, A. J.; Prajapati, D.; Sandhu, J. S. Synlett 2001, 515.
(d) Saikia, P.; Prajapati, D.; Sandhu, J. S. Tetrahedron Lett.
2003, 44, 8725. (e) Borah, H. N.; Prajapati, D.; Boruah, R.
C. Synlett 2005, 2823. (f) Prajapati, D.; Gohain, M. Beilstein
J. Org. Chem. 2006, 2, 11.
(15) General Procedure for the Synthesis of 2,4-Disubstituted
Quinoline Derivatives under Microwave Irradiations
A mixture of 5-chloro-2-aminobenzophenone (1a, 1.65 g, 5
mmol), phenylacetylene (0.52 g, 5 mmol), and In(OTf)3
(0.03 g) was placed in a quartz reaction vessel of a Prolabo
Synthwave Microwave Reactor 402 and allowed to react
under microwave irradiation at 110 °C for 4.5 min. After
completion (monitored by TLC), the reaction mixture was
cooled to r.t. and cold MeOH (15 mL) added. The residue
was filtered and the filtrate was evaporated to obtain the
crude product which was then recrystallized from hot MeOH
to afford quinoline 3a in 93% yield, mp 98 °C. The residue
obtained after filtration contains In(OTf)3 which was used as
such in another experiment and the corresponding 6-chloro-
2-Phenyl-4-(2¢-fluorophenyl)-6-chloroquinoline (3f): mp
124 °C. IR (KBr): 1610, 1375, 1270, 1160, 1125 cm–1. 1H
NMR (CDCl3): d = 7.10–7.23 (m, 7 H), 7.65 (m, 1 H), 7.95
(m, 1 H), 8.10–8.25 (m, 4 H). Anal. Calcd for C21H13ClFN:
C, 75.68; H, 3.90; N, 4.20. Found: C, 75.75; H, 3.98; N, 4.13.
MS: m/z = 333 [M+].
2-Phenyl-4-(2¢-fluorophenyl)quinoline (3g): mp 90 °C. IR
(KBr): 1610, 1375, 1270, 1160, 1125 cm–1. 1H NMR
(CDCl3): d = 7.10–7.23 (m, 7 H), 7.65 (m, 1 H), 7.95 (m, 1
H), 8.10–8.25 (m, 4 H). Anal. Calcd for C21H14FN: C, 84.28;
H, 4.68; N, 4.68. Found: C, 84.36; H, 4.59; N, 4.78. MS:
m/z = 299 [M+].
(16) Kalyanam, N.; Rao, G. W. Tetrahedron Lett. 1993, 34, 1647.
(17) Edens, M.; Boerner, D.; Chase, C. R.; Nass, D.; Schiavelli,
M. D. J. Org. Chem. 1977, 42, 3403.
(18) For some of the most recent work on quinoline synthesis,
see: (a) Ahmed, N.; Lier, E. V. Tetrahedron Lett. 2007, 48,
13. (b) Arcadi, A.; Bianchi, G.; Inesi, A.; Marinelli, F.;
Rossi, I. Synlett 2007, 1031. (c) Sakai, N.; Annaka, K.;
Konakahara, T. J. Org. Chem. 2006, 71, 3653.
(d) Atechian, S.; Nock, N.; Norcross, R. D.; Ratni, H.;
Thomas, A. W.; Verron, J.; Masciadri, R. Tetrahedron 2007,
63, 2811. (e) Wang, G.-W.; Jia, C.-S.; Dong, Y.-W.
Tetrahedron Lett. 2006, 47, 1059. (f) Bose, D. S.; Kumar,
R. K. Tetrahedron Lett. 2006, 47, 813. (g) Lee, B. S.; Lee, J.
H.; Chi, D. Y. J. Org. Chem. 2002, 67, 7884. (h) Jia, C. S.;
Zhang, Z.; Tu, S. J.; Wang, G. W. Org. Biomol. Chem. 2006,
4, 104.
(19) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37; yields of
67% and 55% were reported for 3a and 3h.
(20) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem. Int.
Ed. 1999, 38, 3222.
Synlett 2008, No. 5, 655–658 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.