Microwave promoted solvent-free one-pot three-component reaction to 2-pentafluorophenylquinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.04.179

A novel and efficient one-pot multi-component reaction of pentafluorobenzaldehyde, alkynes and anilines for the synthesis of 2-pentafluorophenyl substituted quinolines under microwave irradiation and a solvent-free condition is presented.

Full text of DOI:10.1016/j.tetlet.2004.04.179

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5771–5773
Microwave promoted solvent-free one-pot three-component reaction
to 2-pentafluorophenylquinoline derivatives
q
a,
Jian-ming Zhang, Wen Yang, Li-ping Song, Xian Cai and Shi-zheng Zhu
a
a
b
b,
*
*
a
Department of Chemistry, School of Science, Shanghai University, No. 99, Shangda Road, Shanghai 200436, China
b
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science,
Shanghai 200032, China
Received 25 February2004; revised 16 April 2004; accepted 18 April 2004
Available online 15 June 2004
Abstract—A novel and efficient one-pot multi-component reaction of pentafluorobenzaldehyde, alkynes and anilines for the syn-
thesis of 2-pentafluorophenyl substituted quinolines under microwave irradiation and a solvent-free condition is presented.
Ó 2004 Elsevier Ltd. All rights reserved.
5
Quinoline derivatives are veryimportant in medicinal
chemistrybecause of their wide occurrence in natural
Billah et al. used anilines and ethyl 1,1,1-trifluoroace-
tate bythree reaction steps to prepare 2-trifluorometh yl -
quinolines in low yield (Eq. 2).
1
products and drugs. Also, quinolines are found to
2
possess a wide spectrum of biological activities. It is
well known that replacement of hydrogen with fluorine
3
NH
2
frequentlyconfers bioactivityto organic molecules.
Therefore, the synthesis of fluorine-containing quinoline
derivatives is of considerable importance due to the
biological activities of the resulting products. Various
methods have been reported for synthesis of fluorine-
containing quinoline derivatives. For example, Gerus
et al. have reported the synthesis of 2-trifluoromethyl-
quinolines in 30% yield from the reaction of
ð2Þ
CF COCH CO Et +
R
3
2
2
N
CF3
R
Recently, we have reported the direct synthesis of
2-fluoroalkyl quinoline derivatives from the reaction of
6
a-fluoroalkyl-aldehyde with anilines (Eq. 3).
3
EtOCH@CHCOCF with anilines followed bytreat-
4
R
HOAc
reflux
ment with PPA (Eq. 1).
RfCF2CH2CHO
+
R
NH2
N
Rf
NH2
COCF3
R = CF , CClF , BrCF , CF (CF ) , CF (CF ) ;
f
3
2
2
3
2 3
3
2 4
O
NH
R = H, OH, CH3;
C H
6
6
PPA
F3C
OEt+
R
ð3Þ
N
CF3
R
R
However, to the best of our knowledge, 2-perfluoro-
phenylquinoline derivatives have not been reported.
ð1Þ
In recent years, microwave-assisted reactions are of
great interest because of simplicityin operation,
enhanced reaction rates and greater selectivity. Thus,
microwave irradiation, which has become a powerful
synthetic tool for the rapid synthesis of a variety of
biologicallyactive compounds under solvent-free
conditions, is used to enhance the rates of classical
Keywords: Microwave; Pentafluorobenzaldehyde; Aniline; Alkyne;
Quinoline.
q
Supplementarydata associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.04.179
*
Corresponding authors. Fax: +86-21-64166128; e-mail: zhusz@
mail.sioc.ac.cn
7
organic reactions. For example, Wang et al. have
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.179

5772
J. Zhang et al. / Tetrahedron Letters 45 (2004) 5771–5773
reported the microwave-assisted amination from aryl
8
triflates without base and catalyst. Furthermore, the
It was noteworthythat the copper(I) bromide pla ye d an
important role in the reaction system, in the absence of
copper(I) bromide, no reaction occurred under the same
condition (entry14, Table 1). However, increasing the
ratio of copper(I) bromide did not improve the yields
obviously, whereas decreasing the ratio of copper(I)
bromide affected the yield drastically (entries 10, 11,
Table 1). It was found that the other catalysts such as
CuCl and CuI had similar catalytic activity in terms of
conversion and reaction time (entries 12, 13, Table 1).
The reaction rates and yields were dramatically en-
hanced bymicrowave. Bycomparison, the same reac-
tion took around 4 h under the traditional thermal
conditions (80 °C, oil bath) to afford expected quinoline
derivatives in moderate yield (64%). Optimal reaction
condition was obtained with 30% copper(I) bromide
under 450 W irradiation power over 3.5 min (entry4,
Table 1). Prolonged irradiation time could not give
higher yield of 4aa (entry9, Table 1).
one-pot multi-component synthetic procedure and the
use of solid acid catalyst such as clay and zeolites have
attracted considerable attention in different areas of
organic synthesis, which can largely simplify the syn-
thetic step and operation under environmentallybenign
9
conditions.
In this paper, we wish to report a novel and efficient
approach for the synthesis of 2-pentafluorophenyl-
substituted quinolines bymicrowave promoted one-pot
three-component reaction of pentafluorobenzaldehyde,
anilines and alkynes on the surface of montmorillonite
clayimpregnated with catal tyi c amount of CuBr in
solvent-free conditions (Scheme 1).
Firstly, the effect and the amount of the copper(I) salt,
microwave irradiation time and irradiation power on the
efficiencyand iye ld were brieflyinvestigated. Penta-
fluorobenzaldehyde, aniline and phenyl acetylene were
used as starting materials in the presence of mont-
morillonite claydoped with copper(I) salt under
microwave irradiation, the results are summarized in
Table 1.
Both electron donating and electron withdrawing sub-
stituents on the aromatic amine afforded the corres-
ponding quinoline derivatives in good to excellent yields
(Table 2). However, it should be indicated that electron
effect of substituent on aromatic amine might affect the
CHO
NH
2
R2
CuBr - Mont.
F
F
F
F
F
R2
R1
+
+
Microwave
F
F
R1
N
F
F
F
1
2(a-d)
3(a-b)
4
R1 = H,
2a
R2 = Ph,
3a
p-OCH , 2b
-CH OH, 3b
3
2
p-NO2, 2c
p-CH3, 2d
-CH OAc, 3c
2
Scheme 1.
10
a
Table 1. One-pot three-component reactions of C
6
F
5
CHO, PhNH
2
and PhCBCH give 4aa under the different reaction conditions
a
b
EntryCopper(I) salt (equiv)
Microwave irradiation
Irradiation time (min)
Yield
Irradiation power (W)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.3)
CuBr (0.1)
CuBr (1)
3.5
3.5
3.5
3.5
3.5
1.0
2.5
3.0
5.0
3.5
3.5
3.5
3.5
3.5
80
150
300
450
700
450
450
450
450
450
450
450
450
450
53
75
82
84
64
59
80
82
83
45
85
77
68
––
0
1
2
3
4
CuCl (0.3)
CuI (0.3)
––
a
Microwave irradiations were carried out using a Sanyo, EM-551S/550S, domestic microwave oven with adjustable irradiation power, C
PhNH
/PhCBCH ¼ 1:1:2.
Isolated yield based on pentafluorobenzaldehyde.
6 5
F CHO/
2
b

J. Zhang et al. / Tetrahedron Letters 45 (2004) 5771–5773
5773
Table 2. Microwave promoted synthesis of 2-pentafluorophenylquin-
a
oline derivatives
In summary, we have reported a microwave promoted
one-pot three-component reaction to give 2-pentafluor-
ophenylquinoline derivatives. Mild reaction conditions,
improved yields, enhanced reaction rates, solvent-free
condition and inexpensive catalyst are the main advan-
tages of this procedure.
b
Entry
Arylamine
Alkyne
Product (Yield)
1
2
3
4
5
6
6
7
8
2a
2b
2c
2d
2a
2b
2c
2d
2b
3a
3a
3a
3a
3b
3b
3b
3b
3c
4aa (84)
4ba (92)
4ca (81)
4da (86)
4ab (70)
4bb (86)
c
––
4db (76)
Acknowledgements
c
––
The authors thank the National Natural Science
Foundation of China (NNSFC) (Nos. 20032010,
20372077) and Innovation Foundation of Chinese
Academyof Sciences for financial support.
a
b
c
Microwave irradiation power: 450 W, time: 3.5–4.0 min.
Isolated yield based on pentafluorobenzaldehyde.
Onlythe corresponding imines were formed.
yields. This may be attributed to the nature of nucleo-
philicityof amine, which is critical effect in the rapid
formation of imine from pentafluorobenzaldehyde and
amine on the claysurface.
References and notes
1
2
3
. Huma, H. Z. S.; Halder, R.; Kalar, S. S.; Das, J.; Iqbal, J.
Tetrahedron Lett. 2002, 43, 6485–6488.
. Yadav, J. S.; Reddy, B. V. S.; Rao, R. S.; Naveenkumar,
V.; Nagaiah, K. Synthesis 2003, 10, 1610–1613.
. Wang, Y. L.; Zhu, S. Z. Synthesis 2002, 13, 1813–1818,
and references cited therein.
Furthermore, other terminal alkynes such as propargyl
alcohol and propargyl acetate were also studied (Table
2
). However, under the same reaction condition, treat-
ment of pentafluorobenzaldehyde with equimolar of
aniline and 2 equivalent propargyl alcohol in the pres-
ence of 30% catalytic amount of copper(I) bromide gave
the expected product in quite lower yield, only 20% yield
of quinoline derivative was isolated, along with the
N-phenyl pentafluorophenyl aldimine (derived in situ
from pentafluorobenzaldehyde and aniline on the clay
surface) as by-product in 60% yield. The better yields
were obtained from increasing the amount of starting
material propargyl alcohol up to 4 equivalent based on
the pentafluorobenzaldehyde, and expected quinoline
derivative was isolated in 86% yield. It should be indi-
cated that treatment of 1 with equimolar of 2c and
4. Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine
Chem. 1994, 69, 195–198.
5. Billah, M.; Buckley, G. M.; Cooper, N.; Dyke, H. J.;
Egan, R.; Ganguly, A.; Gowers, L.; Haughan, A. F.;
Kendall, H. J.; Lowe, C.; Minnicozzi, M.; Montana, J. G.;
Oxford, J.; Peake, J. C.; Picken, C. L.; Piwinski, J. J.;
Naylor, R.; Sabin, V.; Shih, N. Y.; Warneck, J. B. H.
Bioorg. Med. Chem. Lett. 2002, 12, 1617–1619.
6
. Wang, Q. F.; Mao, Y. Y.; Qin, C. Y.; Zhu, S. Z.; Hu, C.
M. Monatshefte f €u r Chemie 2000, 131, 55–63.
. (a) Varma, R. S. Green Chem. 1999, 43–55; (b) Yadav, J.
7
S.; Reddy, B. V. S. Tetrahedron Lett. 2002, 43, 1905–1907.
8. Xu, G.; Wang, Y. G. Org. Lett. 2004, 6, 985–987.
4
equiv of 3b gave N-(4-nitrophenyl)pentafluorophenyl
aldimine only, without the formation of the corre-
sponding quinoline. Neither increasing the irradiation
power nor prolonged the irradiation time could change
the result. Furthermore, when the more reactive 2b and
propargyl acetate (3c) were used as starting materials to
carryout this reaction, no desired products were ob-
tained, although the reaction was carried out under
more drastic reaction conditions. Reactions of 3c with
other anilines such as 2a,c,d were also studied. None of
them gave the satisfied results.
9. Shao, L. X.; Shi, M. Adv. Synth. Catal. 2003, 345, 963–
66.
9
1
0. Data for 4aa: mp 118–119 °C. IR (KBr): m 3127, 1523,
À1
1
1
496, 1400 cm ; H NMR (300 MHz, CDCl ): d 8.23 (d,
3
J ¼ 8:4 Hz, 1H), 8.00 (d, J ¼ 8:4 Hz, 1H), 7.80 (t,
19
J ¼ 8:4 Hz, 1H), 7.62–7.53 (m, 7H); F NMR (282 MHz,
CDCl
3
with CFCl
3
): d )142.8 (d, J ¼ 15:7 Hz, 2F), )153.7
(
(
t, J ¼ 15:7 Hz, 1F), )161.7 (m, 2F). EIMS (70 eV), m=z
þ þ
6 5
þ
rel. int.): 371 (M , 100.00), 204 (M )C
F
, 7.45), 178
(M )C F )CN, 12.30). Anal. Calcd for C H F N: C,
6
5
21 10
5
67.93; H, 2.71; N, 3.77. Found: C, 67.80; H, 2.82; N, 3.61.