Facile ionic liquids-promoted one-pot synthesis of polyhydroquinoline derivatives under solvent free conditions

Article abstract of DOI:10.1055/s-2004-820035

An efficient synthesis of polyhydroquinoline derivatives were reported via four-component coupling reactions of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate in the presence of a catalytic amount of ionic liquid under solvent free condition

Full text of DOI:10.1055/s-2004-820035

LETTER
831
Facile Ionic Liquids-Promoted One-Pot Synthesis of Polyhydroquinoline
Derivatives under Solvent Free Conditions
a
a
a
a,b
O
S
ne-Pot Synth
h
esis of Polyh
u
ydroquinoli
n
ne
D
erivative
-
s
under
J
S
olvent
F
u
ree
C
onditio
n
ns Ji,* Zhao-Qin Jiang, Jun Lu, Teck-Peng Loh*
a
College of Chemistry and Chemical Engineering of Suzhou University, The Key Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou 215006, P. R. China
b
Department of Chemistry, National University of Singapore, Science Drive 3, 117543 Singapore
Fax +86(512)65224783; E-mail: shunjun@suda.edu.cn
Received 17 December 2003
attention currently has been focused on organic reactions
catalyzed by ionic liquids, and several reactions catalyzed
by ionic liquids have been reported with good results,1
which offered some new clues that using ionic liquids as
Abstract: An efficient synthesis of polyhydroquinoline derivatives
were reported via four-component coupling reactions of aldehydes,
dimedone, ethyl acetoacetate and ammonium acetate in the pres-
ence of a catalytic amount of ionic liquid under solvent free condi-
5–20
tions. In the meantime, the catalytic effect of different ionic liquids catalysts for those traditionally reactions may not only be
on the reaction has also been investigated.
possible but also practical and even highly efficient. To
Key words: ionic liquids, catalyze, one-pot synthesis, polyhydro- our knowledge, so far there is no report on this reaction
quinoline derivatives
catalyzed by ionic liquids under solvent free conditions.
In past reports, our group described asymmetric Mannich-
2
1
type reactions
and the syntheses of bis(in-
In recent years, much attention has been directed towards
the syntheses of 1,4-dihydro pyridyl compounds due to
the fact that 1,4-dihydro pyridyl compounds possess a va-
22
dolyl)methanes utilizing ionic liquids as a new reaction
media, and good results have been achieved. In continua-
tion of our work to apply ionic liquids to organic reactions
in the context of green and economical chemistry, herein,
we would like to report a facile synthesis of polyhydro-
quinoline derivatives in the presence of a catalytic amount
of ionic liquid under solvent free conditions, as shown in
Scheme 1.
1
–6
riety of biological activities. For example, 1,4-dihydro
pyridyl compounds as the chain-cutting agent of factor IV
channel can cure the disordered heart ratio.5,6 Relative-
ly speaking, 1,4-dihydro pyridine derivatives combining
single ring have been mostly reported.
1–4
In view of the importance of polyhydroquinoline deriva-
tives, many classical methods for the synthesis of polyhy-
In our initial research, 4-chlorobenzaldehyde was selected
as a representative aldehyde in order to optimize the reac-
tion conditions. As can be seen from Table 1, it was found
that the reaction in the presence of a catalytic amount of
ionic liquid needs shorter reaction time than that without
any catalyst at room temperature (Table 1, entries 1 and
7
–12
droquinoline derivatives were reported
by
conventional heating and refluxing approaches in the
presence of organic solvent. These methods, however, in-
volve long reaction time, harsh reaction conditions, the
use of a large quantity of organic solvent and unsatisfac-
tory yields. Therefore, improvements in such syntheses
have been sought continuously. More recently, Tu et al.
reported the preparation of polyhydroquinoline deriva-
2
). But when the reaction was investigated at 90 °C, the
reaction catalyzed by ionic liquid [hmim]BF was com-
4
pleted with higher yield and in shorter reaction time
(
Table 1, entries 3 and 4). Obviously, the temperature and
1
3,14
tives under microwave irradiation.
the catalyst have important effect on the reaction. So the
Owing to the great potential of ionic liquids as an environ- best condition was that the reaction was catalyzed by ionic
mentally friendly media for catalytic processes, much liquid [hmim]BF
at 90 °C.
4
Cl
O
O
O
NH OAc
4
O
Cl
CHO +
+
COOC H m
2
5
OC2H5
Ionic Liquid
O
N
H
Scheme 1
SYNLETT 2004, No. 5, pp 0831–0835
0
2.
0
4.
2
0
0
4
Advanced online publication: 10.03.2004
DOI: 10.1055/s-2004-820035; Art ID: U28103ST
Georg Thieme Verlag Stuttgart · New York
©

8
32
S.-J. Ji et al.
LETTER
Table 1 The Selection of the Reaction Conditionsa
Cl
O
O
O
NH OAc
4
O
Cl
CHO +
+
5
COOC2H5m
OC H
Ionic Liquid
2
O
N
H
Entry
Temperature (°C)
Ionic liquid
Time (min)
Yield (%)b
1
2
3
25
25
90
90
–
140
90
16
8
76
78
81
95
[hmim]BF4
–
4
[hmim]BF4
a
All reactions were run in 4-chlorobenzaldehyde–ethyl acetoacetate–dimedone–ammonium acetate = 1:1:1:1.5 (mmol) at 80–90 °C under
solvent free conditions.
Isolated yields
b
Using the best conditions reported in Table 1(entry 4), we Considering the reaction time and the yield, ionic liquid
continued to investigate the reaction at the temperature of [hmim]BF was selected as the optimum catalyst for this
4
9
0 °C using seven different ionic liquids, i.e. butylmeth- reaction to promote the synthesis of polyhydroquinoline
ylimidazolium tetrafluoro borate ([bmim]BF ), hexylme- derivatives (Table 2, entry 2). Encouraged by these re-
4
thylimidazolium
tetrafluoroborate
([hmim]BF4), sults, we then continued to study the reaction using vari-
octylmethyl imidazolium tetrafluoroborate ([omim]BF4), ous aldehydes in the presence of a catalytic amount of
nonylmethylimidazolium tetrafluoroborate ([nmim]BF4), ionic liquid [hmim]BF The results were summaized in
4.
decylmethylimidazolium tetrafluoroborate ([dmim]BF4), Table 3 indicating that both aliphatic and aromatic alde-
hexylmethylimidazolium hexafluorophosphate ([hmim] hydes underwent smooth reaction with dimedone, ammo-
PF ), and hexylmethylimidazolium bromide ([hmim]Br), nium acetate and ethyl acetoacetate to give high yields of
6
has been investigated. All the results are listed in Table 2. products (Table 3).
In ionic liquids such as [hmim]BF , [dmim]BF ,
4
4
Clearly, the effect of the nature of the substituents on the
aromatic ring showed no obvious effect on this conver-
sion, because they were obtained in excellent yields; ali-
phatic aldehydes such as heptaldehyde also afforded good
yields of product in 18 minutes. In addition, the structure
of 2d was further confirmed by single crystal X-ray
crystallography (Figure 1).
[
hmim]PF , and [hmim]Br, the desired product was
6
obtained in satisfactory yields.
Table 2 Synthesis of 4-(p-Chlorobenzyl)-3-ethoxyl Carbonyl-
1
,4,5,6,7,8-hexahydro-5-oxo-2,7,7-trimethyl Quinoline Catalyzed by
a
Various Ionic Liquids under Solvent-Free Conditions
Entry
Ionic liquid
[bmim]BF4
[hmim]BF4
[omim]BF4
[nmim]BF4
[dmim]BF4
[hmim]PF6
[hmim]Br
Time (min)
Yield (%)b
1
2
3
4
5
6
7
83
95
91
86
96
95
96
8
15
6
10
10
12
7
a
All reactions were run in 4-chlorobenzaldehyde–ethyl acetoacetate–
dimedone–ammonium acetate = 1:1:1:1.5 (mmol) at 80–90 °C under
solvent free conditions.
Figure 1 The X-ray crystallography of 2d.24
b
Isolated yields
Synlett 2004, No. 5, 831–835 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Polyhydroquinoline Derivatives under Solvent Free Conditions
833
Table 3 Synthesis of Polyhydroquinoline Derivatives with Various Aldehydes Catalyzed by Ionic Liquid [hmim]BF under Solvent-Free
4
Conditions
Entry RCHO
Productsa,25
Time (min)
Yield (%)b
Mp (°C)
Obtained
Reported
CHO
O
1
2a
2b
10
95
227–229
260–261
265–26623
CO Etm
2
N
H
CHO
OCH3
H3CO
2
263–26412,23
245–24612,23
197–19914
O
O
O
9
8
96
95
94
91
93
CO2Etm
N
H
Cl
CHO
Cl
3
2c
2d
2e
2f
246–247
251–253
242–244
267–268
CO2Etm
N
H
CHO
O
O
O
4
5
O
CO2Etm
N
H
CHO
NO2
O N
2
5
O
O
14
12
CO2Etm
CO2Etm
N
H
CHO
CH3
H C
3
6
297–29812,23
N
H
CHO
S
O
7
8
CO Etm
2g
2h
15
26
91
92
248–250
208–210
S
2
N
H
CHOm
Cl
O
Cl
CO2Etm
N
H
CHO
OH
H3CO
HO
OCH3
9
O
2i
10
94
235–237
210–21214
CO2Etm
N
H
Synlett 2004, No. 5, 831–835 © Thieme Stuttgart · New York

8
34
S.-J. Ji et al.
LETTER
Table 3 Synthesis of Polyhydroquinoline Derivatives with Various Aldehydes Catalyzed by Ionic Liquid [hmim]BF under Solvent-Free
4
Conditions (continued)
Entry RCHO
Productsa,25
Time (min)
Yield (%)b
Mp (°C)
Obtained
Reported
CHOm
O
1
0
CO Etm
2j
18
89
153–154
2
N
H
a
1
All products were characterized by IR, H NMR spectroscopy and elemental analysis.
Isolated yields.
b
In summary, an efficient cyclization reaction of dimedone
with various aldehydes, ammonium acetate and ethyl ace-
toacetate utilizing ionic liquids as catalyst under solvent
free conditions was developed with high yields for the
first time. The main advantages of this methodology are:
(8) Sainani, J. B.; Shah, A. C.; Arya, V. P. Indian J. Chem., Sect
B 1994, 33, 526.
(9) Ahluwalia, V. K.; Goyal, B.; Das, U. J. Chem. Res., Synop.
1997, 266.
(
10) Margarita, S.; Estael, O.; Yamila, V.; Beatriz, P.; Lourdes,
M.; Nazario, M.; Margarita, Q.; Carlos, S.; Jose, L. S.;
Hector, N.; Norbert, B.; Oswald, M. P. Tetrahedron 1999,
55, 875.
(11) Ahluwalia, V. K.; Goyal, B.; Das, U. J. Chem. Res.,
Miniprint 1997, 7, 1501.
(
1) relatively simple catalyst system; (2) short reaction
times; (3) higher yields; (4) simple manipulation. Ionic
liquids [hmim]BF4, [dmim]BF4, [hmim]PF6, and
[hmim]Br all exhibited high catalytic activities in this
(
(
(
12) Ahluwalia, V. K.; Goyal, B. Indian J. Chem., Sect. B 1996,
reaction. Efforts to develop more active and available
catalytic system are currently in progress.
35, 1021.
13) Tu, S.-J.; Zhou, J.-F.; Deng, X.; Cai, P.-J.; Wang, H.; Feng,
J.-C. Chin. J. Org. Chem. 2001, 21, 313.
14) Tu, S.-J.; Yu, C.-X.; Liu, X.-H.; Yao, C.-S.; Liu, F.; Gao, Y.
Chin. J. Struct. Chem. 2002, 21, 99.
Acknowledgment
We are thankful for the financial assistance from The National
Natural Science Foundation of China (20172039) and grateful to the
National University of Singapore for providing the research funds.
(15) Welton, T. Chem. Rev. 1999, 99, 2071; and references cited
therein.
(16) Mathews, C. J.; Smith, P. J.; Welton, T. Chem. Commun.
2
000, 1249.
17) Xu, L.; Chen, W.; Xiao, J. Organometallics 2000, 19, 1123.
(18) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 403.
(
References
(
19) Herrmann, W. A.; Böhm, V. P. W. J. Organomet. Chem.
(
1) (a) Jains, R. A.; Silver, P. J.; Triggle, D. J. Adv. Drug Res.
1999, 572, 141.
1
1
987, 16, 309. (b) Bossert, F.; Vater, W. Med. Res. Rev.
989, 9, 291. (c) For a review on calcium channel
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(
21) Chen, S.-L.; Ji, S.-J.; Loh, T.-P. Tetrahedron Lett. 2003, 44,
modulators, see: Martin, N.; Secoane, C. Quim. Ind. 1990,
6, 115.
2405.
3
(
(
(
22) Ji, S.-J.; Zhou, M.-F.; Gu, D.-G.; Wang, S.-Y.; Loh, T.-P.
Synlett 2003, 2077.
(
2) (a) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1. (b) Stout,
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F.; Meyers, H.; Wehinger, E. Angew. Chem. Int. Ed. Engl.
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Miniprint 1997, 7, 1501.
1981, 20, 762. (d) Kuthan, J.; Kurfurst, A. Ind. Eng. Chen.
24) Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Centre,
CCDC No. 226173 for compounds 2d. Copies of this
information may be obtained free of charge from: The
Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
Prod. Res. Dev. 1982, 211, 191.
(
(
3) (a) Chorvat, R. J.; Rorig, K. J. J. Org. Chem. 1988, 53, 5779.
(
b) Kappe, C. O.; Fabian, W. M. F. Tetrahedron 1997, 53,
803. (c) Kappe, C. O. Tetrahedron 1993, 49, 6937.
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984, 23, 301. (b) Goldman, S.; Born, L.; Kazda, S.; Pittel,
2
[
E-mail: linstead@ccdc.cam.ac.uk or deposit@
1
ccdc.cam.ac.uk; Fax:+44 (1223)336033]. Structural
parameters for 2d: data collection: Rigaku Mercury CCD
area detector; radiation: MoK. wavelength = 0.71070 Å;
B.; Schramm, M. J. Med. Chem. 1990, 33, 1559. (c) For an
excellent recent review, see: Goldman, S.; Stoltefuss, J.
Angew. Chem. Int. Ed. Engl. 1991, 30, 1559.
3
crystal size: 0.24 × 0.15 × 0.70 mm ; crystal system:
(
5) (a) Schramm, N.; Thomas, G.; Towart, R.; Franckowiak, G.
Nature (London, U.K.) 1983, 303, 535. (b) Brown, A. M.;
Kunze, D. L.; Yatani, A. Nature (London, U.K.) 1984, 311,
monoclinic; space group: Cc (#9); unit cell: a = 18.607 (6)
Å, b = 9.136 (3) Å, c = 12.157 (4) Å, a = 111.623 (5)°.
(
25) Typical Experimental Procedure: 4-Chlorobenzaldehyde
570.
(1 mmol), dimedone (1 mmol), ammonium acetate (1.5
(
6) (a) Martin, N.; Quintero, M.; Segura, J. L.; Seoane, C.; Soto,
mmol), ethyl acetoacetate (1 mmol) and [hmim]BF (12
4
J. L.; Morales, M.; Suarez, M. L. Ann. Chem. 1991, 827.
mmol%) were successively charged into a 25 mL round-
bottomed flask equipped with a magnetic stirrer. Then the
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gradually formed. After the completion of reaction as
indicated by TLC, the resulting solid product was crushed,
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Heterocycl. Chem. 1995, 32, 235.
(7) Hantzsch, A. Ann. Chem. 1882, 1, 215.
Synlett 2004, No. 5, 831–835 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of Polyhydroquinoline Derivatives under Solvent Free Conditions
835
washed with water, filtered and dried in vacuum to afford the
crude product. A pure product was obtained by further
4 H, 2 × CH ), 2.40 (s, 3 H, CH ), 4.08 (m, 2 H, CH CH ),
2
3
2
3
5.00 (s, 1 H, CH), 5.80 (s, 1 H, NH), 7.00 (d, J = 8.0 Hz, 2
H, ArH) 6.80 (d, J = 8.0 Hz, 2 H, ArH). Anal. Calcd for
C H NO : C, 74.76; H, 7.70; N, 3.96. Found: C, 74.92; H,
recrystallization using absolute alcohol. 2a: IR (KBr): 3290,
–
1 1
1
3
698, 1612 cm . H NMR (400 MHz, CDCl ): d = 0.92 (s,
3
22 27
3
–
1
H, CH ), 1.06 (s, 3 H, CH ), 1.08 (m, 3 H, CH CH ), 2.18
7.79; N, 3.90. 2i: IR (KBr): 3399, 3293, 1698, 1644 cm .
H NMR (400 MHz, CDCl ): d = 0.94 (s, 3 H, CH ), 1.06 (s,
3 H, CH ), 1.22 (t, J = J = 7.2 Hz, 3 H, CH CH ), 2.20 (s,
3
3
2
3
1
(
m, 4 H, 2 × CH ), 2.41 (s, 3 H, CH ), 4.08 (q, J = J = 6.0
2
3
1
2
3
3
Hz, 2 H, CH CH ), 5.06 (s, 1 H, CH), 5.90 (s, 1 H, NH),
2
3
3 1 2 2 3
7
7
2
.03–7.4 (m, 5 H, ArH). Anal. Calcd for C H NO : C,
3 H, CH ), 2.38 (m, 4 H, 2 × CH ), 3.89 (s, 3 H, CH ), 4.12
2
1
25
3
3
2
3
4.31; H, 7.42; N, 4.13. Found: C, 74.57; H, 7.51; N, 4.06.
(q, J = J = 7.2 Hz, 2 H, CH CH ), 5.00 (s, 1 H, CH), 5.40
1 2 2 3
–
1 1
f: IR (KBr): 3275, 1702, 1647 cm . H NMR (400 MHz,
(s, 1 H, OH), 5.76 (s, 1 H, NH), 6.74 (m, 2 H, ArH) 7.00 (d,
1 H, ArH). Anal. Calcd for C H NO : C, 68.55; H, 7.06; N,
CDCl ): d = 0.92 (s, 3 H, CH ), 1.08 (s, 3 H, CH ), 1.24 (t,
3
3
3
22 27
5
J = J = 7.2 Hz, 3 H, CH CH ), 2.16 (s, 3 H, CH ), 2.26 (m,
3.63. Found: C, 68.53; H, 7.11; N, 3.51.
1
2
2
3
3
Synlett 2004, No. 5, 831–835 © Thieme Stuttgart · New York