An efficient and green synthesis of 1,4-dihydropyridine derivatives through multi-component reaction in ionic liquid

Article abstract of DOI:10.1002/hc.20221

Through multi-component condensation of aldehydes, 1,3-dione, Meldrum's acid, and ammonium acetate in an ionic liquid ([bmim][BF₄]), a series of 1,4-dihydropyridine derivatives were prepared in excellent yields in the absence of any additional

Full text of DOI:10.1002/hc.20221

Heteroatom Chemistry
Volume 17, Number 5, 2006
A
n Efficient and Green Synthesis
of 1,4-Dihydropyridine Derivatives through
Multi-Component Reaction in Ionic Liquid
Xue Sen Fan, Yan Zhen Li, Xin Ying Zhang, Gui Rong Qu,
Jian Ji Wang, and Xue Yuan Hu
School of Chemical and Environmental Sciences, Henan Key Laboratory for Environmental
Pollution Control, Henan Normal University, Xinxiang, Henan 453007, People’s Republic of China
Received 6 August 2005; revised 17 December 2005
have been widely studied as a class of organic cal-
ABSTRACT: Through multi-component condensa-
cium channel modulators and as potential candi-
dates for the treatment of cardiovascular diseases
tion of aldehydes, 1,3-dione, Meldrum’s acid, and am-
monium acetate in an ionic liquid ([bmim][BF ]),
4
since their introduction into clinical medicine in the
year of 1975 [1]. It has also been further revealed
that DHP heterocyclic ring is a common feature of
various bioactive compounds such as vasodilator,
bronchodilator, antiatherosclerotic, antitumor, and
antidiabetic agents [2]. Due to their important phar-
macological activities mentioned above, many meth-
ods for the synthesis of DHPs have been reported [3].
However, although these methods have successfully
led to a large library of DHPs for screening as drug
candidates, many of these still suffer from draw-
backs such as unsatisfactory yields, long-reaction
time, and pollution to the environment due to the
use of organic solvent and/or acidic or basic promot-
ers. Therefore, the development of more efficient and
greener methods for the preparation of this kind of
compounds is still an active ongoing research area
and there is scope for further improvement toward
milder reaction conditions and improved yields with
a greener nature.
a series of 1,4-dihydropyridine derivatives were pre-
pared in excellent yields in the absence of any addi-
tional catalysts. In addition, [bmim][BF ] can be re-
4
covered and reused effectively for at least six times
without obvious decrease of its efficiency. Advan-
tages of this novel protocol include simple opera-
tional process, environmental benignancy, and high ef-
ficiency. ꢀC 2006 Wiley Periodicals, Inc. Heteroatom Chem
17:382–388, 2006; Published online in Wiley InterScience
(
www.interscience.wiley.com). DOI 10.1002/hc.20221
INTRODUCTION
Pyridine and their hydrogenated derivatives are
among the most important heterocycles commonly
found in a wide variety of naturally occurring sub-
stances possessing a multiplicity of biological ac-
tivities. Among these, 1,4-dihydropyridines (DHPs)
Multi-component reactions (MCRs) are special
types of synthetically useful organic reactions in
which three or more starting materials react to give
a product. Compared with classical reactions, MCRs
have such advantages as one-pot reaction, giving
products with a minute amount of work and leading
to complex products by reacting structurally simple
Correspondence to: Xue Sen Fan; e-mail: fanxs88@263.net.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20273019.
Contract grant sponsor: Science Foundation of Henan Normal
University for Young Scholars.
Contract grant number: 0307032.
ꢀ
c 2006 Wiley Periodicals, Inc.
3
82

An Efficient and Green Synthesis of 1,4-Dihydropyridine Derivatives through Multi-component Reaction in Ionic Liquid 383
starting materials. These merits make MCRs very
popular in areas like drug discovery process in the
pharmaceutical industry and related areas where
many different compounds are to be synthesized
and screened [4]. On the other hand, the replace-
ment of current chemical process with more envi-
ronmentally benign alternatives is an increasingly
attractive goal in organic synthesis [5]. In this field,
room temperature ionic liquids have emerged and at-
tracted much attention as novel media for catalytic
process during the last decades and several impor-
tant organic transformations have been carried out
successfully in them [6]. In view of the rapidly in-
creasing importance of imidazolium-based ionic liq-
uids as novel reaction media, we have been working
to explore the use of 1-butyl-3-methylimidazolium
mixture was found to afford product 5a in high yield
(Table 1, entry 4). Further investigations showed that
with similar procedure, either higher (Table 1, en-
tries 5 and 6) or lower (Table 1, entries 1–3) reaction
temperature than 80 C would more or less reduce
the yield of 5a.
◦
Next, reactions involving several other aldehy-
des 1 (Scheme 3) and another 1,3-dione, namely
1,3-cyclohexanedione 2b (Scheme 3), were also in-
vestigated. The results are summarized in Table 2.
In all cases, the corresponding products were ob-
tained in good to excellent yields. It is worthy to
be noted that even comparatively unreactive alde-
hydes such as heterocyclic and aliphatic aldehy-
des could undergo similar reaction and give 1,4-
dihydropyridines in good yields (Table 2, entries 9–
11). On the other hand, when 1,3-cyclohexanedione
2b (Scheme 3) was used in place of 5,5-dimethyl-
1,3-cyclohexanedione 2a, this condensation process
could be realized equally well (Table 2, entries 12–
15).
In order to further broaden the scope of this
protocol, an acyclic 1,3-dione, pentane-2,4-dione 2c
(Scheme 4), was also tried. It turned out that like
its cyclic counterparts 2a and 2b, 2c was also found
to undergo the above reaction and afford the corre-
sponding DHP derivative 5p in moderate yield (42%,
Scheme 4). Though the yield is relatively low, it is still
remarkable given the fact that it is the first example,
as far as we know, in which an acyclic 1,3-dione was
successfully employed in this four-component con-
densation process.
tetrafluoroborate ([bmim][BF ]) as recyclable sol-
4
vent system and promoter for greener organic syn-
thesis [7]. As continuation of our research in this
regard, herein we would like to report an efficient
procedure for the preparation of 1,4-dihydropyridine
derivatives through a four-component reaction in-
cluding aldehydes 1, 1,3-dione 2, Meldrum’s acid
3
, and ammonium acetate 4 in [bmim][BF
4
]
(Scheme 1).
RESULTS AND DISCUSSION
Initially, the reaction of m-nitrobenzaldehyde 1a
0.5 mmol) with 5,5-dimethyl-1,3-cyclohexanedione
a (0.5 mmol), ammonium acetate 4 (0.8 mmol),
and Meldrum’s acid 3 (0.5 mmol) was examined
Scheme 2). For the first run, unfortunately, after
the mixture of these four components in 0.5 mL
bmim][BF ] being stirred for several hours at room
(
2
(
On the other hand, it has been reported in many
cases that compared with classical organic solvents,
ionic liquids not only possess a green nature, but also
demonstrate the advantages of actually accelerating
the reaction rate and increasing the yields. Not unex-
pectedly, these merits of ionic liquids were also con-
firmed in this protocol. By running the same reac-
[
4
temperature, no reaction was observed according to
TLC analysis. It was then found out that even with
◦
an increased temperature (80 C), the desired prod-
uct was still reluctant to be formed. Then, an al-
ternative manipulation in terms of the substrates’
addition sequence was tried. Thus, 2a (0.5 mmol)
tion of 1a, 2a, 3, and 4 in [bmim][BF ] and in two
4
classical solvents, namely acetic acid and anhydrous
ethanol respectively, we were able to come to the
conclusion that compared with acetic acid and an-
and 4 (0.8 mmol) were first treated with 0.5 mL
◦
[
bmim][BF
4
] and the mixture was stirred at 80 C un-
til the disappearance of 2 (in about 1 h, monitored
by TLC). Then, 1a (0.5 mmol) and 3 (0.5 mmol) were
added. After being stirred at 80 C for another 3 h, the
hydrous ethanol, reaction run in [bmim][BF ] gave
the corresponding product in much higher yield with
much shorter reaction time (Table 3).
4
◦
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

3
84 Fan et al.
SCHEME 2
TABLE 1 Studies on the Effect of Reaction Temperature on
the Yield of 5a
In conclusion, an efficient and environmental
friendly procedure for the preparation of hydro-
genated pyridine derivatives is described in this pa-
per. The method presented here has the advantages
of high efficiency, green nature, simple operational
procedure, high versatility and ease of recovery and
reuse of the reaction medium. All these merits may
make this method attractive for the scale-up prepa-
ration of DHP derivatives.
Reaction temperature Reaction time Isolated yield
◦
Entry
( C)
(h)
(%)
1
2
3
4
5
6
25
40
60
80
100
120
48
32
12
4
4
4
23
40
81
93
77
67
EXPERIMENTAL
Melting points were measured by a Kofler micro
melting point apparatus and were uncorrected. In-
frared spectra were recorded on a Bruker Vector 22
The recovery and reuse of solvent and/or cata-
lyst are highly preferable in terms of green synthetic
process. Therefore, with the success of the above re-
actions, we continued our research by studying the
−
1
1
spectrometer in KBr with absorption in cm . H
NMR spectra were determined on a Bruker AC 400
spectrometer as DMSO solutions. Chemical shifts (δ)
were expressed in ppm downfield from the internal
standard tetramethylsilane and coupling constants
J were given in Hz. Mass spectra were obtained by
a HP-5989B mass spectrometer. Elemental analyses
were performed on an EA-1110 instrument.
reusage of [bmim][BF
covery and reuse of [bmim][BF
4
]. It turned out that the re-
] is very convenient
4
and highly efficient. Thus, at completion of the con-
densation process, precipitated products were col-
lected by suction and rinsed with cold ethanol, and
[
bmim][BF ] could be recovered easily by concen-
4
trating the filtrate under reduced pressure and then
◦
drying at 100 C for several hours. Studies by using
Typical Procedure for the Preparation
of Compound 5a
1
a and 2a as model substrates showed that the re-
covered [bmim][BF ] could be successively recycled
4
in subsequent reactions without almost any decrease
in its efficiency (Table 4). It should be noted that even
5,5-Dimethyl-1,3-cyclohexanedione 2a (0.5 mmol)
and ammonium acetate 4 (0.8 mmol) were added
to a 10 mL round bottom flask containing 0.5 mL
in the sixth round, reuse of [bmim][BF ] recovered
4
◦
from the fifth round still produced the corresponding
product with fairly good yield (Table 4, round 6).
[bmim][BF ]. The mixture was then stirred at 80 C
4
for about 1 h to give a complete conversion of 2a
SCHEME 3
Heteroatom Chemistry DOI 10.1002/hc

An Efficient and Green Synthesis of 1,4-Dihydropyridine Derivatives through Multi-component Reaction in Ionic Liquid 385
TABLE 2 Preparation of DHPs in [bmim][BF4]
Entry
Products
R1
m-NO C H
4
R2
2
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2a
2a
2a
2a
2a
2a
2a
2a
2a
4
5
5
4
5
5
5
4
8
93
85
89
89
85
83
91
92
78
2
6
p-ClC H4
6
p-OH, m−OCH C H
3
6
3
C H5
6
p-CH C H
3
6
4
o-ClC H4
6
o-BrC H4
6
p-BrC H4
6
10
11
12
13
14
15
5j
5k
5l
5m
5n
5o
CH CH CH CH —
CH3
CH3
H
H
H
2a
2a
2b
2b
2b
2b
8
9
4
4
4
4
71
58
86
85
81
87
3
2
2
2
CH CH CH CH CH CH
3
2
2
2
2
2
p-NO C H
2
6
4
4
o-NO C H
2
6
p-ClC H4
6
m-NO C H
H
2
6
4
(
(
monitored by TLC). Then, m-nitrobenzaldehyde 1a
0.5 mmol) and Meldrum’s acid 3 (0.5 mmol) were
400 MHz) δ: 0.98 (s, 3H, CH
3
), 1.05 (s, 3H, CH ),
3
6
2.15 (d, J = 16.0 Hz, 1H, CH), 2.25 (d, J = 16.0
6
8
added to the reaction mixture and it was stirred for
about another 3 h at 80 C. At completion, the reac-
tion mixture was added with 2 mL water and the pre-
cipitate was collected by suction and rinsed with cold
ethanol to give product 5a with high purity. The fil-
trate was concentrated under reduced pressure and
Hz, 1H, CH), 2.40 (d, J = 16.0 Hz, 1H, CH), 2.48
◦
8
(d, J = 16.0 Hz, 1H, CH), 2.51 (d, J = 16.4 Hz, 1H,
3
3
CH), 3.01 (dd, J = 16.4, 8.0 Hz, 1H, CH), 4.29 (d,
4
J = 8.0 Hz, 1H, CH), 7.61 (m, 2H, Ar-H), 7.96 (s,
1H, Ar-H), 8.05 (m, 1H, Ar-H), 10.23 (br s, 1H, NH);
IR (KBr): 3221 (NH), 1710 (C O), 1609 (N C O)
◦
−1
dried at 100 C to recover the ionic liquid for subse-
cm .
quent use.
Other products were obtained in a similar man-
ner. The melting point and the spectral data (IR, H
NMR) of the known compounds were recorded and
were found to be in accordance with what have been
reported previously. All the new compounds were
ꢁ
7
,7-Dimethyl-4-(4 -chlorophenyl)-2,5-dioxo-1,2,-
1
3
1
d
2
1
,4,5,6,7,8-octahydroquinoline 5b. White solid, mp
◦
◦
1
87–188 C (Lit. [3g] 188–190 C); H NMR (DMSO-
, 400 MHz) δ: 0.96 (s, 3H, CH ), 1.04 (s, 3H, CH ),
.13 (d, J = 16.0 Hz, 1H, CH), 2.22 (d, J = 16.0 Hz,
6
3
3
6
1
fully characterized by IR, H NMR, and elemental
analysis.
6
8
H, CH), 2.37 (d, J = 16.0 Hz, 1H, CH), 2.41–2.43
8
3
(
m, 2H, CH, CH), 2.93 (dd, J = 16.4, 8.4 Hz, 1H,
3
4
CH), 4.12 (d, J = 8.4 Hz, 1H, CH), 7.13 (d, J = 8.8
ꢁ
7
,7-Dimethyl-4-(3 -nitrophenyl)-2,5-dioxo-1,2,3,-
Hz, 2H, Ar-H), 7.32 (d, J = 8.8 Hz, 2H, Ar-H), 10.12
4
,5,6,7,8-octahydroquinoline 5a. White solid, mp
(
1
br s, 1H, NH); IR (KBr): 3220 (NH), 1718 (C O),
◦
◦
1
193–194 C (Lit. [3f] 192–193 C); H NMR (DMSO-d
6
,
−1
612 (N C O) cm .
SCHEME 4
Heteroatom Chemistry DOI 10.1002/hc

3
86 Fan et al.
TABLE 3 Comparison Between Organic Solvents and [bmim][BF ] in the Synthesis of 5a
4
◦
Entry
Solvents
Reaction temperature ( C)
Reaction time (h)
Isolated yields (%)
1
2
3
4
[bmim][BF4]
Acetic acid
Acetic acid
Ethanol
80
Re ux
80
4
93
65
63
30
16
16
16
Re ux
ꢁ
ꢁ
8
3
7
,7-Dimethyl-4-(4 -hydroxyl-3 -methoxylphenyl)-
J = 16.8 Hz, 1H, CH), 2.53 (d, J = 16.0 Hz, CH),
3
2
,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline 5c.
2.90 (dd, J = 16.0, 8.0 Hz, 1H, CH), 4.10 (d, J = 8.0
◦
1
4
Pale yellow solid, mp 238–240 C; H NMR (DMSO-
, 400 MHz) δ: 0.97 (s, 3H, CH ), 1.03 (s, 3H, CH ),
.11 (d, J = 16.0 Hz, 1H, CH), 2.21 (d, J = 16.0 Hz,
H, CH), 2.33 (d, J = 16.8 Hz, 1H, CH), 2.40–2.42
Hz, 1H, CH), 7.02 (d, J = 8.0 Hz, 2H, Ar-H), 7.07 (d,
d
2
1
6
3
3
J = 8.0 Hz, 2H, Ar-H), 9.99 (s, 1H, NH); IR (KBr):
6
−1
3209 (NH), 1716(C O), 1610 (N C O) cm . Anal.
6
8
Calcd for C H NO : C 76.29, H 7.47, N 4.94; Found
C 76.18, H 7.50, N 4.91.
1
8
21
2
8
3
(
m, 2H, CH, CH), 2.82 (dd, J = 16.0, 7.6 Hz, 1H,
CH), 3.78 (s, 3H, OCH
), 4.01 (d, J = 7.6 Hz, 1H,
CH), 6.44 (d, J = 8.0 Hz, 1H, Ar-H), 6.60 (d, J = 8.0
3
3
4
ꢁ
7
,7-Dimethyl-4-(2 -chlorophenyl)-2,5-dioxo-1,2,-
,4,5,6,7,8-octahydroquinoline 5f. White solid, mp
48–250 C (Lit. [3f] 252–254 C); H NMR (DMSO-d
00 MHz) δ: 1.02 (s, 3H, CH ), 1.04 (s, 3H, CH ),
Hz, 1H, Ar-H), 6.67 (s, 1H, Ar-H), 8.77 (s, 1H, OH),
3
2
4
2
1
1
1
C
0.02 (s, 1H, NH); IR (KBr): 3369 (OH), 3222 (NH),
◦
◦
1
6
,
−
1
697(C O), 1617 (N C O) cm . Anal. Calcd for
: C 68.55, H 6.71, N 4.44; Found C 68.49,
H 6.76, N 4.38.
3
3
18
H
21NO
4
6
.15 (d, J = 16.0 Hz, 1H, CH), 2.21 (d, J = 16.0 Hz,
6
3
H, CH), 2.29 (d, J = 16.4 Hz, 1H, CH), 2.43 (d,
8
J = 16.8 Hz, 1H, CH), 2.51 (d, J = 16.8 Hz, 1H,
7
,7-Dimethyl-4-phenyl-2,5-dioxo-1,2,3,4,5,6,7,8-
8
3
CH), 2.99 (dd, J = 16.4, 8.4 Hz, 1H, CH), 4.45
◦
octahydroquinoline 5d. White solid, mp 217–219 C
4
(
d, J = 8.4 Hz, 1H, CH), 6.93–6.96 (m, 1H, Ar-H),
◦
1
(
Lit. [3f] 211–213 C); H NMR (DMSO-d
6
, 400 MHz)
), 2.16 (d,
7
1
1
.21–7.24 (m, 2H, Ar-H), 7.42–7.25 (m, 1H, Ar-H),
δ: 1.00 (s, 3H, CH ), 1.07 (s, 3H, CH
3
3
0.19 (s, 1H, NH); IR (KBr): 3219 (NH), 1713 (C O),
611 (N C O) cm .
6
J = 16.0 Hz, 1H, CH), 2.24 (d, J = 16.0 Hz, 1H,
−1
6
8
CH), 2.40 (d, J = 16.8 Hz, 1H, CH), 2.45–2.47 (m,
8
3
3
2
4
H, CH, CH), 2.93 (dd, J = 16.0, 8.0 Hz, 1H, CH),
ꢁ
7
,7-Dimethyl-4-(2 -bromophenyl)-2,5-dioxo-1,2,-
,4,5,6,7,8-octahydroquinoline 5g. White solid, mp
27–228 C; H NMR (DMSO-d
), 1.04 (s, 3H, CH
4
.15 (d, J = 8.0 Hz, 1H, CH), 7.15 (t, J = 7.2 Hz, 1H,
3
2
Ar-H), 7.19 (d, J = 7.2 Hz, 2H, Ar-H), 7.27 (t, J = 7.2
◦
1
6
, 400 MHz) δ: 1.01
), 2.14 (d, J = 16.0
Hz, 2H, Ar-H), 10.02 (br s, 1H, NH); IR (KBr): 3210
(
s, 3H, CH
3
3
−1
(
NH), 1712 (C O), 1610 (N C O) cm .
6
6
Hz, 1H, CH), 2.20 (d, J = 16.0 Hz, 1H, CH), 2.29
3
(
1
d, J = 16.4 Hz, 1H, CH), 2.43 (d, J = 17.6 Hz,
ꢁ
7
,7-Dimethyl-4-(4 -methylphenyl)-2,5-dioxo-1,2,-
8
8
H, CH), 2.51 (d, J = 17.6 Hz, 1H, CH), 2.98 (dd,
3
1
(
1
,4,5,6,7,8-octahydroquinoline 5e. White solid, mp
99–201 C; H NMR (DMSO-d , 400 MHz) δ: 0.99
3
J = 16.4, 8.8 Hz, 1H, CH), 4.41 (d, J = 8.4 Hz,
◦
1
6
4
1
H, CH), 6.93 (d, J = 7.6 Hz, 1H, Ar-H), 7.13 (t,
s, 3H, CH
3
), 1.07 (s, 3H, CH
3
), 2.14 (d, J = 16.0 Hz,
J = 7.6Hz, 1H, Ar-H), 7.25 (t, J = 7.6 Hz, 1H, Ar-H),
.61 (d, J = 7.6 Hz, 1H, Ar-H), 10.20 (s, 1H, NH);
IR (KBr): 3219 (NH), 1713 (C O), 1611 (N C O)
6
6
H, CH), 2.23 (d, J = 16.0 Hz, 1H, CH), 2.24 (s,
7
8
3
H, CH
3
), 2.39 (d, J = 16.8 Hz, 1H, CH), 2.43 (d,
−
1
cm . Anal. Calcd for C17
H
18BrNO : C 58.63, H 5.21,
2
N 4.02; Found C 58.68, H 5.17, N 3.94.
TABLE 4 Studies on the Reuse of Ionic Liquid (IL) in the
Preparation of 5a
ꢁ
7
,7-Dimethyl-4-(4 -bromophenyl)-2,5-dioxo-1,2,-
Round
Yield (%)
Ionic liquid recovered (%) a
3
1
4
2
,4,5,6,7,8-octahydroquinoline 5h. White solid, mp
96–198 C (Lit. [2] 196–197 C); H NMR (DMSO-d
◦
◦
1
6
,
1
2
3
4
5
6
93
92
91
92
92
91
99
99
99
98
98
97
00 MHz) δ: 0.94 (s, 3H, CH ), 1.02 (s, 3H, CH ),
3
3
6
.12 (d, J = 16.0 Hz, 1H, CH), 2.20 (d, J = 16.0 Hz,
6
8
1H, CH), 2.35 (d, J = 17.6 Hz, 1H, CH), 2.40 (d,
8
J = 17.6 Hz, 1H, CH), 2.40 (d, J = 16.0 Hz, 1H,
3
3
CH), 2.91 (dd, J = 16.0, 8.0 Hz, 1H, CH), 4.09 (d,
a
4
Recovery yield (%) = mass of the IL recovered/mass of the IL used.
J = 8.0 Hz, 1H, CH), 7.05 (d, J = 8.4 Hz, 2H, Ar-H),
Heteroatom Chemistry DOI 10.1002/hc

An Efficient and Green Synthesis of 1,4-Dihydropyridine Derivatives through Multi-component Reaction in Ionic Liquid 387
7
.44 (d, J = 8.4Hz, 2H, Ar-H), 10.11 (s, 1H, NH); IR
164 (15%), 28 (17%). Anal. Calcd for C15
62.93, H 4.93, N 9.79; Found C 62.95, H 4.87, N 9.82.
H
14
N
2
O : C
4
−
1
(KBr): 3220 (NH), 1716 (C O), 1610 (N C O) cm .
7
,7-Dimethyl-4-(2-furanyl)-2,5-dioxo-1,2,3,4,5,6,-
ꢁ
4
-(2 -Nitrophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octa-
7
1
(
,8-octahydroquinoline 5i. Light yellow solid, mp
74–176 C; H NMR (DMSO-d
s, 3H, CH
hydroquinoline 5m. Light yellow solid, mp 217–
◦
1
, 400 MHz) δ: 0.97
◦
1
6
2
19 C; H NMR (DMSO-d
), 2.24 (m, 2H, CH
), 2.41 (d, J = 16.8 Hz, 1H,
CH), 2.61 (m, 2H, CH
), 3.13 (dd, J = 16.8, 8.8 Hz,
H, CH), 4.48 (d, J = 8.8 Hz, 1H, CH), 7.22 (d,
, 400 MHz) δ: 1.99 (m, 2H,
6
3
), 1.05 (s, 3H, CH
3
), 2.17 (d, J = 16.0
CH
2
2
6
6
Hz, 1H, CH), 2.24 (d, J = 16.0 Hz, 1H, CH), 2.31
3
2
8
(
1
d, J = 17.2 Hz, 1H, CH), 2.41 (d, J = 17.2 Hz,
3
4
1
8
3
H, CH), 2.56 (d, J = 16.4 Hz, 1H, CH), 2.84 (dd,
J = 8.0 Hz, 1H, Ar-H), 7.48 (t, J = 8.0 Hz, 1H, Ar-H),
3
J = 16.4, 7.6 Hz, 1H, CH), 4.18 (d, J = 7.6 Hz, 1H,
7
1
1
.62 (t, J = 8.0 Hz, 1H, Ar-H), 7.91 (d, J = 8.0 Hz,
4
CH), 5.94 (s, 1H), 6.31 (s, 1H), 7.51 (s, 1H), 10.09
s, 1H, NH); IR (KBr): 3229 (NH), 1716 (C O), 1613
H, Ar-H), 10.32 (s, 1H, NH); IR (KBr): 3476 (NH),
(
(
694 (C O), 1637 (N C O), 1518 and 1347 (NO
cm . Anal. Calcd for C15
N 9.79; Found C 62.98, H 4.85, N 9.74.
2
)
−
1
N C O) cm . Anal. Calcd for C15
H 6.61, N 5.40; Found C 69.40, H 6.69, N 5.42.
H
17NO
3
: C 69.48,
−1
H
14
N
2
4
O : C 62.93, H 4.93,
7
,7-Dimethyl-4-butyl-2,5-dioxo-1,2,3,4,5,6,7,8 oc-
ꢁ
4
-(4 -Chlorophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-oct-
tahydroquinoline 5j. Light yellow solid, mp 120–
◦
ahydroquinoline 5n. White solid, mp 177–179 C;
H NMR (DMSO-d
◦
1
1
22 C; H NMR (DMSO-d
J = 6.4 Hz, 3H, CH ), 0.96 (s, 3H, CH
CH ), 1.15–1.29 (m, 6H, CH CH CH
6
, 400 MHz) δ: 0.82 (t,
), 1.02 (s, 3H,
), 2.11 (d,
1
6
, 400 MHz) δ: 1.97 (m, 2H, CH ),
2
3
3
2
1
.30 (t, J = 8.0 Hz, 2H, CH
2
), 2.45 (d, J = 16.4 Hz,
3
2
2
2
3
H, CH), 2.53 (t, J = 8.0 Hz, 2H, CH
2
), 2.92 (dd,
6
6
J = 16.0 Hz, 1H, CH), 2.20 (d, J = 16.0 Hz, 1H, CH),
3
J = 16.4, 8.0 Hz, 1H, CH), 4.16 (d, J = 8.0 Hz,
8
2
1
.22 (d,J = 17.2 Hz, 1H, CH), 2.28 (d, J = 16.4 Hz,
4
1
H, CH), 7.16 (d, J = 8.0 Hz, 2H, Ar-H), 7.33(d,
3
8
H, CH), 2.36 (d, J = 17.2 Hz, 1H, CH), 2.55 (dd,
J = 8.0 Hz, 2H, Ar-H), 10.16 (s, 1H, NH); IR (KBr):
3
J = 16.4, 7.2 Hz, 1H, CH), 2.85 (d, J = 7.2 Hz,
−
1
3
454 (NH), 1706 (C O), 1619 (N C O) cm . MS
4
1
1
C
H, CH), 9.91 (s, 1H, NH); IR (KBr): 3234 (NH),
+
m/z: 275 (M , 74%), 240 (29%), 207 (19%), 28
100%). Anal. Calcd for C15
.12, N 5.08; Found C 65.30, H 5.14, N 5.05.
−1
711 (C O), 1599 (N C O) cm . Anal. Calcd for
: C 72.25, H 9.30, N 5.62; Found C 72.19,
H 9.36, N 5.57.
(
5
H
14ClNO : C 65.34, H
2
15
H23NO
2
ꢁ
4
-(3 -Nitrophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octa-
7
,7-Dimethyl-4-hexyl-2,5-dioxo-1,2,3,4,5,6,7,8-
hydroquinoline 5o. Light yellow solid, mp 224–
octahydroquinoline 5k. Light yellow solid, mp
◦
1
◦
1
226 C; H NMR (DMSO-d , 400 MHz) δ: 2.00 (m,
9
0
CH
7–99 C; H NMR (DMSO-d
.84 (t, J = 6.4 Hz, 3H, CH
), 1.02 (s, 3H, CH
CH CH CH CH CH
6
,
400 MHz) δ:
6
2
H, CH
2
), 2.32 (t, J = 8.0 Hz, 2H, CH
2
), 2.53 (d,
3
), 0.96 (s, 3H,
3
J = 16.0 Hz, 1H, CH), 2.56 (t, J = 8.0 Hz, 2H, CH
2
),
3
3
), 1.18–1.27 (m, 10H,
3
3
.00 (dd, J = 16.0, 8.0 Hz, 1H, CH), 4.34 (d, J = 8.0
2
6
2
2
2
2
), 2.10 (d, J = 16.0 Hz,
4
6
Hz, 1H, CH), 7.60 (m, 2H, Ar-H), 7.99 (s, 1H, Ar-H),
8.06 (m, 1H, Ar-H), 10.27 (s, 1H, NH); IR (KBr):
3464 (NH), 1710 (C O), 1613 (N C O), 1526 and
1
H, CH), 2.20 (d, J = 16.0 Hz, 1H, CH), 2.21 (d,
8
J = 17.6 Hz, 1H, CH), 2.27 (d, J = 16.4 Hz, 1H,
3
8
CH), 2.36 (d, J = 17.6 Hz, 1H, CH), 2.55 (dd,
−
1
+
3
1349 (NO ) cm . MS m/z: 286 (M , 38%), 269
(100%), 239 (43%), 207 (19%), 28 (66%). Anal. Calcd
J = 16.4, 7.2 Hz, 1H, CH), 2.85 (d, J = 7.2 Hz, 1H,
2
4
CH), 9.91 (s, 1H, NH); IR (KBr): 3226 (NH), 1695
−1
+
for C H N O : C 62.93, H 4.93, N 9.79; Found
(
1
C O), 1635 (N C O) cm . MSm/z: 277 (M , 10%),
92 (100%), 136 (10%). Anal. Calcd for C17
C 73.61, H 9.81, N 5.05; Found C 73.65, H 9.78, N
15 14
2
4
C 62.84, H 4.99, N 9.85.
H
27NO :
2
ꢁ
5
.00.
5-Acetyl-6-methyl-4-(3 -nitrophenyl)-3,4-dihydro-
◦
1
pyridin-2(1H)-one 5p. mp 175–178 C; H NMR
(DMSO-d , 400 MHz) δ: 2.09 (s, 3H, CH ), 2.35 (s,
3H, CH
ꢁ
4
-(4 -Nitrophenyl)-2,5-dioxo-1,2,3,4,5,6,7,8-octa-
6
3
◦
3
hydroquinoline 5l. Yellow solid, mp 222–224 C;
H NMR (DMSO-d
H, CH
3
), 2.37 (d, J = 16.0 Hz, 1H, CH), 2.99 (dd,
1
3
6
, 400 MHz) δ: 1.97–2.01 (m,
J = 16.0, 8.0 Hz, 1H, CH), 4.40 (d, J = 8.0 Hz, 1H,
4
2
2
), 2.31 (t, J = 8.0 Hz, 2H, CH
2
), 2.50 (d,
CH), 7.65 (m, 2H, Ar-H), 8.03 (s, 1H, Ar-H), 8.11
(m, 1H, Ar-H), 9.99 (s, 1H, NH); IR (KBr): 3471
3
J = 16.0 Hz, 1H, CH), 2.56 (t, J = 8.0 Hz, 2H, CH
2
),
3
−1
3
.01 (dd, J = 16.0, 8.0 Hz, 1H, CH), 4.30 (d, J = 8.0
(NH), 1625 (C O), 1594 (N C O) cm . MS m/z:
4
+
Hz, 1H, CH), 7.42 (d, J = 8.0 Hz, 2H, Ar-H), 8.15 (d,
274 (M , 20%), 257 (100%), 227 (24%), 176 (16%),
J = 8.0 Hz, 2H, Ar-H), 10.25 (s, 1H, NH); MS m/z:
43 (10%). Anal. Calcd for C14
H 5.14, N 10.21; Found C 61.22, H 5.18, N 10.29.
H
14
N
2
4
O : C 61.31,
+
2
86 (M , 100%), 269 (45%), 257 (33%), 239 (15%),
Heteroatom Chemistry DOI 10.1002/hc

3
88 Fan et al.
REFERENCES
[4] Rossen, K. P. P.; Dimichele. L. M.; Voante, R. P.; Rei-
der, P. J. Tetrahedron Lett 1998, 39, 6823–6826.
[5] (a) Tundo, P.; Anastas, P.; Black, D. S.; Breen,
J.; Collins, T.; Memoli, S.; Miyamoto, J.; Polyakoff,
M.; Tumas, W. Pure Appl Chem 2000, 72, 1207–1228;
(b) Anastas, P. T.; Kirchhoff, M. M. Acc Chem Res
2002, 35, 686–694; (c) Eissen, M.; Metzger, J. O.;
Schmidt, E.; Schneidewind, U. Angew Chem Int Ed
2002, 41, 414–436.
[6] (a) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M.
S. Tetrahedron 2005, 61, 1015–1060; (b) Sun, J. M.;
Fujita, S. I.; Arai, M. J. Organomet Chem 2005, 690,
3490–3497; (c) Baudequin, C.; Baudoux, J.; Levillain,
J.; Cahard, D.; Gaumont, A. C.; Plaquevent, J. C. Tetra-
hedron: Asymmetry 2003, 14, 3081–3093; (d) Zhao,
D. B.; Wu, M.; Kou, Y.; Min, E. Catal Today 2002, 74,
157; (e) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z.
Chem Rev 2002, 102.
[
[
1] (a) Janis, R. A.; Silver, P. J.; Triggle, D. J. Adv Drug
Res 1987, 16, 309–591; (b) Bossert, F.; Meyer, H.;
Wehinger, E. Angew Chem, Int Ed Engl 1981, 20,
7
1
62–769; (c) Nakayama, H.; Kasoaka, Y. Heterocycles
996, 42, 901–909.
2] (a) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle,
D. J.; Rothe, H. Drug Design Discovery 1992, 8, 273;
(
b) Mannhold, R.; Jablonka, B.; Voigdt, W.; Schoe-
nafinger, K.; Schravan, K. Eur J Med Chem 1992, 27,
29–235; (c) Godfraid, T.; Miller, R.; Wibo, M. Phar-
2
macol Rev 1986, 38, 321–416.
3] (a) Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61,
[
2
465–2470; (b) Sabitha, G.; Reddy, G. S.; Reddy, C.
S.; Yadav, J. S. Tetrahedron Lett 2003, 44, 4129–4139;
c) Stout, D. M.; Meyers, A. I. Chem Rev 1982, 82,
(
2
2
23–243; (d) Correa, W. H.; Scott, J. L. Green Chem
001, 3, 296–301; (e) Ji, S.; Jiang, Z.; Lu, J.; Loh, T.
[7] (a) Zhang, X. Y.; Fan, X. S.; Niu, H. Y.; Wang, J. J.
Green Chem 2003, 5, 267; (b) Fan, X. S.; Hu, X. Y.;
Zhang, X. Y.; Wang, J. J. Can J Chem 2005, 83, 16–21;
(c) Wang, J. J.; Fan, X. S.; Zhang, X. Y.; Han, L. J. Can
J Chem 2004, 82, 1192–1196; (d) Fan, X. S.; Hu, X.
Y.; Zhang, X. Y.; Wang, J. J. Aust J Chem 2004, 57,
1067–1071.
Synlett 2004, 5, 831–835; (f) Su a´ rez, M.; Ochoa, E.;
Verdecia, Y.; Pita, B. Moran, L.; Martin, N.; Quin-
teiro, M.; Seoane, C.; Soto, J. L.; Vovoa, H.; Blaton,
N.; Peters, O. M. Tetrahedron 1999, 55, 875–884; (g)
Tu, S.; Wei, Q.; Ma, H.; Shi, D.; Gao, Y.; Cui, G. Synth
Commun 2001, 31, 2657–2661.
Heteroatom Chemistry DOI 10.1002/hc