One-pot synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives via L-proline catalyzed hantzsch multicomponent reaction under ultrasound irradiation

Article abstract of DOI:10.1002/cjoc.201090151

L-Proline efficiently catalyzed the multi-component Hantzsch reaction in EtOH at 60°C under ultrasound irradiation to afford the corresponding 1,4-dihydropyridine and polyhydroquinoline derivatives in high yields. This method offers the advantages of neut

Full text of DOI:10.1002/cjoc.201090151

FULL PAPER
One-Pot Synthesis of 1,4-Dihydropyridine and Polyhydro-
quinoline Derivatives via L-Proline Catalyzed Hantzsch
Multicomponent Reaction under Ultrasound Irradiation
Guo, Shengrong*(郭圣荣)
Yuan, Yanqin(袁艳琴)
Department of Chemistry, Lishui University, Lishui, Zhejiang 323000, China
L-Proline efficiently catalyzed the multi-component Hantzsch reaction in EtOH at 60 ℃ under ultrasound irra-
diation to afford the corresponding 1,4-dihydropyridine and polyhydroquinoline derivatives in high yields. This
method offers the advantages of neutral and mild reaction conditions, high to excellent yields of the products and
simple workup.
Keywords multi-component Hantzsch reaction, 1,4-dihydropyridines, polyhydroquinoline, L-proline
Introduction
like cinchona alkaloids and amino acids is well
known,15-16 small organic molecules have been shown
as quite promising and highly efficient organocatalysts
for multi-component reactions.17 The amino acid L-
proline is an abundant bifunctional chiral molecule that
is inexpensive, the two functional groups can both act as
acid or base and can also facilitate chemical transforma-
tions in concert, similar to enzymatic catalysis. As the
mechanism of multi-component Hantzsch reaction orig-
inally involves aldol related reactions such as Knoeve-
nagel condensation and Michael addition, the use of
L-proline for the same reaction will be an useful and
attractive modification. Kumar17 and Karade18 reported
the use of L-proline as an organocatalyst for the multi-
component Hantzsch reaction and get excellent yields.
Herein, we would like to report the studies of a facile
Hantzsch condensation in the presence of amino acid
organocatalyst at 60 ℃ using substituted aldehyde (1),
acetoacetate ester (2), and ammonium acetate to pro-
duce 1,4-dihydropyridine derivatives (3) in high yields.
We examined this reaction under three different sets of
reaction conditions: (I) organic solvents, and (II) water
under ultrasonic irradiation.
4-Substituted 1,4-dihydropyridines (1,4-DHPs) are
analogues of nicotinamide adenine nucleotide (NADH)
coenzymes and an important class of drugs.1 Current
literature reveals that these compounds possess a variety
of biological activities.2 Furthermore, hydrogenation
methods for the conversion of these compounds to pyri-
dines have been investigated intensively.3 These exam-
ples indicate clearly the remarkable potential of novel
1,4-dihydropyridine derivatives as a source of valuable
drug candidates and useful intermediates in organic
chemistry. Thus, the synthesis of this heterocyclic nu-
cleus is of much importance.
Classical methods for the synthesis of 1,4-dihydro-
pyridines are one-pot condensation of an aldehyde with
ethyl acetoacetate and ammonium acetate, either in ace-
tic acid or under reflux in alcohols.4 However, these
methods suffer from several drawbacks such as long
reaction time, an excess of organic solvent, lower prod-
uct yields, and harsh refluxing conditions. Therefore, it
is necessary to develop more efficient and versatile
methods for the preparation of 1,4-DHPs and the pro-
gress in this area is remarkable, including the recent use
of microwaves,5 ionic liquids,6 refluxing at high tem-
perature,7 SiO2-HClO4,8 silica sulfuric acid,9 ZnO,10
Results and discussion
Yb(OTf)3,11 Ceric ammonium nitrate,12 ZrCl4 and
Firstly, we followed the typical experimental proce-
dure, a solution of substituted aldehyde, acetoacetate
ester, and ammonium acetate in ethanol was stirred in
the presence of catalytic amount of 10 mol% L-proline
for a certain period of time required to complete the
reaction (TLC), resulting in the formation of 1,4-dihy-
dropyridine derivatives 3 (Scheme 1). After the reaction
was completed, cooling the reaction mixture to 0 ℃,
13
solid-phase organic synthesis (SPOS) techniques.14 Al-
though some reactions are satisfactory in terms of yield,
however, most of these methods employ expensive or
poisonous catalysts, not commercially available cata-
lysts, and suffer from long reaction times. Thus, it is
clearly evident that the development of more flexible
and effective protocols is required.
The catalytic property of small organic molecules
*
E-mail: guosr9609@163.com; Tel.: 0086-0578-2271087; Fax: 0086-0578-2271366
Received September 23, 2009; revised January 9, 2010; accepted January 26, 2010.
Project supported by the Natural Science Foundation of Zhejiang Province, China (No. Y407240) and Lishui University (No. KY07002).
Chin. J. Chem. 2010, 28, 811— 817
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Guo & Yuan
FULL PAPER
aqueous medium. Indeed, water is recognized as an at-
tractive medium for many organic reactions. The reac-
tion was carried out successfully at 60 ℃ leading to
moderate yields of the products using 10 mol% of
L-proline in water (Table 1 IIa). Upon refluxing in
ethanol the reaction rate was increased and the reaction
was completed within 1 h, but the yield was somewhat
decreased.
Scheme 1
The catalyst plays a crucial role in the success of the
reaction in terms of the rate and the yields of
1,4-dihydropyridine derivatives. We further studied the
catalytic efficiency of other organocatalysts on the
Hantzsch reaction. In all cases the catalyst was taken as
10 mol% and reaction was done at 60 ℃ under ultra-
sonic irradiation for 2 h. The results of this study are
shown in Table 2. Initially, we tried this reaction with
simple secondary amines (diethylamine or piperidine) as
catalyst in the absence of L-proline (Entries 1, 2), the
product was isolated in low yield, instead, the Knoeve-
nagel condensation was observed. We further screened a
number of amino acids to optimize the reaction condi-
tions. It was observed that basic amino acids like
L-histidine and L-lysine resulted in poor conversion of
3a (Entries 3, 4) and the acidic amino acids were found
somewhat better (Entries 5, 6), but best result of 95%
yield was obtained with neutral amino acids like
L-proline (Entry 7). The use of 10 mol% of L-proline is
sufficient to push the reaction forward. Lower or higher
amounts of L-proline did not lead to significant im-
provement in the yield of 1,4-dihydropyridine. For ex-
ample, using L-proline (5 mol%) as catalyst, the reac-
tion gave yellow solid product in 78% yield. By chang-
ing the amount of the catalyst such as 7.5 mol% and 20
mol%, the reaction resulted in the formation of 3a in
80% and 90% yield respectively (Table 2). Lastly, we
also carried out reactions without any catalyst, but the
1,4-dihydropyridine derivatives were isolated in poor
25% yield and the major product isolated was a dime-
done aldehyde adduct.
the soid products were precipitated from the mixture,
filtered to get most of the products. The filtrate liquor
was then poured into crushed ice to get residue solid
product. The two parts of solid products were put to-
gether and recrystallized from ethanol to get straw yel-
low colored crystalline 1,4-dihydropyridine 3a in 95%
yield. The results of L-proline catalyzed synthesis of
1,4-dihydropyridine derivatives using ultrasound irra-
diations are given in Table 1 (Ia, Ib). Using L-proline as
promoter for the synthesis of 1,4-dihydropyridine de-
rivatives does not only represent a dramatic improve-
ment at 60 ℃ with regard to yield (83%—96%) over
conventional thermal heating or reflux, and the reaction
time also considerably decreased (0.5—2.50 h) com-
pared to classical synthesis (6—8 h).
Table 1 One-pot synthesis of 1,4-dihydropyridines 3a—3h
catalyzed by L-proline in ethanol under classical conditions and
using ultrasound irradiation at 60 ℃
Table 2 Screening of organocatalysts for synthesis of 3a under
different conditionsa
Yieldc/% (Time/h)
Product
R
m.p./℃
95—96
Ia
Ib
IIa
Entry Organocatalyst
Catalyst/mol%
Time/h Yieldb/%
95 (1.5) 85 (6.0) 79 (3.5)
65d (0.5) 53d(3.0) 45d(1.5)
3a
H
1
Diethylamine
Piperidine
10
10
10
10
10
10
10
5
24
8
21
32
51
85
88
91
95
78
80
90
25
2
3b 4-F
3c 3-F
89 (1.0) 82 (8.5) 78 (4.0) 167—168
87 (1.5) 80 (6.6) 81 (3.5) 160—163
92 (1.0) 88 (5.0) 82 (3.5) 135—137
90 (1.0) 82 (7.0) 78 (3.5) 164—166
3
L-Lysine
2.0
2.0
2.0
2.0
1.5
1.5
1.5
1.5
3.5
4
L-Histidine
L-Glutamic acid
L-Asparatic acid
L-Proline
3d 4-CH3
5
3e 4-CH3O
6
3f
2-Cl, 6-CH3 96 (0.5) 90 (3.5) 86 (3.5) 171—172
7
3g 3-CH3, 4-F 86 (0.5) 82 (6.0) 76 (4.5) 153—155
8
L-Proline
3h 2-F, 5-F
83 (2.5) 78 (7.5) 80 (3.5) 175—177
a Reagents and conditions: 1 (3 mmol), 2 (6.1 mmol), NH4OAc (6
9
L-Proline
7.5
20
0
10
11
L-Proline
mmol), L-proline (10 mol%) under ultrasound irradiation at 60
b
c
℃. Catalyzed by L-proline without ultrasound irradiation. Iso-
L-Proline
lated yields. d Refluxing.
a
Reagents and conditions: 1 (3 mmol), 2 (6 mmol), NH4OAc (4
mmol), organocatalyst, under ultrasound irradiation at 60 ℃.
Secondly, to avoid the use of ecologically sus-
pected organic solvents, we carried out the reaction in
b Isolated yields.
812
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Chin. J. Chem. 2010, 28, 811— 817

One-Pot Synthesis of 1,4-Dihydropyridine and Polyhydroquinoline Derivatives
In the majority of instances, the crude product was
so pure that it was directly subjected to NMR analysis.
All yields are those of isolated products after purifica-
tion and the structures of the products were confirmed
from melting point and spectroscopic data, the structure
of 3c was unambiguously confirmed by an X-ray crys-
tallographic analysis (Figure 1, Table 3), and it shows
that the target product 1,4-dihydropyridine was fully
formed.
four-component coupling reaction of 4-arylsulfanyl-
benzaldehyde, ethyl acetoacetate, 1,3-cyclohexanedione
and ammonium acetate in EtOH at 60 ℃ catalyzed by
L-proline with ultrasonic irradiation for 1—3 h.
Using the optimized reaction conditions, we synthe-
sized a number of polyhydroquinoline derivatives and
the results are shown in Table 4. The results of Table 4
indicate clearly the feasibility of four-component
unsymmetrical Hantzsch reaction in ethanol catalyzed
by amino acid L-proline. The products were synthesized
in excellent yields under ultrasonic irradiation. Indeed,
we found 91% of isolated yield with 24% ee of 4a. This
ee value is slightly higher than that obtained under
proline/DMF system (21% ee) and comparable with
other amino acid observed in alcohol. Unfortunately, all
the amino acid examined demonstrated low enantiose-
lectivities in the reaction.
Scheme 2
Figure 1 The crystal structure of 3c.
To determine whether the ultrasound irradiation was
another essential factor to realize the high conversions
of this condensation, the same reaction was carried out
in same conditions without using ultrasound irradiation.
When the reaction mixture was irradiated with ultra-
sound, almost quantitative conversion was observed
(TLC). As a result (Table 1) the reaction time was de-
creased by about 4－6 h. It is important to note that in
the absence of catalysis and without using ultrasound
irradiation, the yield of the reactions decreased to 5%—
10%.
In summary, the use of inexpensive L-proline in a
catalytic quantity is a general practical alternative to
existing procedures for multicomponent Hantzsch syn-
thesis of 1,4-dihydropyridine and polyhydroquinoline
derivatives. The procedure offers several advantages
including increased variations of substituent in the
product with high yields, operational simplicity, mini-
mum environmental effects and above all, the ease in
After successfully synthesizing a series of Hantzsch
esters in excellent yields under ultrasonic irradiation, we
turned our attention towards the synthesis of polydy-
droquionoline derivatives via unsymmetrical Hantzsch
reaction using L-proline as catalyst under ultrasonic ir-
radiation conditions (Scheme 2). We carried out the
Table 3 Selected bond lengths (Å) and angles (°) for 3c
S(1)—C(7) 1.776(3) N(1)—C(15)
C(13)—C(19) 1.526(4)
S(1)—C(6)
1.766(3)
1.521(4)
1.456(4)
1.379(4)
1.371(4)
1.359(4)
0.8600
C(13)—C(14)
C(14)—C(23)
N(1)—C(18)
C(14)—C(15)
N(1)—H(1A)
C(18)—C(19)
1.347(4)
C(6)-S(1)-C(7)
103.30(14)
110.6(2)
118.6(3)
119.5(3)
120.5(3)
C(10)-C(13)-C(14)
C(15)-C(14)-C(13)
C(14)-C(15)-C(16)
C(19)-C(18)-C(17)
C(18)-C(19)-C(13)
111.2(2)
120.5(3)
128.6(3)
127.3(3)
120.0(3)
C(10)-C(13)-C(19)
C(23)-C(14)-C(13)
N(1)-C(15)-C(16)
N(1)-C(18)-C(17)
C(20)-C(19)-C(13)
111.9(2)
114.9(2)
112.8(3)
113.2(3)
119.4(3)
C(14)-C(13)-C(19)
C(14)-C(15)-N(1)
C(19)-C(18)-N(1)
C(18)-C(19)-C(20)
Chin. J. Chem. 2010, 28, 811— 817
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Guo & Yuan
FULL PAPER
Table 4 One-pot synthesis of polyhydroquinoline 4a—4g catalyzed by L-proline in ethanol under classical conditions and using ultra-
sound irradiation at 60 ℃
Product
4a
R
Yieldc/%
Time/h
1.50
1.00
1.50
0.75
0.75
0.50
0.50
eed/%
24, 21 e, 22 f, 19g
m.p./℃
H
91
87
89
87
85
92
85
251—253
227—229
268—271
276—278
195—197
207—209
250—253
4b
4-F
19
4c
3-CH3
14
4d
3-OCH3, 4-OCH3
3-F, 4-OCH3
2-Cl, 6-CH3
2-F, 5-F
18
4e
9
4f
23, 17 f,15g
4g
7
a Reagents and conditions: 1 (3 mmol), 2 (3 mmol), 3 (3 mmol), NH4OAc (5 mmol), L-proline (10 mol%) and using ultrasound irradiation
at 60 ℃. b Catalyzed by L-proline without using ultrasound irradiation. Isolated yields. d Determined by chiral HPLC analysis using a
c
Chiralcel OB column. e DMF as solvent. f L-Glutamic acid as catalyst. g L-Lysine as catalyst.
purification of products simply by crystallization.
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3b)
1
White solid, m.p. 167—168 ℃; H NMR (CDC13, 300
MHz) δ: 1.22 (t, J ＝7.1 Hz, 6H), 2.32 (s, 6H),
4.09—4.14 (m, J＝7.1 Hz, 4H), 4.95 (s, 1H), 5.60 (s, br,
1H, NH), 6.98—7.01 (m, 2H), 7.14—7.19 (m, 4H),
7.27—7.30 (m, 2H); 13C NMR (CDC13, 75 MHz) δ:
14.25, 19.57, 39.39, 59.75, 104.00, 116.04, 116.33,
128.96, 130.14, 133.21, 133.30, 133.41, 143.84, 146.94,
167.46; IR (KBr) ν: 3348, 3066, 3030, 2807, 1686, 1657,
1610, 1508, 1464, 1431, 1－128, 1092, 1049, 853, 818,
Experimental
Melting points are uncorrected; infrared (IR) spectra
were run on a Bruker spectrometer and expressed in
－ 1
1
cm
(KBr); H NMR spectra were recorded on a
Bruker AVANCE-300 MHz in CDCl3 or DMSO solu-
tions; mass spectra were determined using a Finigan
8230 mass spectrometer. Elemental analyses were con-
ducted using a Yanaco MT-5CHN elemental analyzer;
thin-layer chromatography (TLC) was GF254 with pe-
troleum ether and ethyl acetate as eluent.
1
789, 745＋, 668, 588, 525 cm ; MS (EI, 70 eV) m/z (%):
455 (M , 32.13), 454 (M－1, 67.75), 453 (M－2,
78.70), 381, 309, 310, 183, 127, 96, 77, 45, 29. Anal.
calcd for C25H26FNO4S: C 65.91, H 5.75, N 3.07; found
C 65.96, H 5.88, N 3.11.
General procedure for the synthesis of 1,4-dihydro-
pyridines
Diethyl
4-(4-(3-fluorophenylthio)phenyl)-2,6-
A mixture of 4-arylsulfanyl-benzaldehyde (3 mmol),
ethylacetoacetate (6 mmol), ammonium acetate (4 mmol)
and L-proline (10 mol%) was heated in ethanol (15 mL)
at 60 ℃ under ultrasonic irradiation for the time as
mentioned in Table 1. The reaction was monitored by
TLC. After completion of reaction, the reaction mixture
was poured into crushed ice and the solid product,
which separated was filtered and recrystallized from
ethanol to get pure yellow coloured crystalline
polyhydroquinoline derivative 3a—3h.
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3c)
1
White solid, m.p. 154—155 ℃; H NMR (CDC13, 300
MHz) δ: 1.22 (t, J ＝7.1 Hz, 6H), 2.34 (s, 6H),
4.11—4.16 (m, J＝7.1 Hz, 4H), 4.98 (s, 1H), 5.63 (s, br,
1H, NH), 6.97—7.02 (m, 2H), 7.10—7.12 (m, 1H),
7.25—7.33 (m, 5H); 13C NMR (CDC13, 75 MHz) δ:
14.26, 19.65, 39.56, 59.79, 103.94, 112.81, 112.90,
115.51, 115.83, 124.45, 129.129, 130.15, 132.66,
140.11, 143.84, 148.23, 167.42; IR (KBr) ν: 3286, 3035,
2869, 1680, 1656－, 1618, 1507, 1469, 1127, 1112, 104＋9,
1
858, 668, 588 cm ; MS (EI, 70 eV) m/z (%): 455 (M ,
Spectroscopic data of 3a— 3h
45.19), 454 (M－1, 27.09), 453 (M－2, 80.08), 408,
381, 309, 310, 183, 127, 96, 77, 45, 29. Anal. calcd for
C25H26FNO4S: C 65.91, H 5.75, N 3.07; found C 65.52,
H 5.18, N 3.21.
Diethyl 2,6-dimethyl-4-(4-(phenylthio)phenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3a) White solid,
m.p. 95—96 ℃; 1H NMR (CDC13, 300 MHz) δ: 1.23 (t,
J＝7.1 Hz, 6H), 2.34 (s, 6H), 4.07—4.11 (m, J＝7.1 Hz,
4H), 4.99 (s, 1H), 5.90 (s, br, 1H, NH), 7.21—7.28 (m,
9H); 13C NMR (CDC13, 75 MHz) δ: 14.27, 19.58, 39.43,
59.76, 103.99, 126.55, 129.01, 130.31, 131.23, 132.28,
136.64, 143.90, 147.22, 167.49; IR (KBr) ν: 3368, 3098,
3003, 2950, 2828, 1680, 1653, 1613, 1502, 1466, 1431,
1377, 1－333, 1128, 843, 817, 805, 787, 745, 665, 587,
Diethyl 2,6-dimethyl-4-(4-(p-tolylthio)phenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (3d) White solid,
m.p. 135—137 ℃; 1H NMR (CD3COCD3, 300 MHz) δ:
1.18 (t, J＝7.2 Hz, 6H), 2.32 (s, 6H), 2.35 (s, 3H),
4.05—4.12 (m, J ＝ 7.1 Hz, 4H), 5.02 (s, 1H),
6.92—7.02 (m, 4H), 7.18—7.35 (m, 4H), 7.90 (s, br, 1H,
13
NH); C NMR (CD3COCD3, 75 MHz) δ: 14.23, 17.89,
1
525 cm ; MS (EI, 70 eV) m/z (%): 436 (M－1, 14.53),
19.55, 39.40, 59.05, 103.00, 115.89, 128.32, 128.86,
134.14, 135.21, 135.90, 145.21, 146.67, 160.32, 167.16;
IR (KBr) ν: 3218, 3006, 288－7, 1716, 1665, 1508, 1464,
435 (M－2, 87.59), 408, 376, 363, 291, 182, 111, 77, 45.
Anal. calcd for C25H27NO4S: C 68.62, H 6.22, N 3.20;
found C 68.36, H 6.28, N 3.31.
1
1431, 857, 788, 745, 668 cm ; MS (EI, 70 eV) m/z (%):
Diethyl
4-(4-(4-fluorophenylthio)phenyl)-2,6-
814
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Chin. J. Chem. 2010, 28, 811— 817

One-Pot Synthesis of 1,4-Dihydropyridine and Polyhydroquinoline Derivatives
451 (M＋ , 49.10), 450 (M－1, 78.01), 449 (M－2,
58.09), 422, 349, 305, 109, 91, 69, 43. Anal. calcd for
C26H29NO4S: C 69.15, H 6.47, N 3.10; found C 68.97,
H 6.58, N 3.19.
General procedure for the synthesis of polyhydro-
quinoline
A mixture of 1,3-cyclohexanedione (3 mmol), 4-
arylsulfanyl-benzaldehyde (3 mmol), ethylacetoacetate
(3 mmol), ammonium acetate (4 mmol) and L-proline
(10 mol%) was heated in ethanol (15 mL) at 60 ℃ un-
der ultrasonic irradiation for the time as mentioned in
Table 3. The reaction was monitored by TLC. After
completion of reaction, the reaction mixture was poured
into crushed ice and the solid product, which separated
was filtered and recrystallized from ethanol to get pure
yellow coloured crystalline polyhydroquinoline deriva-
tive 4a—4 g.
Diethyl 4-(4-(4-methoxyphenylthio)phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3e)
White solid, m.p. 164—166 ℃; 1H NMR (CD3COCD3,
300 MHz) δ: 1.16 (t, J＝7.2 Hz, 6H), 2.29 (s, 6H), 3.79
(s, 3H), 4.02—4.06 (m, J＝7.1 Hz, 4H), 4.96 (s, 1H),
6.92—6.96 (m, 2H), 7.01—7.07 (m, 2H), 7.19 (m, 2 H),
7.35—7.42 (m, 2H), 7.99 (s, br, 1H, NH); 13C NMR
(CD3COCD3, 75 MHz) δ: 13.75, 17.87, 39.08, 54.85,
59.03, 102.69, 115.01, 128.10, 128.65, 134.90, 135.13,
145.10, 146.82, 160.00, 167.06; IR (KBr) ν: 3218, 3006,
2887, 1716, 1665, 1508, 1464, 1431, 857, 788, 745, 668
Spectroscopic data of 4a— 4g
－1
cm . Anal. calcd for C26H29NO5S: C 66.79, H 6.25, N
Ethyl 2-methyl-5-oxo-4-(4-(phenylthio)phenyl)-
3.00; found C 66.84, H 6.31, N 3.05.
Diethyl 4-(4-(2-chloro-6-methylphenylthio)phen-
yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
(4a)
1
Yellow crystal solid, m.p. 251—253 ℃; H NMR
(CDC13, 300 MHz) δ: 1.16 (t, J＝6.9 Hz, 3H), 1.98 (t,
J＝4.9 Hz, 2H), 2.29—2.35 (m, 2H), 2.37 (s, 3H), 2.40
(t, J＝4.9 Hz, 2H), 4.01—4.08 (m, 2H), 5.06 (s, 1H),
5.93 (br, 1H), 7.20—7.29 (m, 9H); 13C NMR (CDC13,
75 MHz) δ: 14.2, 19.4, 21.0, 27.5, 36.2, 37.0, 59.9,
105.9, 113.2, 126.6, 129.3, 129.6, 130.5, 131.2, 131.6,
131.9, 136.2, 137.8, 143.7, 147.1, 149.8, 167.3, 195.7.
Anal. calcd for C25H23F2NO3S: C 65.92, H 5.09; found
C 65.89, H 5.05.
1
ate (3f) White solid, m.p. 171—172 ℃; H NMR
(CD3COCD3, 300 MHz) δ: 1.16 (t, J＝7.2 Hz, 6H), 2.29
(s, 3H), 2.31 (s, 6H), 4.01—4.08 (m, J＝7.1 Hz, 4H),
5.02 (s, 1H), 6.89 (s, 1H), 7.10—7.13 (m, 1H),
7.20—7.24 (m, 3H), 7.33—7.36 (m, 2H), 8.02 (s, br, 1H,
13
NH); C NMR (CD3COCD3, 75 MHz) δ: 13.81, 17.81,
18.85, 39.52, 59.06, 102.54, 115.01, 126.34, 128.51,
129.54, 131.57, 131.68, 131.98, 132.04, 135.93, 138.46,
145.22, 145.35, 149.18, 166.99; IR (KBr) ν: 33－06, 3184,
Ethyl 4-(4-(4-fluorophenylthio)phenyl)-2-methyl-
5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
1
1752, 1668, 1500, 1458, 857, 788, 665 cm . Anal.
1
calcd for C26H28ClNO4S: C 64.25, H 5.81, N 2.88;
found C 64.31, H 5.74, N 2.95.
Diethyl 4-(4-(4-fluoro-3-methylphenylthio)phen-
yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl-
(4b) Yellow crystal solid, m.p. 227—229 ℃; H
NMR (CDC13, 300 MHz) δ: 1.20 (t, J＝7.0 Hz, 3H),
1.90—1.98 (m, 2H), 2.31—2.36 (m, 2H), 2.38 (s, 3H),
2.41—2.45 (m, 2H), 4.03—4.11 (m, 2H), 5.07 (s, 1H),
6.04 (s, 1H), 6.97—7.02 (m, 2H), 7.11—7.28 (d, J＝8.2
Hz, 2H), 7.29—7.35 (m, 4H); 13C NMR (CDC13, 75
MHz) δ: 14.2, 19.4, 21.0, 27.5, 36.2, 37.0, 59.9, 105.9,
113.2, 116.0, 116.3, 128.9, 130.1, 133.2, 133.4, 133.5,
143.4, 146.3, 149.6, 167.3, 195.7. Anal. calcd for
C25H24FNO3S: C 68.63, H 5.53; found C 68.70, H 5.58.
Ethyl 2-methyl-5-oxo-4-(4-(m-tolylthio)phenyl)-
1
ate (3g) White solid, m.p. 153—155 ℃; H NMR
(CD3COCD3, 300 MHz) δ: 1.19 (t, J＝7.2 Hz, 6H), 2.25
(s, 3H), 2.29 (s, 6H), 4.03—4.09 (m, 4H), 5.05 (s, 1H),
6.80 (s, 1H), 7.10—7.14 (m, 1H), 7.21—7.28 (m, 3H),
7.31—7.39 (m, 2H), 7.96 (s, br, 1H, NH); 13C NMR
(CD3COCD3, 75 MHz) δ: 13.82, 17.79, 18.82, 39.55,
59.06, 102.51, 117.08, 127.36, 128.55, 129.89, 131.68,
132.94, 137.95, 137.76, 138.66, 145.28, 150.18, 166.90;
IR (KBr) ν: 3342, 3086, 1705, 1637, 1553, 1476, 1415,
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
(4c)
1
Yellow crystal solid, m.p. 268—271 ℃; H NMR
(CDC13, 300 MHz) δ: 1.19 (t, J ＝7.0 Hz, 3H),
1.92—1.99 (m, 2H), 2. 25—2. 32 (m, 2H), 2.35 (s, 3H),
2.39 (s, 3H), 2.41—2.45 (m, 2H), 4.05 (q, J＝7.0 Hz,
2H), 5.05 (s, 1H), 5.89 (s, 1H), 7.12 (t, J＝8.3 Hz, 4H),
7.23 (t, J＝8.3 Hz, 4H); 13C NMR (CDC13, 75 MHz) δ:
14.2, 19.4, 21.0, 21.1, 27.5, 36.0, 37.2, 59.9, 105.9,
113.3, 128.8, 129.9, 131.7, 133.6, 137.1, 143.3, 145.8,
149.4, 167.3, 196.0. Anal. calcd for C26H27NO3S: C
72.03, H 6.28; found C 72.10, H 6.32.
－1
855, 668 cm . Anal. calcd. for C26H28FNO4S: C 66.50,
H 6.01, N 2.98; found C 66.57, H 6.07, N 2.95.
Diethyl 4-(4-(2,5-difluorophenylthio)phenyl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (3h)
White solid, m.p. 175—177 ℃; 1H NMR (CD3COCD3,
300 MHz) δ: 1.13 (t, J＝7.2 Hz, 6H), 2.31 (s, 6H),
4.02—4.08 (m, 4H), 5.15 (s, 1H), 6.69 (s, 1H),
6.95—7.04 (m, 2H), 7.08—7.17 (m, 1H), 7.21—7.31
(m, 3H), 8.02 (s, br, 1H, NH); 13C NMR (CD3COCD3,
75 MHz) δ: 14.54, 19.89, 39.53, 61.08, 104.52, 115.56,
117.39, 119.59, 120.79, 128.67, 129.98, 130.96, 136.76,
142.81, 158.20, 160.91, 167.20; IR (K－Br) ν: 3323, 3116,
Ethyl 4-(4-(3,4-dimethoxyphenylthio)phenyl)-2-
methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carb-
oxylate (4d) Yellow crystal solid, m.p. 276—278 ℃;
1H NMR (CDC13, 300 MHz) δ: 1.16 (t, J＝7.0 Hz, 3H),
1.90—1.98 (m, 2H), 2.35 (s, 3H), 2.37—2.45 (m, 4H),
3.80 (s, 3H), 3.81 (s, 3H), 4.04 (q, J＝7.0 Hz, 2H), 5.02
(s, 1H), 5.89 (s, 1H), 6.42—6.49 (m, 2H), 6.99 (d, J＝
1
1685, 1579, 1521, 1466, 877, 658 cm . Anal. calcd for
C25H25F2NO4S: C 63.41, H 5.32, N 2.96; found C 63.45,
H 5.35, N 2.90.
Chin. J. Chem. 2010, 28, 811— 817
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
815

Guo & Yuan
FULL PAPER
8.2 Hz, 2H), 7.16 (d, J＝8.2 Hz, 2H), 7.23 (d, J＝8.4 Hz,
1H); 13C NMR (CDC13, 75 MHz) δ: 14.2, 19.4, 21.0,
27.5, 35.9, 37.0, 55.5, 55.9, 59.8, 99.1, 105.9, 105.2,
113.1, 113.3, 128.2, 128.6, 134.1, 135.9, 143.3, 144.9,
149.4, 159.9, 161.4, 167.4, 195.9. Anal. calcd for
C27H29NO5S: C 67.62, H 6.09; found C 67.52, H 6.13.
Ethyl 4-(4-(3-fluoro-4-methoxyphenylthio)phen-
yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-
carboxylate (4e) Yellow crystal solid, m.p. 195—197
C25H26FNO4S; Mr ＝455.53; temperature 298(2) K;
crystal system: triclinic; space group: P-1; a ＝
7.5539(16) Å, b＝11.059(2) Å, c＝14.841(3) Å, V＝
1145.5(4) Å3, Z＝2, ρ ＝1.321 Mg/m3, m＝0.181
calcd
－1
mm , F(000)＝480, crystal size＝0.38×0.22×0.18
mm3, θ range＝1.98° to 23.32°; Index ranges: －7≤h
≤8, －12≤k≤12, －16≤l≤16; reflections collected
5247, independent reflections 3307 [R(int)＝0.0178],
completeness to θ＝23.32°, 99.3%; max/min transmis-
sion 0.9681/0.9344; data/restraints/parameters 3307/0/
293; goodness-of-fit on F2 1.090; final R indices [I＞
2σ(I)]: R1＝0.0626, wR2＝0.1428; R indices (all data):
R1＝0.0722, wR2＝0.1490 and the other details see Ta-
ble 3. The structure was solved by direct methods
(SHELXS-97) and refined by full-matrix least squares
methods (SHELXL-97) with anisotropic temperature
factors for the non-H atoms. All H atoms were placed at
chemically acceptable positions and were refined with
isotropic temperature factors.
1
℃; H NMR (CDC13, 300 MHz) δ: 1.20 (t, J＝7.0 Hz,
3H), 1.93—2.02 (m, 2H), 2.37 (s, 3H), 2.39—2.45 (m,
4H), 3.88 (s, 3H), 4.04—4.11 (m, 2H), 5.07 (s, 1H),
6.20 (s, 1H), 6.90 (t, J＝8.4 Hz, 1H), 7.07—7.13 (m,
4H), 7.23 (d, J＝8.2 Hz, 2H); 13C NMR (CDC13, 75
MHz) δ: 14.2, 19.4, 21.0, 27.4, 36.1, 37.0, 42.3, 56.3,
59.9, 105.7, 113.1, 113.8, 119.8, 120.0, 128.4, 128.9,
129.7, 133.4, 143.6, 146.1, 149.9, 167.3, 195.9. Anal.
calcd for C26H26FNO4S: C 66.79, H 5.61; found C 66.84,
H 5.72.
Ethyl 4-(4-(2-chloro-6-methylphenylthio)phenyl)-
2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-car-
boxylate (4f) Yellow crystal solid, m.p. 207—209 ℃;
1H NMR (CDC13, 300 MHz) δ: 1.17 (t, J＝7.0 Hz, 3H),
1.91—2.02 (m, 2H), 2.30 (s, 3H), 2.39 (s, 3H), 2.40—
2.47 (m, 4H), 4.00—4.12 (m, 2H), 5.09 (s, 1H), 6.16 (s,
1H), 6.98 (d, J＝1.5 Hz, 2H), 7.11—7.04 (m, 2H), 7.16
(d, J＝8.2 Hz, 2H), 7.29 (d, J＝8.2 Hz, 2H); 13C NMR
(CDC13, 75 MHz) δ: 14.3, 19.4, 19.9, 20.9, 27.5, 36.3,
37.0, 59.9, 105.7, 113.1, 126.6, 129.3, 129.6, 130.5,
131.2, 131.6, 131.9, 136.2, 137.8, 143.7, 147.1, 149.8,
167.3, 195.8. Anal. calcd for C26H26ClNO3S: C 66.73, H
5.60; found C 66.79, H 5.55.
Ethyl 4-(4-(2,5-difluorophenylthio)phenyl)-2-me-
thyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxy-
late (4g) Yellow crystal solid, m.p. 250—253 ℃;
1H NMR (CDC13, 300 MHz) δ: 1.23 (t, J＝7.0 Hz, 3H),
1.96—2.03 (m, 2H), 2.33—2.49 (m, 4H), 2.45 (s, 3H),
4.02—4.12 (m, 2H), 5.13 (s, 1H), 5.88 (s, 1H), 6.60—
6.66 (m, 1H), 6.80—6.85 (m, 1H), 6.96—7.03 (m, 1H),
7.33—7.39 (m, 4H); 13C NMR (CDC13, 75 MHz) δ:
14.3, 19.9, 20.9, 27.5, 36.3, 37.0, 59.9, 109.8, 113.8,
128.9, 129.0, 129.9, 130.5, 131.8, 132.6, 133.6, 135.9,
137.8, 143.7, 147.1, 149.8, 166.5, 195.7. Anal. calcd for
C25H23F2NO3S: C 65.92, H 5.09; found C 65.84, H 5.11.
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Chin. J. Chem. 2010, 28, 811— 817
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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