Cd(NO3)2.4H2O catalyzed one-pot synthesis of 1,4-dihydropyridine and polyhydroquinoline derivatives through the Hantzsch multicomponent condensation

Article abstract of DOI:10.1002/jccs.201200162

The synthesis of various 1,4-dihydropyridine and polyhydroquinoline derivatives was achieved in good to excellent yields using cadmium (II) nitrate as catalyst to promote the classical andmodified Hantzsch conditions in good yields under mild conditions.

Full text of DOI:10.1002/jccs.201200162

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CHEMICAL SOCIETY
Article
Cd(NO3)2.4H2O Catalyzed One-Pot Synthesis of 1,4-Dihydropyridine and
Polyhydroquinoline Derivatives through the Hantzsch Multicomponent Condensation
Radia Tafer,a Raouf Boulcina,a Bertrand Carbonib and Abdelmadjid Debachea,*
aLaboratoire de Synthèse des Molécules d’Intérêts Biologiques, Département de Chimie, Faculté des Sciences Exactes,
Université Mentouri de Constantine, 25000 Constantine, Algérie
bSciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes,
CEDEX, France
(Received: Mar. 21, 2012; Accepted: Jul. 31, 2012; Published Online: ??; DOI: 10.1002/jccs.201200162)
The synthesis of various 1,4-dihydropyridine and polyhydroquinoline derivatives was achieved in good to
excellent yields using cadmium (II) nitrate as catalyst to promote the classical and modified Hantzsch con-
ditions in good yields under mild conditions.
Keywords: Hantzsch reaction; 1,4-Dihydropyridines; Polyhydroquinolines; Cadmium (II) nitrate;
One-pot condensation.
INTRODUCTION
Hantzsch 1,4-dihydropyridines (1,4-DHPs) and their
ing bakers’yeast,15 high temperature in refluxing solvent,16
and rare earth metal triflates such as Yb(OTf)3 and
Sc(OTf)3.17
derivatives are well known as calcium channel blockers,
and have emerged for many years, as one of the most im-
portant classes of drugs for the treatment of angina pec-
toris, hypertension and other cardiovascular diseases.1 Cur-
rent literature reveals that these compounds possess a vari-
ety of biological activities.2 For example, they are widely
prescribed as vasodilator, bronchodilator, antiatheroscle-
rotic, antitumor, geroprotective, hepatoprotective and anti-
diabetic agents.3 Other studies have revealed that 1,4-
DHPs exhibit several other medicinal applications which
include neuroprotectant3a,4 and platelet anti-aggregratory
activity,3c in addition to acting as a cerebral anti-ischemic
agent in the treatment of Alzheimer’s disease and as a
chemosensitizer in tumor therapy.3d
Although most of these processes offer distinct ad-
vantages, they suffer from certain drawbacks such as lon-
ger reaction times, unsatisfactory yields, high costs, harsh
reaction conditions, and the use of volatile organic sol-
vents. Thus, the possibility of performing multicomponent
reactions under facile conditions with new catalysts could
enhance their efficiency from an economic as well as a
green point of view. Therefore, a new efficient method for
the preparation of 1,4-DHPand their derivatives is desired.
RESULTS AND DISCUSSION
Previously, we have reported that phenylboronic
acid18 and triphenylphosphine,19 could act as a beneficial
catalysts in Hantzsch condensation reactions. More re-
cently, we have disclosed the details of our study that led us
to suggest the use of triethylamine as a base Lewis catalyst
in the Hantzsch one pot condensation.20
Thus, the synthesis of 1,4-dihydropyridines is of con-
tinuing interest. Classical method for the synthesis of this
nucleus is one-pot condensation of aldehydes with ethyl
acetoacetate, and ammonia either in acetic acid or by
refluxing in alcohol.5 This method, however, involves long
reaction time, harsh reaction conditions, the use of a large
quantity of volatile organic solvents and generally gives
low yields. Therefore, it is necessary to develop an efficient
and versatile method for the preparation of 1,4-DHPs and
the progress in this field is remarkable including recently
the promotion of microwave,6 TMSCl,7 ionic liquid,8 poly-
mer,9 molecular iodine,10 silica gel/NaHSO4,11 microwave/
ultrasound irradiation,12 2,4,6-trichloro(1,3,5)triazine,13
ionic liquid/3,4,5-trifluorobenzeneboronic acid,14 ferment-
We herein present a systematic study of a facile
Hantzsch condensation by using cadmium (II) nitrate under
mild conditions to produce 1,4-dihydropyridine deriva-
tives 4 in high yields (Scheme I). In our initial experiments,
we examined the effect of different solvents and others set
of reaction conditions on the Hantzsch muticomponent
condensation. In a first attempt, a mixture of a benzalde-
hyde 1a (1 mmol), ethyl acetoacetate 2a (2 mmol), and am-
monium acetate 3 (4 mmol) in ethanol was stirred at reflux
in the presence of a catalytic amount of cadmium (II) ni-
* Corresponding author. Tel/Fax: 213 31 81 88 62; E-mail: a_debache@yahoo.fr
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Tafer et al.
When we used other Lewis acid such as Ca(NO3)2.
4H2O, Fe(NO3)2.6H2O, and Ni(NO3)2.4H2O, the condensa-
tions smoothly proceeded whereas longer reaction times
were required (entries 11-13). It was found that the reaction
in the presence of 10 mol % of Cd(NO3)2 need shorter reac-
tion time and excellent yield of the desired product than
that with other catalysts.
Scheme I
trate (20 mol%) for a certain period of time required to
complete the reaction (TLC). Dihydropyridine 4a was ob-
tained as the only product but in moderate yield (Table 1,
entry 2).
Using the optimized conditions, we continued to
study the reaction using various aldehydes. The results
summarized in Table 2 indicate that both aromatic and
heterocyclic aldehydes underwent smooth reactions with
ethyl acetoacetate and ammonium acetate to give well to
high yields of the corresponding DHPs. Also, both the elec-
tron rich and electron-deficient aldehydes worked well
leading to high yields of products. Clearly, the effect of the
nature of the substituents on the aromatic ring showed no
obvious effect on this conversion.
To determine the appropriate concentration of the cat-
alyst, we have investigated the model reaction described
above under different concentrations of cadmium (II) ni-
trate such as 50, 10, 5, and 2 mol%. We found that the prod-
uct is obtained in 47%, 88%, 76%, and 67% yields, respec-
tively (entries 1, 3-5). This indicates that 10 mol% of
Cd(NO3)2.4H2O produces the best results with respect to
product yield. Uncatalyzed reaction run in parallel under
otherwise identical conditions gave only poor yield (32%)
of the corresponding product within the time required for
completion of the other catalyzed transformations (entry
6).
For benzaldehyde (entry 1), and 4-methylbenzalde-
hyde (entry 4), the resulting yields of the corresponding
DHPs were higher than those for the reactions with 4-meth-
oxybenzaldehyde (entry 2) and 3-methylbenzaldehyde (en-
try 5). The reaction with 2-methoxybenzaldehyde (entry 3)
is longer but the yield is comparable with other reactions.
Similar results were obtained with electron-withdrawing
aldehydes (entries 6-9). When heterocyclic aldehydes were
used (entries 11 and 12), the conversions were lower even
if the high yields are achieved.
Several solvents, such as CH3CN, THF, H2O were
also surveyed by using Cd(NO3)2.4H2O as catalyst (entries
7-9). Most of the reactions worked poorly at reflux except
that when the reaction was investigated at 80 °C under sol-
vent-free conditions, the reaction was completed with high
yield (90%) within 3 hours (entry 10).
The reactions are fairly general, clean and efficient.
Table 1. Optimization of the reaction using different conditionsa
Amount of
catalyst (%)
Entry
Solvent
Catalyst
Time (h) Yieldb (%)
1
EtOHc
EtOHc
EtOHc
EtOHc
EtOHc
EtOHc
CH3CNc
THFc
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
-
50
20
10
5
8
8
47
72
88
76
67
32
65
35
51
90
81
68
76
2
3
8
4
8
5
2
8
6
-
8
7
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Cd(NO3)2.4H2O
Ca(NO3)2.4H2O
Fe(NO3)2.6H2O
Ni(NO3)2.4H2O
10
10
10
10
10
10
10
8
8
10
8
9
H2Oc
10
11
12
13
Noned
Noned
Noned
Noned
3
6
8
8
a The reactions were conducted by condensation of benzaldehyde 1a (1 equiv.), ethyl
acetoacetate 2a (2 equiv.), and ammonium acetate 3 (4 equiv.).
b Isolated yields.
c At reflux.
d At 80 °C.
2
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Hantzsch Multicomponent Condensation
Table 2. Cd(NO3)2.4H2O-Mediated Hantzsch synthesis of 1,4-dihydropyridine 4a-la
M.p (°C)
Measured Reported
Entry
DHP
Ar
Time (h) Yieldb (%)
1
4a
4b
4c
4d
4e
4f
C6H5
3
2
4
2
3
2
3
3
3
4
4
4
90
77
84
81
72
80
92
89
82
87
90
79
157-159
162-164
141-143
136-138
122-124
128-130
163-165
130-132
140-142
145-147
172-174
160-162
158-160 21
161-163 21
140-14222
135-13723
122-12418
129-13121
162-16421
128-13018
141-14312b
148-15022
171-17321
160-16121
2
4-(MeO)-C6H4
2-(MeO)-C6H4
4-(Me)-C6H4
3-(Me)-C6H4
4-(NO2)-C6H4
3-(NO2)-C6H4
3,5-(Cl2)-C6H3
3-(Cl)-C6H4
Styryl
3
4
5
6
7
4g
4h
4i
8
9
10
11
12
4j
4k
4l
2-thienyl
2-furyl
a All reactions were performed using aldehyde (1 equiv.), ethyl acetoacetate (2 equiv.), and
ammonium acetate (4 equiv.) under solvent-free conditions at 80 °C.
b Isolated yields.
The experimental procedures are very simples. The high
Scheme III. There is evidence that Cd(NO3)2.4H2O can cat-
alyze aldol related reactions such as Knovenagel condensa-
tion as well as Michael additions. In this Hantzsch reaction,
cadmium (II) nitrate is supposed to facilitate the condensa-
tion between aldehyde 1 and ethyl acetoacetate 2a for the
formation of the corresponding Knovenagel product 6a,
and the Michael addition between this intermediate and
enamines 7a-b obtained from the reaction of ethyl aceto-
acetate 2a (or dimedone 2b) and ammonium acetate 3, for
the formation of an open chain intermediates 8a-b which
yields transformation did not form any significant amount
of undesirable side-products.
After successfully synthesizing a series of Hantzsch
1,4-dihydropyridines in excellent yields, we turned our at-
tention towards the synthesis of polyhydroquinoline deriv-
atives (PHQs) via unsymmetrical Hantzsch reaction under
similar conditions. We carried out the four component con-
densation reaction of benzaldehyde 1a, ethyl acetoacetate
2a, dimedone 2b, and ammonium acetate 3 in the presence
of 10 mol% of Cd(NO3)2.4H2O at 80 °C under solvent free
conditions. The corresponding polyhydroquinoline 5a was
obtained in good yield (72%) after 8 hours; however very
better result was achieved when the reaction was investi-
gated in ethanol at reflux (yield = 92%). So the best condi-
tions were that the reaction was catalyzed by 10 mol% of
Cd(NO3)2.4H2O under refluxing ethanol (Scheme II).
Scheme III
Scheme II
As shown in Table 3, it was found that this procedure
works also with a wide variety of substrates. Aromatic,
heterocyclic and conjugated aldehydes afforded the desired
products in high yields under the same reaction conditions.
The proposed mechanism for the formation of 1,4-
dihydropyridines or polyhydroquinolines is shown in
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Article
Tafer et al.
Table 3. Cadmium(II)nitrate-Catalyzed Hantzsch synthesis of polyhydroquinolines 5a-l
under optimized conditionsa
M.p (°C)
Entry
PHQ
Ar
Time (h) Yieldb (%)
Measured
Reported
C6H5
5a
5b
5c
5d
5e
5f
1
6
5
92
86
89
83
82
90
84
69
87
90
96
92
202-204
252-254
198-200
258-260
256-258
234-236
180-182
242-244
236-238
204-206
238-240
246-248
204-20517a
258-25917a
193-19524
261-26217a
-
237-23817a
182-18425
240-24225
234-23526
206-20717a
241-24217a
248-24917a
4-(OMe)-C6H4
2-(OMe)-C6H4
4-(Me)-C6H4
3-(Me)-C6H4
4-(OH)-C6H4
3-(NO2)-C6H4
2.4-(Cl2)-C6H3
3-(Cl)-C6H4
2
3
4.5
4
4
5
6
6
5
5g
5h
5i
7
4.5
5
8
9
6
5j
10
11
12
Styryl
2-Thienyl
5
5k
5l
6
2-furyl
6
a All reactions were carried out using aldehyde (1 equiv.), dimedone (1 equiv.), ethyl
acetoacetate (1 equiv.), and ammonium acetate (4 equiv) under refluxing ethanol.
b Isolated yields.
undergo cyclohydration to furnish the desired DHPs 4 or
PHQs 5 products.
crystallization from ethanol.
Spectroscopic data for selected compounds:
Ethyl 4-phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4a)
CONCLUSION
M.p = 157-159 °C. 1H NMR (CDCl3, 250 MHz) d: 1.23 (t, J
= 7.1 Hz, 6H), 2.35 (s, 6H), 4.09 (q, J = 7.1 Hz, 4H), 5.10 (s, 1H),
6.07 (s, 1H), 7.48-7.12 (m, 5H). 13C NMR (CDCl3, 62.9 MHz) d:
14.2, 19.5, 39.3, 59.1, 103.1, 126.2, 128.3, 131.7, 137.7, 144.9,
167.2. FT-IR (KBr) nmax: 3349, 1701, 1649, 1488, 1217 cm-1.
Ethyl 4-(4-methylphenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4d)
M.p = 136-138 °C. 1H NMR (CDCl3, 250 MHz) d: 1.23 (t, J
= 7.1 Hz, 6H), 2.30 (s, 3H), 2.35 (s, 6H), 4.09 (q, J = 7.1 Hz, 4H),
5.10 (s, 1H), 6.07 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6
Hz, 2H). 13C NMR (CDCl3, 62.9 MHz) d: 14.2, 19.5, 21.6, 40.1,
59.9, 103.0, 123.8, 128.9, 143.1, 144.8, 146.2, 167.5. FT-IR
(KBr) nmax: 3319, 1701, 1647, 1487, 1215 cm-1.
In conclusion, we have demonstrated an easy, effi-
cient and versatile method for the synthesis of dihydro-
pyridine and polyhydroquinoline derivatives from the reac-
tion of aromatic or heterocyclic aldehydes, b-ketoesters or
1,3-dicarbonyl compounds, and ammonium acetate cata-
lyzed by cadmium (II) nitrate under mild conditions. The
process does not require the use of harmful metal catalyst
and thus, is a simple, environmentally friendly, and high
yielding reaction for the synthesis of 1,4-dihydropyridines
or polyhydroquinolines via one-pot multicomponent
Hantzsch reaction. Furthermore, all aromatic aldehydes
that carry either electron-donating or electron-withdrawing
substituents reacted under this protocol, allowing the pro-
duction of 1,4-DHPs or PHQs in high yields.
Ethyl 4-(3,5-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4h)
M.p = 130-132 °C. 1H NMR (CDCl3, 250 MHz) d: 1.30 (t, J
= 7.1 Hz, 6H), 2.33 (s, 6H), 4.10 (q, J = 7.1 Hz, 4H), 5.34 (s, 1H),
6.15 (s, 1H), 7.32-7.12 (m, 3H). 13C NMR (CDCl3, 62.9 MHz) d:
14.1, 19.4, 39.7, 59.9, 102.9, 127.1, 127.8, 134.6, 144.9, 151.1,
167.2. FT-IR (KBr) nmax: 3332, 1701, 1649, 1487, 1211 cm-1.
Ethyl 4-styryl-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4j)
EXPERIMENTAL
Typical experimental procedure for the synthesis of
dihydropyridines 4a-j
A mixture of aldehyde (1 mmol), ammonium acetate (4
mmol), ethyl acetoacetate (2 mmol) and cadmium (II) nitrate (10
mol%), was magnetically stirred at 80 °C under solvent free con-
ditions. After complete conversion as indicated by TLC, the reac-
tion mixture was cooled then poured onto crushed ice and the sep-
arated solid was filtered. The crude product was purified by re-
M.p = 145-147 °C. 1H NMR (CDCl3, 250 MHz) d: 1.31 (t, J
= 7.1 Hz, 6H), 2.33 (s, 6H), 4.20 (q, J = 7.1 Hz, 4H), 5.37 (d, J =
4
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Hantzsch Multicomponent Condensation
5.9 Hz, 1H), 6.17 (s, 1H), 6.21 (dd, J = 15.8, 5.9 Hz, 1H), 6.29 (d,
J = 15.8 Hz, 1H), 7.43-7.31 (m, 5H). 13C NMR (CDCl3, 62.9
MHz) d: 14.4, 19.5, 39.4, 59.7, 102.4, 121.4, 126.8, 128.0, 128.3,
130.5, 131.7, 137.7, 144.9, 167.2. FT-IR (KBr) nmax: 3336, 1691,
1645, 1488, 1218 cm-1.
Ethyl-5-(3-nitrophenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5g)
M.p = 180-182 °C 1H NMR (250 MHz, CDCl3, DMSO-d6)
.
d: 0.97 (s, 3H, CH3), 1.13 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H),
2.17-2.30 (m, 4H), 2.51 (s, 3H), 4.10 (q, J = 7.1 Hz, 2H), 4.87 (s,
1H), 5.87 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.69 (dt, J = 1.4, 7.9 Hz,
1H), 8.06-8.11, (m, 2H). 13C NMR (62.9 MHz, CDCl3, DMSO-d6)
d: 14.1, 19.3, 27.6, 32.2, 40.6, 43.5, 50.5, 59.9, 103.2, 112.8,
118.3, 122.3, 129.5, 134.4, 145.4, 148.5, 149.5, 157.9, 162.4,
195.9. FT-IR (KBr) nmax: 3618, 2318, 1689, 1523 cm-1.
Typical experimental procedure for the synthesis of
polyhydroquinolines 5a-q
A mixture of aldehyde (1mmol), ammonium acetate (4
mmol), dimedone (1 mmol) ethyl acetoacetate (1 mmol), and cad-
mium (II) nitrate (10 mol%), was refluxed in ethanol for the ap-
propriate time indicated in Table 3. After complete conversion as
indicated by TLC, the reaction mixture was cooled then poured
onto crushed ice, and extracted with ethyl acetate. The organic
layer was washed with brine, dried over sodium sulfate, and con-
centrated. The crude product was purified by recrystallization
from ethanol.
Ethyl-5-(3-chlorophenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5i)
M.p = 236-238 °C. 1H NMR (200 MHz, CDCl3, DMSO-d6)
d: 0.95 (s, 3H), 1.05 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H), 2.01-2.21 (m,
4H), 2.40 (s, 3H), 4.05 (q, J = 7.2 Hz, 2H), 4.60 (s, 1H), 5.60 (s,
1H), 7.10-7.30 (m 4H). 13C NMR (62.9 MHz, CDCl3, DMSO-d6)
d: 14.4, 19.4, 26.6, 31.2, 40.4, 46.8, 52.9, 60.2, 103.3, 111.2,
125.9, 127.1, 128.7, 131.1, 132.3, 141.0, 149.5, 150.7, 167.5,
195.7. FT-IR (KBr) nmax: 3063, 2956, 1721, 1640 cm-1.
Spectroscopic data for selected compounds:
Ethyl 4-phenyl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-
hydroquinoline-3-carboxylate (5a)
M.p = 202-204 °C. 1H NMR (250 MHz, CDCl3, DMSO-d6)
d: 0.94 (s, 3H), 1.08 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H), 2.14-2.33 (m,
4H), 2.38 (s, 3H), 4.05 (q, J = 7.1 Hz, 2H), 5.05 (s, 1H), 5.78 (s,
1H), 7.08-7.31 (m, 5H). 13C NMR (62.9 MHz, CDCl3, DMSO-d6)
d: 14.4, 19.4, 26.5, 31.2, 40.4, 46.8, 50.5, 59.5, 101.3, 111.2,
124.7, 128.6, 129.5, 137.6, 145.1, 149.5, 157.4, 162.7, 195.9.
FT-IR (KBr) nmax: 3290, 1698, 1612 cm-1.
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Ethyl 4-(3-methylphenyl)-2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5e)
M.p = 256-258 °C. 1H NMR (250 MHz, CDCl3, DMSO-d6)
d: 0.97 (s, 3H, CH3), 1.05 (s, 3H), 1.23 (s, 3H), 1.21 (t, J = 7.1 Hz,
3H), 2.10-2.20 (m, 4H), 2.50 (s, 3H), 4.08 (q, J = 7.1 Hz, 2H), 4.98
(s, 1H), 5.65 (s, 1H), 6.95-7.15 (m, 4H). 13C NMR (62.9 MHz,
CDCl3, DMSO-d6) d: 14.2, 19.1, 21.5, 27.2, 28.9, 32.2, 35.9, 40.2,
50.4, 58.7, 103.8, 113.2, 120.1, 124.7, 137.6, 145.1, 157.4, 161.2,
162.7, 195.9. FT-IR (KBr) nmax: 2962, 2191, 1654, 1365 cm-1.
HRMS (ESI): m/z calcd for C22H27NO3Na: 376.18886 [M+Na]+,
found: 376.189.
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