An efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2009.07.018

An efficient one-step synthesis of 1,4-dihydropyridines in good to excellent yields via the triphenylphosphine-catalyzed Hantzsch three-component reaction of an aromatic aldehyde, ethyl acetoacetate and ammonium acetate is described.

Full text of DOI:10.1016/j.tetlet.2009.07.018

Tetrahedron Letters 50 (2009) 5248–5250
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An efficient one-step synthesis of 1,4-dihydropyridines via a
triphenylphosphine-catalyzed three-component Hantzsch reaction
under mild conditions
a
a
a
a
Abdelmadjid Debache a, , Wassima Ghalem , Raouf Boulcina , Ali Belfaitah , Salah Rhouati ,
*
Bertrand Carboni b
a Laboratoire des Produits Naturels D’origine Végétale et de Synthèse Organique, Département de Chimie, Faculté des Sciences, Université Mentouri de Constantine,
25000 Constantine, Algeria
b Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes CEDEX, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-step synthesis of 1,4-dihydropyridines in good to excellent yields via the triphenylphos-
phine-catalyzed Hantzsch three-component reaction of an aromatic aldehyde, ethyl acetoacetate and
ammonium acetate is described.
Received 23 May 2009
Revised 22 June 2009
Accepted 3 July 2009
Available online 9 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hantzsch reaction
1,4-Dihydropyridines
Triphenylphosphine
One-step condensation
In recent years, considerable attention has been paid to the syn-
thesis of 1,4-dihydropyridines owing to their significant biological
activity.1 1,4-Dihydropyridine-containing drugs (1,4-DHPs), such
as nifedipine, nicardipine, amlodipine, felodipine and others have
been found to be useful as calcium channel blockers,2–4 and are
used most frequently as cardiovascular agents for the treatment
of hypertension (Fig. 1).5
Interest in 1,4-dihydropyridines is also sustained by their struc-
tural similarity to nicotinamide dinucleotide, a cofactor used by
many reductases in metabolism.15,18
In order to model and understand these biological properties
and to develop new chemotherapeutic agents based upon the
A number of dihydropyridine calcium antagonists have been
introduced as potential drugs for the treatment of congestive heart
failure and angina pectoris.6–8 The 1,4-DHPs may lead to other ben-
eficial effects such as regression of left ventricular pressure and
vascular hypertrophy, renal protection and antiatherogenic activ-
ity.9–11 Furthermore, the dihydropyridine skeleton is common in
many vasodilator, bronchodilator, antiatherosclerotic, antitumour,
antidiabetic, geroprotective and hepatoprotective agents.12,13 They
also function as neuroprotectants, as anti-platelet treatment of
aggregators and are important in Alzheimer’s disease as anti-
ischaemic agents.14 Among 1,4-DHPs, there are also examples of
drug-resistance modifiers,15 antioxidants16 and a drug for the
treatment of urinary urge incontinence.17
NO2
O
CH3
N
NO2
H3CO2C
H3C
H3CO2C
H3C
CO2CH3
O
N
H
CH3
N
H
CH3
nifedipine
nicradipine
R1
H3CO2C
H3C
CO2C2H5
R2
N
H
amlodipine (R1 = 2-Cl; R2 = CH2O(CH2)2NH2
)
felodipine (R1 = 2,3-Cl2; ; R2 =CH3
)
* Corresponding author. Tel./fax: +213 31 81 88 62.
E-mail address: a_debache@yahoo.fr (A. Debache).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.018

A. Debache et al. / Tetrahedron Letters 50 (2009) 5248–5250
5249
Table 1
be easily achieved with a catalytic amount of triphenylphosphine
as a Lewis base.36 This method is very flexible and makes possible
the preparation of a large number of 3,4-dihydropyrimidin-2-ones.
In continuation of our work in this area,37 we have found that
the Hantzsch reaction occurs very smoothly in the presence of
PPh3.
Triphenylphosphine-catalyzed Hantzsch synthesis of 1,4-dihydropyridine 4f under
different conditionsa
NO2
NO2
O
O
O
O
H5C2O
H3C
OC2H5
CH3
AcONH
+
OC2H5
+
4
H3C
CHO
Thus, treatment of one equivalent of 3-nitrobenzaldehyde 1f
and ammonium acetate 3 with 2 equiv of ethyl acetoacetate 2 in
the presence of 10 mol % of PPh3 in ethanol at reflux afforded the
corresponding 1,4-dihydropyridine 4f in 85% yield (Table 1, entry
6). Next, the reaction conditions were optimized. Ethanol proved
to be a much better solvent in terms of yield than all the others
tested including tetrahydrofuran (entry 1), acetonitrile (entry 2)
and water (entry 3) which afforded the desired product in moder-
ate yields (40–75%). Neat conditions furnished DHP 4f in 72% yield
(entry 4). Under the same conditions as entry 6, reaction with
20 mol % of triphenylphosphine in ethanol at reflux raised the yield
to an excellent 94%. However, there was no improvement in the
reaction rates and yields on decreasing the amount of PPh3 to 5
or 2 mol %. Also, higher amounts of PPh3 did not improve the re-
sults to any great extent. To demonstrate the efficiency of our cat-
alyst, a blank reaction was carried out in the absence of PPh3. After
five hours at reflux in ethanol only a 36% yield of 4f was obtained.
Furthermore, the reaction in the presence of various catalysts
was examined. When FeCl3Á6H2O was used as the catalyst, the
reaction proceeded smoothly to afford the desired product in good
yield (entry 10). On the other hand, RuCl3 and InCl3 gave 4f in mod-
erate yields (entries 11 and 12).
N
H
4f
1f
2
3
Entry
Solventb
Catalyst (mol %)
Yieldb of 4f (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
THF
CH3CN
H2O
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (10)
PPh3 (5)
PPh3 (2)
None
PPh3 (50)
FeCl3Á6H2O (20)
RuCl3 (20)
InBr3 (20)
40
75
66
72
94
85
78
74
36
80
81
68
76
Nonec
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
a
m-Nitrobenzaldehyde/ethyl acetoacetate/ammonium acetate = 1:2:1, reflux,
5 h.
b
Isolated yield.
Reaction at 80 °C.
c
1,4-DHP motif, considerable effort has been devoted to establish
efficient and rapid methods for their synthesis. 1,4-DHPs are gen-
erally synthesized using the Hantzsch method,19 which involves
cyclocondensation of an aldehyde, a b-ketoester and ammonia
either in acetic acid or under reflux in alcohols for long reaction
times which typically leads to low yields.20,21 Recently, a number
of modified methods have been developed.22,15 Other procedures
comprise the use of microwaves,23 ionic liquids,24 high tempera-
tures at reflux,25 TMSCl–NaI,26 InCl3,27 I2,28 SiO2/NaHSO4,29 SiO2/
HClO4,30 CAN,31 Na- and Cs-Norit carbons,32 tetrabutylammonium
hydrogen sulfate,18 fermenting Baker’s yeast,33 organocatalysts34
and metal triflates.35
The reactions of various aldehydes possessing either electron-
donating or electron-withdrawing substituents with ethyl acetoac-
etate and ammonium acetate in the presence of a catalytic amount
(20 mol %) of triphenylphosphine afforded high yields of the corre-
sponding 1,4-DHPs (72–95%) in short times. The results are pre-
sented in Table 2.
In all cases, crude products were obtained by extracting the
reaction mixtures with ethyl acetate and were then purified by
crystallization from ethanol.38
The products were characterized by IR, 1H NMR and 13C NMR
spectroscopy, and also by comparison with authentic samples.
Product 4h was structurally determined by X-ray single crystal dif-
fraction (Fig. 2).
As Lewis acids have been used as catalysts for the synthesis of
1,4-dihydropyridines, we sought to develop a synthesis of these
biologically interesting heterocyclic compounds using Lewis base
catalysis. We have reported that the Biginelli condensation can
From a mechanistic point of view, the first step of this reaction
can be visualized as the triphenylphosphine-catalyzed formation
Table 2
Triphenylphosphine-catalyzed Hantzsch synthesis of 1,4-dihydropyridines 4a–l
O
Ar
O
O
O
H
H5C2O
H3C
OC2H5
CH3
PPh3 (20 mol%)
AcONH4
+
O
H3C
OC2H5
+
Ar
N
H
EtOH, reflux, 2-5 h
1
2
3
4
Entry
Ar
Time (h)
Product
Yielda (%)
Mp (°C)
Measured
Reported
1
2
3
4
5
6
7
8
9
C6H5
5
3.5
3
3
2
4.5
2
3.5
4
4
5
4a
4b
4c
4d
4e
4f
4g
4h
4i
72
90
75
85
81
94
92
93
80
95
91
94
156–158
136–138
158–160
140–142
145–147
163–165
130–132
162–164
129–131
145–147
172–174
160–162
158–16040a
135–13723a
161–16340a
141–14340c
147–14840a
162–16440a
129–13140a
—
4-Me–C6H4
4-MeO–C6H4
3-Cl–C6H4
4-Cl–C6H4
3-(NO2)–C6H4
4-(NO2)–C6H4
4-Br–C6H4
3,5-Cl2–C6H3
Styryl
—
10
11
12
4j
4k
4l
148–15040b
171–17340a
160–16140a
2-Thienyl
2-Furyl
5
a
Isolated yield.

5250
A. Debache et al. / Tetrahedron Letters 50 (2009) 5248–5250
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Figure 2. ORTEP of 4 h.39
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CH3
O
H5C2O
Ar
OH
H
H
O
Ar
O
Ar
O
O
- PPh3
O
P
O
+
Ph
H5C2O
H3C
H
Ph
OC2H5
3
O
H
Ph
CH3
O
5
O
H5C2O
OC2H5
3
+ 6
3
H2N
CH3
H3C
6
O
Ar
O
O
Ar
O
cyclisation
H5C2O
H3C
OC2H5
CH3
H5C2O
H3C
OC2H5
CH3
dehydration
N
H
O
HN
7
4
Scheme 1.
of Knoevenagel product 5. A second key intermediate is ester en-
amine 6, produced by condensation of the second equivalent of
the b-ketoester with ammonia. Condensation of these two frag-
ments gives intermediate 7, which subsequently cyclizes to the
1,4-dihydropyridine 4 (Scheme 1).
31. Ko, S.; Yao, C. F. Tetrahedron 2006, 62, 7293.
32. Perozo-Rondon, E.; Calvino-Casilda, V.; Martin-Aranda, R. M.; Casal, B.; Duran-
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35. Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.; Fan, Z.; Tian, H.; Qian, C.-T.
Tetrahedron 2005, 61, 1539.
36. Debache, A.; Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron
Lett. 2008, 49, 6119.
37. (a) Debache, A.; Boulcina, R.; Tafer, R.; Belfaitah, A.; Rhouati, S.; Carboni, B.
Chin. J. Chem. 2008, 26, 2112; (b) Debache, A.; Boulcina, R.; Belfaitah, A.;
Rhouati, S.; Carboni, B. Synlett 2008, 509.
38. A typical experimental procedure for the preparation of 1,4-dihydropyridines 4 is as
follows: A mixture of aldehyde 1 (5 mmol), ethyl acetoacetate 2 (10 mmol),
ammonium acetate 3 (10 mmol) and triphenylphosphine (20 mol %) was heated
at reflux in ethanol (10 mL) for the appropriate time (Table 2, monitored by TLC).
The reaction mixture, after being cooled to rt was poured into cold water and
extracted with ethyl acetate. The organic layer was washed with brine and water
and dried over Na2SO4. After evaporation of the solvent, the crude yellow
products were purified by crystallization from ethanol to afford 1,4-
dihydropyridines 4 in 72–95% yields.Selected data for compound 4h:Diethyl 4-
(4-bromophenyl)-2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylate: Mp
162–164 °C. 1H NMR (250 MHz, CDCl3): d 1.25 (t, J = 7.1 Hz, 6H, 2CH3CH2), 2.29
(s, 6H, 2CH3), 4.10 (q, J = 7.1 Hz, 4H, 2CH3CH2), 4.96 (s, 1H, CH), 6.47 (s, 1H, NH),
7.16 (d, J = 8.4 Hz, 2H, 2CHarom.), 7.33 (d, J = 8.4 Hz, 2H, 2CHarom.). 13C NMR
(62.9 MHz, CDCl3): d 14.2, 19.3, 39.3, 59.8, 103.4, 119.8, 130.0, 130.8, 144.5,
146.9, 167.6. FT-IR (KBr): 3342, 1691, 1643, 1489, 1210, 1124, 779 cmÀ1. All the
other products were characterized by IR, 1H NMR and 13C NMR spectroscopy, and
by comparison with authentic samples.
In summary, we have reported that triphenylphosphine is a
highly efficient catalyst for the synthesis of a variety of 4-substi-
tuted-1,4-dihydropyridines by means of a three-component con-
densation of an aldehyde, ethyl acetoacetate and ammonium
acetate in one pot. This method is applicable to a wide range of
substrates, including aromatic and heterocyclic aldehydes, and
provides the corresponding 1,4-dihydropyridines in good to excel-
lent yields. The present methodology offers advantages such as re-
duced reaction times and economic viability of the catalyst,
compared with conventional methods and other catalysts.
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