FeNH4(SO4)2·12H2O (alum)-catalyzed preparation of 1,4-dihydropyridines: Improved conditions for the Hantzsch reaction

Article abstract of DOI:10.1007/s00706-011-0672-6

FeNH₄(SO₄)₂-12H₂O (alum) efficiently catalyzes the one-pot three-component reaction of dimedone, aldehydes, and 3-aminocrotonate to afford 1,4-dihydropyridines. The work-up is easy, and the products are obtained

Full text of DOI:10.1007/s00706-011-0672-6

Monatsh Chem (2012) 143:931–933
DOI 10.1007/s00706-011-0672-6
ORIGINAL PAPER
FeNH4(SO4)2Á12H2O (alum)-catalyzed preparation
of 1,4-dihydropyridines: improved conditions
for the Hantzsch reaction
•
Ali A. Mohammadi Armin Hadadzahmatkesh
•
Mohammad R. Asghariganjeh
Received: 28 November 2010 / Accepted: 19 October 2011 / Published online: 17 November 2011
Ó The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract FeNH4(SO4)2Á12H2O (alum) efficiently cata-
lyzes the one-pot three-component reaction of dimedone,
aldehydes, and 3-aminocrotonate to afford 1,4-dihydro-
pyridines. The work-up is easy, and the products are
obtained in good to excellent yields and high purity.
antitumor, antidiabetic, antidepressive, analgesic, vasodila-
tor, sedative, hypnotic, and anti-inflammatory activity [10],
in addition to acting as a cerebral anti-ischemic agent in the
treatment of Alzheimer’s disease [11] and as a chemosen-
sitizer in tumor therapy [12].
In continuation of our ongoing work on multi-compo-
nent reactions (MCRs) [13–16], we now wish to report a
facile and rapid one-pot three component reaction for
preparation of DHP derivatives 4a–4k from dimedone 1,
aldehydes 2a–2k, and 3-aminocrotonates 3a, 3b using non-
toxic and readily available FeNH4(SO4)2Á12H2O as heter-
ogeneous catalyst (Scheme 1).
Keywords Hantzsch reaction Á 1,4-Dihydropyridines Á
FeNH4(SO4)2Á12H2O Á Multi-component reactions
Introduction
The conventional synthesis of 1,4-dihydropyridines (1,4-
DHPs) introduced by Hantzsch in 1881 involves one-pot
condensation of an aldehyde, ammonia, and a ketoester in
acetic acid [1]. Several methods have been developed to
improve the efficiency of the Hantzsch reaction for syn-
thesis of 1,4-DHPs, for example the use of microwaves [2],
ionic liquids [3], high temperature [4], and acid catalysts,
for example Mg(ClO4) [5], CeCl3Á7H2O/NaI [6], Sc(OTf)3
[7], HY-Zeolite [8], and p-TSA [9].
Results and discussion
When a mixture of dimedone 1, aldehyde 2a, and 3-am-
inocrotonate 3a in EtOH was stirred at r.t., the reaction was
complete within 5 h. Work-up of the reaction mixture
showed that dimethyl 1,4-dihydropyridine 4a was prepared
in 94% yield (Scheme 1).
1,4-Dihydropyridines have been reported to have diverse
biological activity, for example anticonvulsant, antianxiety,
Encouraged by this success, we extended this reaction of
dimedone to a range of other aldehydes 2b–2k and 3-am-
inocrotonates 3a, 3b under similar conditions, and 1,4-
DHPs 4b–4k were obtained in good yield [21]. The opti-
mized results are summarized in Table 1.
In summary, we have described a successful strategy, an
efficient and convenient green synthesis, for the prepara-
tion of some new 1,4-DHPs in a three-component
cyclocondensation reaction of dimedone, aldehydes, and
3-aminocrotonate. The method has several advantages,
including high yield of products, use of inexpensive, non-
toxic, and readily available FeNH4(SO4)2Á12H2O catalyst,
and an easy experimental work-up procedure, that make it
a useful process for synthesis of 1,4-dihydropyridines.
A. A. Mohammadi (&) Á A. Hadadzahmatkesh
Department of Chemistry, Sabzevar Branch,
Islamic Azad University, Sabzevar, Iran
e-mail: aliamohammadi@iaus.ac.ir
M. R. Asghariganjeh
Department of Chemistry, Omidieh Branch,
Islamic Azad University, Omidieh, Iran
123

932
A. A. Mohammadi et al.
R1
Scheme 1
R1
CHO
O
O
2a-2k
O
FeNH4(SO4)·12H2O
EtOH, r.t.
O
OR2
+
OR2
N
H
O
H2N
1
3a, 3b
4a 4k
-
acetate–n-hexane, 1:1), water was added to the reaction
mixture, and the resulting solid was separated by filtration.
The crude product was recrystallized form ethanol.
The catalyst is very inexpensive and nontoxic. The
catalyst in the aqueous phase can be recovered by remov-
ing the water under vacuum, then washing with acetone
and ethanol and drying at room temperature. It can be
recycled and used in subsequent reactions without reduc-
tion in activity.
Table 1 FeNH4(SO4)2Á12H2O (alum)-catalyzed synthesis of 1,4-
dihydropyridines
Product R1
R2 Time/ Yield/% M.p./°C Ref. m.p./°C
h:min
4a
4b
4c
4d
4e
4f
H
Et 4:30
Et 4:30
94
93
92
93
91
90
88
94
92
93
92
188–189 190 [17]
268–269 270 [17]
255–257 256 [18]
243–245 243 [18]
240–242 243 [18]
183–185 184–186 [9]
205–207 207–209 [19]
p-Me
p-MeO Et 4:00
p-Cl Et 4:45
p-NO2 Et 4:30
Methyl 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-phe-
nylquinoline-3-carboxylate (4h, C20H23NO3)
p-F
o-Cl
H
Et 4:45
Et 5:00
Me 4:30
Me 4:30
4g
4h
4i
White powder; m.p.: 253–254 °C; IR (KBr): v = 3,203,
253–254
–
1
3,016, 2,918, 1,707 (C=O), 1,626 (C=O) cm-1; H NMR
p-Me
271–273 272 [20]
(DMSO-d6): d = 0.95 (s, 3H, CH3), 1.14 (s, 3H, CH3),
2.13 (d, 1H, J = 12.7 Hz, CH2), 2.27 (d, 1H, J = 13.2 Hz,
CH2), 2.32 (d, 1H, J = 15.2 Hz, CH2), 2.41 (s, 3H, CH3),
2.43 (d, 1H, J = 13.2 Hz, CH2), 3.64 (s, 3H, OCH3), 5.13
(s, 1H, CH), 7.12 (d, 1H, J = 7.2 Hz, Ar), 7.26 (t, 2H,
J = 7.5 Hz, Ar), 7.32 (d, 2H, J = 7.5 Hz, Ar), 8.14 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6): d = 19.25, 27.36, 29.86,
32.85, 36.56, 40.17, 40.43, 40.72, 40.81, 41.03, 51.13,
105.21, 110.78, 126.15, 128.14, 128.19, 145.41, 147.68,
149.85, 168.43, 195.88 ppm; MS: m/z (%) = 325 (M?,
35), 248 (100), 77 (25), 51 (25), 39 (25).
4j
m-MeO Me 5:00
p-NO2 Me 5:00
258–259
252–253
–
–
4k
Reaction conditions: dimedone (1 mmol), aldehyde (1 mmol),
3-aminocrotonate (1 mmol), FeNH4(SO4)2Á12H2O (20 mol%), 5 cm3
EtOH, r.t.
Experimental
Melting points were measured in open capillary tubes on an
Electrothermal 9200 apparatus. Mass spectra were recor-
ded on a Shimadzu QP 1100 BX mass spectrometer. IR
spectra were recorded as KBr pellets on a Shimadzu
Methyl 1,4,5,6,7,8-hexahydro-4-(3-methoxyphenyl)-2,7,7-
trimethyl-5-oxoquinoline-3-carboxylate (4j, C21H25NO4)
White powder; m.p.: 258–259 °C; IR (KBr): v = 3,203,
1
3,022, 2,888, 1,707 (C=O), 1,621 (C=O) cm-1; H NMR
1
IR-470 spectrophotometer. H and 13C NMR spectra were
(DMSO-d6): d = 0.89 (s, 3H, CH3), 1.06 (s, 3H, CH3),
2.01 (d, 1H, J = 7.8 Hz, CH2), 2.07 (d, 1H, J = 15.5 Hz,
CH2), 2.12 (d, 1H, J = 7.2 Hz, CH2), 2.29 (d, 1H,
J = 8.5 Hz, CH2), 2.94 (s, 3H, CH3), 3.58 (s, 3H,
OCH3), 3.70 (s, 3H, OCH3), 4.93 (s, 1H, CH), 6.85–7.02
(m, 4H, Ar), 8.98 (s, 1H, NH) ppm; 13C NMR (DMSO-d6):
d = 19.18, 27.43, 29.93, 32.83, 35.65, 39.58, 39.85, 40.14,
40.42, 40.70, 40.98, 41.27, 51.10, 51.21, 55.40, 102.99,
109.91, 126.24, 126.44, 127.55, 130.31, 132.87, 146.38,
150.23, 150.32, 167.57, 194.86 ppm; MS: m/z (%) = 355
(M?, 65), 340 (25), 248 (100), 57 (40), 41 (30).
determined on a Bruker 300 DRX Avance instrument at
300 and 75 MHz.
General procedure for preparation of 1,4-
dihydropyridines 4a–4k
To a mixture of 1 mmol dimedone, 1 mmol aldehyde, and
1 mmol 3-aminocrotonate in 5 cm3 EtOH was added 0.1 g
FeNH4(SO4)2Á12H2O (20 mol%), and the reaction was
stirred at r.t. for the time indicated in Table 1. After
completion of the reaction (monitored by TLC, ethyl
123

(Alum)-catalyzed preparation of 1,4-dihydropyridines
933
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(DMSO-d6): d = 1.03 (s, 3H, CH3), 1.23 (s, 3H, CH3),
2.11 (d, 1H, J = 9.4 Hz, CH2), 2.34 (d, 1H, J = 16.1 Hz,
CH2), 2.50 (d, 1H, J = 14.2 Hz, CH2), 2.56 (s, 3H, CH3),
2.69 (d, 1H, J = 9.5 Hz, CH2), 3.74 (s, 3H, OCH3), 5.18 (s,
1H, CH), 7.62 (d, 2H, J = 8.4 Hz, Ar), 8.30 (d, 2H,
J = 8.4 Hz, Ar), 9.51 (s, 1H, NH) ppm; 13C NMR
(DMSO-d6): d = 19.24, 27.25, 29.87, 33.02, 37.28,
50.91, 51.68, 102.93, 109.91, 124.10, 129.47, 146.51,
147.31, 151.02, 155.67, 167.78, 195.21 ppm; MS:
m/z (%) = 370 (M?, 60), 340 (25), 248 (100), 83 (40),
55 (80), 39 (85).
Acknowledgments We gratefully acknowledge financial support
from the Research Council of Islamic Azad University, Branch
Sabzevar.
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