Ultrasound-mediated, uranyl nitrate hexahydrate-catalyzed synthesis of 1,4-dihydropyridines under mild conditions

Article abstract of DOI:10.1007/s11164-014-1784-5

Abstract Synthesis of 1,4-dihydropyridines by three-component condensation reaction of aldehyde, 1,3-dicarbonyl compounds, and ammonium acetate have been found to be efficiently catalyzed by uranyl nitrate hexahydrate [UO₂(NO₃)₂ ·6H₂O] at room temperature under ultrasound irradiation. This novel synthetic method offers the advantages of high yields, short reaction times, simplicity, and easy workup compared to the conventional methods reported in the literature.

Full text of DOI:10.1007/s11164-014-1784-5

Res Chem Intermed
DOI 10.1007/s11164-014-1784-5
Ultrasound-mediated, uranyl nitrate hexahydrate-
catalyzed synthesis of 1,4-dihydropyridines under mild
conditions
•
B. Palakshi Reddy S. Sarveswari V. Vijayakumar
•
Received: 1 March 2014 / Accepted: 6 August 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Synthesis of 1,4-dihydropyridines by three-component condensation
reaction of aldehyde, 1,3-dicarbonyl compounds, and ammonium acetate have been
found to be efficiently catalyzed by uranyl nitrate hexahydrate [UO2(NO3)2Á6H2O]
at room temperature under ultrasound irradiation. This novel synthetic method
offers the advantages of high yields, short reaction times, simplicity, and easy
workup compared to the conventional methods reported in the literature.
Keywords 1,4-DHPs Á Uranyl nitrate hexahydrate Á Ultrasound irradiation
Introduction
1,4-Dihydropyridine (1,4-DHPs) derivatives are known as an important class of
heterocycles owing to their potential biological activity, and for their therapeutics
use such as antihypertensive [1, 2], hypnotic, anti-inflammatory [3], antihypoxic,
antiischemic drugs [4] and calcium channel modulators of the nifedipine type [5].
For synthesis of 1,4-DHPs, several methods have been reported [6–10]. The
presence of ester groups at the 3- and 5-positions on the 1,4-DHPs ring is of
crucial importance for its pharmacological effects. Recently, some new 3,5-
disubstituted 1,4-DHPs were synthesized which exhibit pharmacological effects
such as antihypertensive, bronchodilatory and antitubercular agent [11, 12]. DHPs
are also have significant biological activities, ranging from anti-tumour, fungicidal,
bactericidal and anti-inflammatory and antiviral activities [13, 14]. In continuation
of our interest in 1,4-DHPs [15–22], we here report a simple and efficient protocol
for the synthesis of 1,4-DHPs via three-component reaction of aldehydes, 1,3-
B. Palakshi Reddy Á S. Sarveswari Á V. Vijayakumar (&)
Centre for Organic and Medicinal Chemistry, VIT University, Vellore, 632 014 Tamil Nadu, India
e-mail: kvpsvijayakumar@gmail.com
123

B. Palakshi Reddy et al.
dicarbonyls and ammoniumacetate in the presence of uranyl nitrate haxahydrate as
a catalyst under ultrasonic irradiation. Uranyl nitrate hexahydrate is usually used
as an electron-dense stain for transmission electron microscopy. However, it has
also found application as a local catalyst in the polymerization of methacrylates
[23].
Experimental
IR spectra were recorded using an AVATAR 330 equipped with DTGS detector.
NMR spectra were measured on a Bruker AMX-400 instrument at RT in CDCl3
using TMS as internal reference. The coupling constants J are in Hz. HRMS spectra
were recorded on macromass spectrometer (Waters) by the electron-spray method
(ES). Melting points were determined in open capillaries and are uncorrected.
Sonication was performed in a Make (E-Chrom Tech, Taiwan), equipped with a
1.3 9 10-2-m-long probe, which was immersed directly into the reaction mixture.
The operating frequency was 22 kHz and the output power was 800 W through
manual adjustment.
General procedure for synthesis of 1,4-DHPs
To a solution of aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone
(2.0 mmol) and ammonium acetate (1.0 mmol) in ethanol (3 mL), uranyl nitrate
(10 mol%) was added and the resultant reaction mixture was sonicated at room
temperature for the required time (Table 1). The progress of the reaction was
monitored by TLC. After completion of the reaction, the mixture was poured into
crushed ice. The obtained solid was filtered, washed thoroughly with water, dried,
and purified by recrystallisation in ethanol. The plausible reaction mechanism was
proposed for the UO2(NO3)2Á6H2O catalyzed reaction of aldehyde, 1,3-dicarbonyl
compound and ammonium acetate (Fig. 1).
Diethyl 2,6-dimethyl-4-(thiophen-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4 h)
Yield: 95 %. m.p.: 172–173 °C; IR (KBr, cm-1):3,403, 3,327, 1,673, 1,633, 1,591,
1,528, 113. 1H-NMR (400 MHz, CDCl3) dH: 1.24 (t, J = 7.2 Hz, 6H), 2.31 (s, 6H),
4.10–4.19 (m, 4H), 5.32 (s, 1H), 5.81 (s, NH), 6.76–6.83 (m, 2H), 7.02 (d,
J = 6.0 Hz, 1H); 13C-NMR (125 MHz, CDCl3) dC: 14.00, 18.60, 33.91, 59.31,
102.25, 122.53, 122.57, 125.91, 145.36, 151.81, 167.22.HRMS (m/z): Calcd.
forC17H21NO4S: 335.1189. Found: 335.1180 (M?).
Diethyl-4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(4j)
Yellow solid. M.p. 227–229 °C. IR (KBr, cm-1): 3,345, 2,981, 1,662 and 1,486. 1H-
NMR (400 MHz, CDCl3): d 0.88 (t, J = 7.5 Hz, 6H), 2.77 (s, 6H), 3.66–3.76 (q,
123

Ultrasound-mediated, uranyl nitrate hexahydrate-catalyzed
Table 1 Optimization conditions of benzaldehyde (1.0 mmol), ethyl acetoacetate (2.0 mmol), and
ammonium acetate (1.0 mmol), with ultrasonic irradiation
Entry
Catalyst
Mole
(%)
Solvent
Time (min)
Yield (%)
1
2
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
UO2(NO3)2Á6H2O
FeCl3Á6H2O
Nil
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeCN
MeCN
MeCN
MeCN
40
40
25
20
15
15
20
40
40
120
70
70
80
85
96
96
90
75
77
45
3
2.5
5
4
5
10
20
10
10
10
Nil
6
7
8
9
AlCl3Á6H2O
10
Nil
NH2
O
O
O
O
NH3
AcONH4
O
O
H2N
UO2(NO3)2.6H2O
R
O
O
O
R
R
R
R
UO2(NO3)2.6H2O
O
UO2(NO3)2.6H2O
O
O
H
O
R
O
O
O
O
R
Ph
R
UO2(NO3)2.6H2O
Ph
UO2(NO3)2.6H2O
H
H
Ph
Ph
H
Ph
H
O
O
R
O
OH
R
Ph
O
H
R
O
Ph
O
R
Ph
O
O
O
Ph
HO
R
R
O
R
R
R
1,4-DHP
N
H
O
HN
O
HN
UO2(NO3)2.6H2O
OH
H
H
O
H2N
UO2(NO3)2.6H2O
UO2(NO3)2.6H2O
Fig. 1 Plausible mechanism for the uranyl nitrate hexahydrate-catalyzed synthesis of 1,4-dihydropyridines
J = 6.0 Hz, 4H), 4.49 (s, 1H), 6.30 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H),
7.60 (s, –NH, 1H), 8.27 (s, –OH, 1H). HRMS: Calcd. forC19H23NO5: 345.1575.
Found: 345.1582 (M?).
123

B. Palakshi Reddy et al.
Dimethyl-4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
(5 h)
Yellow solid. M.p. 198–199 °C. IR (KBr, cm-1): 3,339, 3,003, 2,950, 1,680, 1,647
1
and 1,611. H-NMR (400 MHz, CDCl3): d 2.86 (s, 6H), 3.28 (s, 6H), 4.51 (s, 1H),
6.31 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 8.0 Hz, 2H), 7.73 (s, –NH, 1H), 8.35 (s,
–OH, 1H). HRMS (m/z): Calcd. forC17H19NO5: 317.1,265. Found: 317.1,270 (M?).
3,5-Diacetyl-2,6-dimethyl-1,4-dihydro-4-(4-ethylphenyl)-3,5-pyridine (6i)
Yellow solid. M.p. 179–181 °C. IR (KBr, cm-1): 3,343, 3,008, 2,960, 1,689 and
1,649. 1H-NMR (400 MHz, CDCl3): 0.88 (t, J = 7.1 Hz, 3H), 1.89 (s, 6H), 2.34 (m,
J = 7.0 Hz, 2H), 2.37 (s, 6H), 4.81 (s, 1H), 6.63 (d, m, J = 7.8 Hz, 2H), 7.78 (d, o,
J = 7.5 Hz, 2H). HRMS (m/z):Calcd. forC17H19NO5: 297.1725.Found:297.1725
(M?).
Results and discussion
The formation of 1,4-DHPs using various aldehydes, ethyl/methyl acetoacetate/
acetylacetone and ammonium acetate under ultrasonic irradiation was examined and
the results are summarized in Table 2. Initially, the reactions were carried out at
room temperature for 15–30 min in the presence of 10 mol% of the uranyl nitrate
hexahydrate at 22 kHz under ultrasonic irradiation. To determine the amount of the
catalyst required, the reaction of benzaldehyde, ethyl acetoacetate and ammonium
acetate was selected as the model reaction and conducted under sonication in the
presence of varying concentrations (mol%) of the uranyl nitrate and it was found
that optimum yield was observed while using 10 mol% of the catalyst (Table 1).
Using lesser amounts of the catalyst resulted in lower yields, while higher amounts
of the catalyst did not affect reaction times and yields. In the absence of the catalyst,
the yield was found to be low. The reaction was also carried out using different
solvents such as methanol, ethanol, acetonitrile and chloroform, as well as a solvent-
free system at reflux conditions with 10 mol% of UO2(NO3)2.6H2O as the catalyst.
Under these conditions, it was noticed that the highest yield and shorter reaction
duration was achievable with ethanol (in 40 min, 90 % yield) while the others took
longer durations to yield lesser products. Hence, the ultrasonic irradiation which
required only 15 min duration to complete the reaction dominates the reflux reaction
conditions. So the use of the ultrasound improves the yield as well as the rate of
reaction. To prove the generality of the reaction, a wide range of substituted
aldehydes with electron-donating as well as electron-withdrawing substituents were
used and found to have excellent yields of 1,4-DHPs (Table 2). Unlike those of
ethyl/methyl acetoacetate products, the reaction of acetyl acetone products
proceeded at lower rates and less efficiency to afford the 1,4-DHPs. Known
123

Ultrasound-mediated, uranyl nitrate hexahydrate-catalyzed
Table 2 Synthesis of 1,4-DHPs using uranyl nitrate hexahydrate as catalyst under ultrasonic irradiation
Entry
Ar
R
Time (min)
Yield (%) d
mp (°C)
4a
4b
4c
4d
4e
4f
C6H5
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Me
15
20
20
25
25
25
20
25
30
30
30
25
15
20
25
30
30
25
30
30
25
20
25
25
25
25
30
25
30
30
25
30
96
92
89
90
87
85
91
89
86
90
88
86
92
90
86
87
88
89
90
92
90
90
89
87
86
90
88
90
89
90
88
90
158–160 (158–160) [24]
145–146 (144–146) [24]
153–155 (158–160) [24]
165–167 (162–164) [24]
181–182 (178–180) [25]
188–190 (190–192) [25]
162–164 (162–164) [26]
172–173 (171–173) [24]
136–137 (135–138) [27]
227–229 (227–228) [28]
172–175 (180–182) [25]
147–148 (146–147) [29]
198–200 (197–198) [30]
210–212 (210–212) [31]
174–176 (174–176) [31]
185–186 (185–186) [30]
173–174 (173–174) [30]
194–197 (195–196) [32]
201–203 (200–202) [33]
198–199 (198–199) [30]
196–198 (195–196) [30]
155–156 (150–152) [34]
210–211 (210–211) [34]
195–197 (195–197) [35]
159–160 (158–159) [35]
169–172 (171) [36]
4-ClC6H4
4-CH3OC6H4
3-NO2C6H4
4-Pyridyl
3-Pyridyl
4-BrC6H4
2-Thienyl
4-CH3C6H4
4-HOC6H4
3-HOC6H4
2,5-Me2C6H3
C6H5
4g
4h
4i
4j
4k
4l
5a
5b
5c
5d
5e
5f
3-NO2C6H4
4-CH3C6H4
2-ClC6H4
4-CH3OC6H4
2-Furyl
5g
5h
5i
2-Thienyl
4-HOC6H4
4-ClC6H4
CH3
6a
6b
6c
6d
6e
6f
3-NO2C6H4
2-NO2C6H4
2-Furyl
Me
Me
Me
2-Thienyl
3-Pyridyl
3-ClC6H4
3-CH3OC6H4
4-C2H5C6H4
4-Pyridyl
4-BrC6H4
Me
Me
262–263 (262–263) [37]
222–224 (221–222) [35]
200–201 (196–198) [34]
179–181 (179–181) [20]
245–246 (245–246) [38]
109–111 (109–111) [39]
6g
6h
6i
Me
Me
Me
6j
Me
6k
Me
Reaction conditions: aldehyde (1.0 mmol), ethyl/methyl acetoacetate/acetylacetone (2.0 mmol), ammo-
nium acetate (1.0 mmol), uranyl nitrate hexahydrate (10 mol%)
compounds were identified by comparing their spectroscopic data and melting
points with reported literature values, and hence only representative compounds
were included in the ‘‘Experimental’’ section.
123

B. Palakshi Reddy et al.
Ar
O
O
O
O
Uranyl nitrate
hexahydrate
R
R
ArCHO
2
CH3COONH4
3
+
+
H3C
R
))))), Ethanol
1
H3C
N
H
CH3
R = CH3, OCH3, OC2H5.
4a-l: R = OEt
5a-i: R = OMe
6a-k: R = Me
Conclusion
An efficient and simple alternative method for the synthesis of substituted 1,4-DHPs
under ultrasonic irradiation using UO2(NO3)2Á6H2O as the catalyst was developed
with operational simplicity, good yields, shorter reaction time, low costs, and easy
workup procedure.
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