Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines using ammonium carbonate in water

Article abstract of DOI:10.1016/j.tetlet.2009.12.098

Various known and new 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines are prepared efficiently via Biginelli and Hantzsch reactions using ammonium carbonate in water. Competition between Biginelli and Hantzsch reactions is observed with pyridine carbaldehydes. Using this methodology, Hantzsch esters are synthesized in higher yields and purities than with other procedures without the use of a catalyst or an organic solvent.

Full text of DOI:10.1016/j.tetlet.2009.12.098

Tetrahedron Letters 51 (2010) 1187–1189
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Tetrahedron Letters
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Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines
using ammonium carbonate in water
*
Fatemeh Tamaddon , Zahra Razmi, Abbas Ali Jafari
Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Various known and new 3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines are prepared effi-
ciently via Biginelli and Hantzsch reactions using ammonium carbonate in water. Competition between
Biginelli and Hantzsch reactions is observed with pyridine carbaldehydes. Using this methodology, Han-
tzsch esters are synthesized in higher yields and purities than with other procedures without the use of a
catalyst or an organic solvent.
Received 27 October 2009
Revised 8 December 2009
Accepted 16 December 2009
Available online 24 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Hantzsch reaction
Biginelli reaction
1,4-Dihydropyridines
3,4-Dihydropyrimidine-2(1H)-ones
(NH4)2CO3
1. Introduction
with 30 mol % of ammonium carbonate in water for three hours
at ꢀ55–60 °C.
Organic transformations in aqueous media without using haz-
ardous reagents or solvents are of interest.1 3,4-Dihydropyrimi-
din-2(1H)-ones (DHPMs) and 1,4-dihydropyridines (1,4-DHPs)
are typically prepared via Biginelli2 and Hantzsch3 reactions. The
structural similarity to hydrogenase coenzymes and the clinical
use of 1,4-DHPs as calcium channel stimulating drugs have at-
tracted the attention of organic chemists.4–8 These reactions be-
long to the category of multi-component reactions involving the
one-pot, acid-catalyzed condensation of aldehydes, b-keto esters
and ammonia or urea as the source of nitrogen.4a,9,10 Recently, a
base-catalyzed version of these reactions was reported in EtOH
at reflux.11 Modified syntheses of 1,4-DHPs and DHPMs have been
advanced also in aqueous media.12 However, more efficient syn-
theses of these biologically active compounds in aqueous media
is important.
In order to study the scope and generality of the ammonium
carbonate-catalyzed Biginelli reaction in water, a series of DHPMs
was synthesized from the substituted heteroaromatic, aromatic
and enolizable aliphatic aldehydes. In all cases, the desired prod-
ucts were isolated in excellent yields, except for pyridine carbalde-
hydes (Table 1). To our surprise, analysis of the products in these
cases confirmed the formation of new Hantzsch esters in moderate
yields (entries 10–12). Similar results were obtained when the
model reaction of benzaldehyde and ethyl acetoacetate was
attempted with thiourea or guanidine in water; diethyl 2,6-di-
methyl-4-phenyl-1,4-dihydropyridin-3,5-dicarboxylate was form-
ed instead of a 3,4-dihydropyrimidinone.
R1
H3C
H
O
O
CO2R
CH3
H2O, 55-60 o
C
RO2C
H3C
R1CHO + (NH4)2CO3
We were interested in studying Biginelli and Hantzsch reactions
in aqueous media using ammonium carbonate with the aim to de-
velop an operationally simple method for the synthesis of a large
range of 1,4-DHPs and DHPMs (Scheme 1).
+
2
N
H
RO
1,4-DHP
R1
We began our study with the base-catalyzed synthesis of 3,4-
dihydropyrimidin-2(1H)-ones via the Biginelli reaction. The model
reaction of benzaldehyde, ethyl acetoacetate and urea in water was
optimized by investigating various parameters such as base, sol-
vent and conditions. The optimized conditions required heating
H
N
H3C
H
O
RO2C
H3C
O
H2O, 55-60 ºC
R1CHO
(NH2)2CO
+
+
O
(NH4)2CO3 (30 mol%)
N
H
RO
R=Me, Et
R1=Ar, H, Alkyl
DHPM
* Corresponding author. Tel.: +98 3518122666; fax: +98 3518210644.
E-mail address: ftamaddon@yazduni.ac.ir (F. Tamaddon).
Scheme 1. Ammonium carbonate-mediated synthesis of 1,4-DHPs and DHPMs in
water
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.098

1188
F. Tamaddon et al. / Tetrahedron Letters 51 (2010) 1187–1189
Table 1
powder. It decomposes in aqueous media to produce two moles
of ammonia.
Ammonium carbonate-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones using
urea in water
The reaction proceeded in a considerably lower yield under sol-
vent-free conditions due to sublimation of ammonium carbonate
(entry 8). No significant change was observed on the results using
0.5 equiv of ammonium carbonate. This trend suggests that hydro-
gen bonding, the mild buffered pH of the reaction media and the
assistance of water to break down (NH4)2CO3 may all be responsi-
ble for acceleration of the reaction rate.
R1
H
N
H3C
H
O
RO2C
H3C
O
O
H2O, 55-60 ºC
R1CHO
(NH2)2CO
+
+
(NH4)2CO3 (30 mol%)
N
H
RO
Entry
R
Time (h)
Mp (°C) found (reported)
Yielda (%)
The optimized reaction conditions were extended to the con-
densation of other aldehydes with b-keto esters and ammonium
carbonate at 55–60 °C. Aromatic aldehydes bearing both elec-
tron-deficient and electron-rich substituents as well as aliphatic
aldehydes afforded the desired 1,4-DHPs in excellent yields (Table
3). Problematic substrates such as enolizable aliphatic aldehydes
(entries 16–19) and heteroaryl aldehydes including 2-furyl and
2-, 3- and 4-pyridine carbaldehydes reacted efficiently with ethyl
acetoacetate and (NH4)2CO3 to afford the desired 1,4-DHPs in
excellent yields (entries 12–15).
1
2
3
4
5
6
7
8
9
C6H5
4
200–203 (200–202)11c
215–216 (216–217)11c
210–212 (209–211)9c
190–192 (192–193)13
200–202 (199–201)14
207–208 (207–208)15
220–223 (225–226)11c
208–211 (207–210)14
206–208 (206–208)16
92
90
95
95
89
93
92
94
91
4-MeC6H4
4-ClC6H4
3-ClC6H4
4-MeOC6H4
3-MeOC6H4
4-HOC6H4
4-O2NC6H4
2-Furyl
4.5
4.5
4
3.5
3.5
3.5
3
3
4
3.5
3
b
b
10
11
12
2-Pyridylb
3-Pyridylb
4-Pyridylb
—
—
—
—
b
b
b
b
The structures of the products were determined by IR, 1H NMR
and 13C NMR spectroscopy, mass, CHN analysis and also by com-
parison with authentic samples.
—
—
a
Isolated yield
1,4-DHP product was isolated.
b
To evaluate the utility of this procedure in large scale reactions,
a 10-fold scale Hantzsch reaction was carried out successfully on
the model reaction to give the corresponding product 1a in 95%
yield.
In conclusion, we have prepared a variety of known and new
3,4-dihydropyrimidin-2(1H)-ones and 1,4-dihydropyridines in
water via Biginelli and Hantzsch reactions using ammonium car-
bonate as a solid ammonia source. The products were obtained
in high yields and purities compared with previous methods with-
out the use of a catalyst or an organic solvent.
The competition between the Hantzsch and Biginelli reactions
in the presence of ammonium carbonate encouraged us to investi-
gate the ammonium carbonate-mediated Hantzsch reaction in
water by controlling the mole ratio of ethyl acetoacetate.
Although the preparation of DHPs via Hantzsch reaction has
been studied,4–6 there is no report on the effect of the ammonia
source on this reaction. Thus, we studied a model four-component
condensation of ethyl acetoacetate, benzaldehyde and an ammo-
nium salt (mole ratio = 2:1:1) in water under different conditions
(Table 2). We were pleased to find that among the conditions
screened, the corresponding 1,4-DHP was obtained quantitatively
with (NH4)2CO3 at ꢀ55–60 °C in water (entry 6) in the absence of
any catalyst. This process is less laborious than previously reported
procedures.
2. General experimental procedure for the synthesis of 3,4-
dihydropyrimidinones in water
Aldehyde (2 mmol), alkyl acetoacetate (2 mmol) and either
urea/thiourea or guanidine (2.5 mmol) were stirred together fol-
Ammonium carbonate is a less toxic (LD50 = 1497 mg/kg), low
melting (58 °C) solid source of ammonia which is used as baking
Table 3
Catalyst-free synthesis of 1,4-dihydropyridines using ammonium carbonate in water
R1
Table 2
H3C
H
O
Catalyst-free Hantzsch reaction with various ammonium salts in water
CO2R
CH3
RO2C
H3C
H2O, 55-60 ºC
R1CHO
+
(NH4)2CO3
2
+
O
H
Ph
H3C
2
N
H
1a-s
CO2Et
CH3
RO
EtO2C
O
O
Solvent
Ammonium salt
+
PhCHO
+
55-60 ºC
H3C
N
H
EtO
Entry
R
R1
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
OEt
OMe
OEt
OMe
OMe
OEt
OEt
OEt
OEt
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
C6H5
C6H5
3.5
2
3
2
3
3.5
2.5
3
2
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
99
95
98
95
98
95
95
95
98
95
90
90
98
95
98
93
91
82
88
Entry
Ammonium salt
Solvent
Time (h)
Yielda (%)
4-ClC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-HOC6H4
3-HOC6H4
4-O2NC6H4
4-O2NC6H4
2-O2NC6H4
2-Pyridyl
3-Pyridyl
4-Pyridyl
2-Furyl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NH4Cl
NH4Cl
NH4OAc
NH4OAc
EtOH
H2O
EtOH
H2O
EtOH
H2O
H2O/EtOH (50:50)
None
5
5
5
5
3.5
3.5
3.5
5
5
5
5
5
5
4
4
4
0
0
45
50
90
99
97
62
0
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2CO3
(NH4)2SO4
NH4NO3
(NH4)6Mo7O24
NH4VO3
(NH4)2[Ce(NO3)6]
NH4HCO3
H4N+HCOOÀ
NH4CO2NH2
4
2.5
2
H2O
H2O/EtOH (50:50)
H2O/EtOH (50:50)
H2O/EtOH (50:50)
H2O/EtOH (50:50)
H2O
60b
0
0
15
80
68
83
2
1.5
2.5
3
3.5
4
Cinnamyl
Cinnamyl
n-Propyl
iso-Propyl
H2O
H2O
a
Isolated yield
a
b
Isolated yield.
A mixture of the 1,4-DHP and pyridine products was isolated.

F. Tamaddon et al. / Tetrahedron Letters 51 (2010) 1187–1189
1189
lowed by the addition of
a
catalytic amount of (NH4)2CO3
d = 14.68, 19.75, 38.23, 60.27, 103.57, 123.55, 136.27, 144.00,
145.39, 147.40, 149.80, 167.64 ppm. MS (EI): m/z: 330 (M+, 40),
301 (55), 285 (54), 252 (100), 224 (85), 196 (85), 150 (28), 106
(22), 51 (18).
(30 mol %) in H2O (1 mL) and the reaction was heated at 55–
60 °C for the appropriate time (Table 1). After completion of the
reaction (TLC monitoring), ice-cold water was added to the reac-
tion mixture and the precipitate was filtered. In some cases the
products were recrystallized from EtOH/H2O.
4.4. Diethyl 2,6-dimethyl-4-(4-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (1n)
3. General experimental procedure for the catalyst-free one-pot
synthesis of 1,4-dihydropyridines in water
Pale yellow solid, mp = 178–180 °C, FT-IR:
mmax (KBr): 3200 (NH
stretching), 1704 (C@O) cmÀ1 1H NMR (500 MHz, CDCl3): d = 1.24
.
A mixture of aldehyde (2 mmol), alkyl acetoacetate (4 mmol)
and anhydrous ammonium carbonate (2 mmol) was stirred in
H2O (2 mL) at 55–60 °C. After completion of the reaction (TLC mon-
itoring), the mixture was diluted with cold H2O (20 mL) and fil-
tered to remove the precipitated product which was further
purified by recrystallization in some cases.
(t, J = 7.11 Hz, 6H, 2 Â CH3–CH2), 2.37 (s, 6H, 2 Â CH3), 4.07–4.15
(m, 4H, O–CH2CH3), 5.03 (s, 1H, CH), 6.63 (br s, 1H, NH), 7.25 (dd,
J = 4.61, 1.48 Hz, 2H), 8.45 (dd, J = 4.60, 1.49 Hz, 2H) ppm. 13C
NMR (125 MHz, CDCl3): d = 14.67, 19.78, 39.89, 60.34, 102.93,
123.79, 145.67, 149.55, 156.76, 167.62 ppm. MS (EI): m/z: 330
(M+, 1), 307 (100), 278 (30), 262 (38), 233 (24), 178 (5), 105 (11),
77 (11), 51 (10).
4. Spectral data for new compounds
Acknowledgement
4.1. Diethyl 2,6-dimethyl-4-(3-hydroxyphenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (1h)
We acknowledge the research council of Yazd University.
Pale yellow solid, mp = 180–182 °C, FT-IR:
mmax (KBr): 3349 (OH
and NH stretching), 1648 (C@O) cmÀ1 1H NMR (500 MHz, CDCl3):
.
References and notes
d = 1.26 (t, J = 7.1 Hz, 6H, 2ÂCH3–CH2), 2.33 (s, 6H, 2 Â CH3), 4.09–
4.18 (m, 4H, O–CH2CH3), 5.00 (s, 1H, CH), 5.13 (br s, 1H, OH), 5.70
(br s, 1H, NH), 6.63 (dd, J = 7.95, 2.39 Hz, 1Harom), 6.80 (s, 1Harom),
6.89 (d, J = 7.69 Hz, 1Harom), 7.09 (t, J = 7.8 Hz, 1Harom) ppm. 13C
NMR (125 MHz, CDCl3): d = 14.62, 19.22, 39.44, 59.64, 103.22,
113.36, 115.39, 119.43, 149.97, 157.07, 168.15 ppm. Anal. Calcd
for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C, 66.04; H,
6.67; N, 4.00.
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Pale yellow solid, mp = 192–194 °C, FT-IR: mmax (KBr): 3174 (NH
stretching), 1688 (C = O) cmÀ1. 1H NMR (500 MHz, CDCl3): d = 1.23
(t, J = 7.11 Hz, 6H, 2 Â CH3–CH2), 2.28 (s, 6H, 2 Â CH3), 4.06–4.12
(m, 4H, O–CH2CH3), 5.22 (s, 1H, CH), 7.16 (td, J = 4.88, 0.63 Hz,
1H), 7.43 (d, J = 7.77, 1H), 7.61 (td, J = 7.66, 1.69 Hz, 1H), 8.53 (d,
J = 3.98 Hz, 1H), 8.62 (br s, 1H, NH) ppm. 13C NMR (125 MHz,
CDCl3): d = 14.71, 19.31, 43.24, 59.96, 102.15, 122.19, 124.71,
136.11, 146.73, 148.65, 165.63, 168.14 ppm. MS (EI): m/z: 330
(M+, 8.5), 307 (8), 285 (7), 252 (100), 239 (7), 224 (10), 196 (18),
170 (7), 106 (5), 78 (7), 51 (5).
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Pale yellow solid, mp = 190–192 °C, FT-IR:
mmax (KBr): 3174 (NH
stretching), 1688 (C@O) cmÀ1 1H NMR (500 MHz, CDCl3): d = 1.24
.
(t, J = 7.13 Hz, 6H, 2 Â CH3–CH2), 2.36 (s, 6H, 2 Â CH3), 4.07–4.14
(m, 4H, O–CH2CH3), 5.01 (s, 1H, CH), 6.61 (s, 1H, NH), 7.19 (dd,
J = 7.83, 4.98 Hz, 1H), 7.64–7.66 (m, 1H), 8.39 (dd, J = 4.79, 1.57 Hz,
1H), 8.55 (d, J = 1.94 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3):
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