4-Bis(triphenylphosphonium)-2-butene peroxodisulfate as an efficient oxidizing agent for one-pot synthesis of ethyl pyrimidin-2(1H)-one-5-carboxylates

Article abstract of DOI:10.1134/S1070363217040284

An efficient one-pot synthesis of pyrimidin-2(1H)-ones via three-component condensation of aldehyde, ethyl acetoacetate and urea using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate [BTPBPDS] as an oxidant is described.

Full text of DOI:10.1134/S1070363217040284

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 4, pp. 842–845. © Pleiades Publishing, Ltd., 2017.
1,4-Bis(triphenylphosphonium)-2-butene Peroxodisulfate
as an Efficient Oxidizing Agent for One-Pot Synthesis
of Ethyl Pyrimidin-2(1H)-one-5-carboxylates1
M. Gorjizadeh* and M. Afshari
Department of Chemistry, Shoushtar Branch, Islamic Azad University, Shoushtar, Iran
*e-mail: m.gorjizadeh@iau-shoushtar.ac.ir
Received January 11, 2017
Abstract—An efficient one-pot synthesis of pyrimidin-2(1H)-ones via three-component condensation of aldehyde,
ethyl acetoacetate and urea using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate [BTPBPDS] as an
oxidant is described.
Keywords: pyrimidin-2(1H)-ones, 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate, oxidation, one-pot
DOI: 10.1134/S1070363217040284
INTRODUCTION
As a part of our ongoing study devoted to develop-
ing versatile and efficient methods for the synthesis of
important heterocyclic compounds [14, 15], we report
herein a new procedure for one-pot synthesis of
pyrimidin-2(1H)-ones.
Multi-component reactions (MCRs), leading to
interesting heterocyclic scaffolds, are particularly
useful for construction of diverse chemical libraries of
“drug-like” molecules. Typically, purification of products
accumulated in MCRs is simple because all organic
reagents involved are consumed and incorporated into
the structure of a target compound [1].
RESULTS AND DISCUSSION
A two-step synthesis of pyrimidin-2(1H)-ones
under study is presented in Scheme 1. Thus, the reac-
tion of an aromatic aldehyde with ethyl acetoacetate
and urea in the presence of catalytic amount of 1,4-bis-
Pyrimidines revealed a wide range of pharma-
ceutical activities including antiviral, antimicrobial,
gastric antisecretory, diuretic, antimalarial, and anti-
HIV [2–7]. Itami and co-workers [8] have reported that
pyrimidine cores with extended π-systems exhibited
unusual fluorescent properties. Despite of high bio-
logical activity of pyrimidines and particularly
pyrimidin-2(1H)-ones, only a limited number of syn-
thetic approaches to those are available [9]. One of the
common methods involves oxidation of 3,4-dihydro-
pyrimidin-2(1H)-ones (DHPMs) to pyrimidin-2(1H)-
ones. 3,4-Dihydropyrimidin-2(1H)-ones can be easily
synthesized from ethyl acetoacetate, an aromatic
aldehyde and urea [10]. Dehydrogenation of DHPMs
by an oxidizing agent could provide an efficient ap-
proach to pyrimidin derivatives. Phosphonium salts
have attracted close attention due to their thermal
stability, easy handling, non-toxicity, high reactivity,
and recyclability [11–13].
(triphenylphosphonium)-2-butene
peroxodisulfate
(BTPBPDS) led to formation of the corresponding 3,4-
dihydropyrimidin-2(1H)-ones 4.
3,4-Dihydropyrimidin-2(1H)-ones
4
bearing
a
variety of functional groups were prepared in high
yields in a short period of time (Table 1). BTPBPDS
could play a crucial role in accelerating the steps of
dehydration and enolization of the β-ketoester.
Subsequently, compounds 4 underwent oxidation by
BTPBPDS (Scheme 1, Table 1). This step proceeded
within 55–110 min in CH3CN under reflux. Sensitive
functional groups such as methoxy, nitro, and furyl
remained unaffected in the process.
According to the recent study [16] adsorption on
solid supports (alumina, silica gel, or montmorillonite
K-10 clay) can change the reactivity and selectivity of
oxidants. The test oxidation of 4 by peroxodisulfate
adsorbed by solid supports in the process of dehydro-
1 The text was submitted by the authors in English.
842

1,4-BIS(TRIPHENYLPHOSPHONIUM)-2-BUTENE PEROXODISULFATE
843
Scheme 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and pyrimidin-2(1H)-ones.
Ar
O
EtO2C
H3C
NH
EtO
Me
BTPBPDS (0.2 mmol)
reflux, CH3CN, 20 min
Ar
NH2
+
+
N
H
4
O
O
H
O
H2N
O
1
2
3
reflux, CH3CN
BTPBPDS
Ar
EtO2C
H3C
N
N
H
O
5
genation gave no appreciable amount of products, thus
BTPBPDS was used.
were accumulated in high yield within 4 h (Scheme 2,
Table 2).
Ability of BTPBPDS to promote both steps
stimulated our study of one-pot synthesis of
pyrimidines starting from the same substrates. When
ethyl acetoacetate, urea and aldehydes were stirred in
aqueous acetonitrile under reflux in the presence of
BTPBPDS, the corresponding pyrimidin-2(1H)-ones 5
Both electron donating and electron withdrawing
substituents on the precursors supported formation of
the corresponding dihydropyrimidine derivatives in
high yields. Aliphatic substituents such as propyl and
cyclohexyl (Table 2, entries 10 and 11) also underwent
oxidative dehydrogenation without formation of any
Table 2. One-pot synthesis of pyrimidin-2(1H)-ones
Table 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones 4
and pyrimidin-2(1H)-ones 5
Entry no.
Ar
Yield a, %
mp, °C
131–133
183–186
139–141
151–153
155–156
106–108
180–182
128–130
99–100
Product 4
yielda,
Product 5
time, yielda,
1
Ph
81
84
86
82
78
89
80
84
91
79
83
Ar
mp, °C
mp, °C
2
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
4-O2N–C6H4
3-Br–C6H4
4-CN–C6H4
3-Pyridyl
2-Furyl
%
88
94
95
90
84
92
86
85
95
90
93
min
%
80
89
90
87
79
83
85
84
92
82
85
Ph
204–205 82
207–208 85
213–215 65
200–202 55
206–208 90
187–189 85
218–220 110
210–212 90
208–210 85
158–160 75
235–237 85
132–133
183–185
139–140
152–153
155–156
106–108
179–182
128–129
99–100
3
4-Cl–C6H4
4-Me–C6H4
4-MeO–C6H4
4-O2N–C6H4
3-Br–C6H4
4-CN–C6H4
3-Pyridyl
2-Furyl
4
5
6
7
8
9
10
n-C3H7
107–109
100–102
n-C3H7
107–109
11
C6H11
C6H11
101–102
a The products were characterized by comparison of their spectroscopic.
a Isolated yield based on the aldehyde.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 4 2017

844
GORJIZADEH, AFSHARI
Scheme 2. One-pot synthesis of pyrimidin-2(1H)-ones.
Ar
O
EtO2C
H3C
N
BTPBPDS (1.1 mmol)
reflux, CH3CN, 4 h
EtO
Ar
NH2
+
+
N
H
O
Me
O
H
O
H2N
O
1
2
3
5
dealkylation byproduct. BTPBPDS was essential for
this transformation. All attempts to carry out the
reactions without the oxidant did lead to the products
and only the starting materials were isolated.
One-pot synthesis of pyrimidin-2(1H)-ones (general
procedure). To a solution of ethyl acetoacetate
(1 mmol), urea (1 mmol) and aromatic aldehyde
(1 mmol) in acetonitrile–water (10 : 2 mL) was added
1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate
(1.1 mmol). The reaction mixture was refluxed upon
stirring for 4 h. Water (10 mL) was added and the
mixture was extracted with chloroform (3 × 15 mL).
The organic layer was separated and dried over
MgSO4. The solvent was evaporated and the product
was purified by column chromatography on silica gel
using a mixture of ethyl acetate and n-hexane (1 : 3) as
an eluent.
EXPERIMENTAL
Materials and methods. All products are known
compounds and were identified by comparison of their
physical and spectral data with those of authentic
samples [9, 15, 17]. 13C NMR spectra were measured
on a 400 MHz Brucker Spectrometer. 1,4-Bis(triphenyl-
phosphonium)-2-butene peroxodisulfate (BTPBPDS)
was prepared according to the earlier study [18]. Other
chemicals were purchased from the Merck Chemical
Company, Darmstadt, Germany. Purity of the products
and reaction monitoring were performed by TLC on
silica gel polygram SILG/UV 254 plates.
Ethyl 6-methyl-4-(4-cyanophenyl)pyrimidin-2(1H)-
one-5-carboxylate (7). Yield 80%, mp 180–182°C.
13C NMR spectrum, δ, ppm: 13.9 (CH3), 19.5 (CH3),
61.4 (CH2), 108.8 (C), 114.3 (C), 119.9 (C), 130.3
(CH), 134.8 (CH), 140.06 (C), 156.6 (C), 162.1 (C),
167.2 (C), 170.20 (C). Found, %: C 63.62; H 4.61; N
14.86. Anal. C15H13N3O3. Calculated, %: C 63.59; H
4.63; N 14.83.
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones (4)
(general procedure). A mixture of ethyl aceto-acetate
(1.0 mmol) with aldehyde (1.0 mmol), urea (1 mmol),
and 1,4-bis(triphenylphosphonium)-2-butene peroxo-
disulfate (0.2 mmol) in acetonitrile was refluxed for
20 min. Upon completion of the reaction water was
added, and the solid product was filtered off, washed
with ice-cold water, dried, and recrystalized from
ethanol.
Ethyl 6-methyl-4-(3-pyridyl)-pyrimidin-2(1H)-one-
5-carboxylate (8). Yield 84%, mp 128–130°C. 13C
NMR spectrum, δ, ppm: 13.2 (CH3), 18.4 (CH3), 61.2
(CH2), 108.2 (C), 123.3 (CH), 129.7 (C), 134.4 (CH),
145.1 (CH), 150.2 (CH), 157.3 (C), 164.5 (C), 166.6
(C), 170.1 (C). Found, %: C 60.01; H 5.09; N 15.98.
C13H13N3O3. Calculated, %: C 60.22; H 5.06; N 16.2.
Oxidation of 3,4-dihydropyrimidin-2(1H)-ones
(general procedure). To a solution of 3,4-dihydro-
pyrimidin-2(1H)-one (1 mmol) in acetonitrile and
water (10.2 mL) 1,4-bis(triphenylphosphonium)-2-
butene peroxodisulfate (1 mmol) was added in small
portions. The reaction mixture was refluxed for the
appropriate time (Table 1). Upon completion of the
process, the reaction mixture was cooled down to room
temperature and filtered. Water (15 mL) was added
and the mixture extracted with chloroform (3 ×
15 mL). The combined organic layers were dried over
MgSO4 and concentrated in vacuo. The product was
purified by column chromatography using a mixture of
diethyl ether and n-hexane (1 : 4) as an eluent.
CONCLUSIONS
The novel and efficient approach to the synthesis of
pyrimidin-2(1H)-ones is developed.
ACKNOWLEDGMENTS
We are grateful to the Islamic Azad University
Shoushtar Branch for support of this work.
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