A greener, efficient approach to michael addition of barbituric acid to nitroalkene in aqueous diethylamine medium

Article abstract of DOI:10.3390/molecules19011150

An efficient method for the synthesis of a variety of pyrimidine derivatives 3a-t by reaction of barbituric acids 1a,b as Michael donor with nitroalkenes 2a-k as Michael acceptor using an aqueous medium and diethylamine is described. This 1,4-Addition strategy offers several advantages, such as using an economic and environmentally benign reaction media, high yields, versatility, and shorter reaction times. The synthesized compounds were identified by 1H-NMR, 13C-NMR, CHN, IR, and MS. The structure of compound 3a was further confirmed by single crystal X-ray structure determination.

Full text of DOI:10.3390/molecules19011150

Molecules 2014, 19, 1150-1162; doi:10.3390/molecules19011150
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Greener, Efficient Approach to Michael Addition of
Barbituric Acid to Nitroalkene in Aqueous
Diethylamine Medium
Hany J. Al-Najjar 1, Assem Barakat 1,2,*, Abdullah M. Al-Majid 1, Yahia N. Mabkhot 1,
Manuel Weber 3, Hazem A. Ghabbour 4 and Hoong-Kun Fun 4
1
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455,
Riyadh 11451, Saudi Arabia; E-Mails: hany_33@hotmail.com (H.J.A.-N.);
amajid@ksu.edu.sa (A.M.A.-M.); yahia@ksu.edu.sa (Y.N.M.)
2
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426,
Ibrahimia- 21321 Alexandria, Egypt
3
Department of Chemistry, University of California, Berkeley, CA 94720, USA;
E-Mail: manuelweber@berkeley.edu
4
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University,
P. O. Box 2457, Riyadh 11451, Saudi Arabia; E-Mails: ghabbourh@yahoo.com (H.A.G.);
hfun.c@ksu.edu.sa (H.-K.F.)
* Author to whom correspondence should be addressed; E-Mail: ambarakat@ksu.edu.sa;
Tel.: +9661-467-5884; Fax: +9661-467-5992.
Received: 5 December 2013; in revised form: 7 January 2014 / Accepted: 10 January 2014 /
Published: 17 January 2014
Abstract: An efficient method for the synthesis of a variety of pyrimidine derivatives 3a–t
by reaction of barbituric acids 1a,b as Michael donor with nitroalkenes 2a–k as Michael
acceptor using an aqueous medium and diethylamine is described. This 1,4-addition
strategy offers several advantages, such as using an economic and environmentally benign
reaction media, high yields, versatility, and shorter reaction times. The synthesized
1
compounds were identified by H-NMR, 13C-NMR, CHN, IR, and MS. The structure of
compound 3a was further confirmed by single crystal X-ray structure determination.
Keywords: Michael reactions; barbituric acid; aqueous media; green chemistry

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1. Introduction
The Michael reaction is one of the most powerful tools for the formation of carbon–carbon bonds in
organic synthesis [1–6]. The addition of various active methines compounds to nitroalkenes has
received increased attention since the conjugated addition products are aliphatic nitro compounds. These
are recognized as versatile synthetic building blocks which can be either transformed into biologically
active compounds such as tetrahydropyrans, amino acids, pyrrolidines and lactones [7–9], or readily
converted into other functionalities such as ketones, amines, carboxylic acids, nitrile oxides, etc. [10–13].
Extensive studies have been devoted to the development of catalytic systems for Michael additions of
various active methines such as pronucleophiles to nitroalkenes including cinchona organocatalysts [14],
enzymes [15], various chiral amines [16,17], transition metal-free organocatalysts [18–20] and chiral metal
complexes [21–25].
Recently, the utilization of water as a solvent has emerged as an extensively investigated topic in
organic transformations for its environmental friendly character, low cost and properties conferring
unique selectivity and reactivity [26]. For these reasons, the development of synthetically useful
reactions that take place in water is of considerable topical interest.
Barbituric acids constitute an interesting family of pyrimidinetrione heterocycles [27–29]. They are
well-known in medicinal chemistry as sedatives, hypnotics, anticonvulsants and anxiolytic agents [30–32].
Barbituric acids are also particularly utilized as nucleophiles. In continuation of our research
program [33–37], we have investigated the reaction of barbituric acids, as nucleophiles with
nitroalkenes as Michael acceptors in water using diethylamine to afford multifunctional pyrimidine
systems for biological and pharmacological evaluation. To the best of our knowledge, this is the first
successful method of this type using aqueous diethylamine as reaction medium.
2. Results and Discussion
We initiated our investigations by using 1,3-dimethylbarbituric acid (1a) as C-based nucleophile
and nitroalkene (2a) as a Michael acceptor for the 1,4-addition strategy in the presence of aqueous
diethylamine at ambient temperature, as shown in Table 1. These are the optimal reaction conditions
for the construction of Michael product by this strategy [38].
As expected, the Michael product 3a was obtained in quantitative yield after 1 h (Table 1, entry 1).
In addition, other secondary amines were examined. It was found that iPr2NH generated the Michael
product in a significant yield of 85% (Table 1, entry 2). Additionally, (cyclohexyl)2NH and morpholine
afforded the product in substantial yields of 82% and 78%, respectively (Table 1, entries 3, 4). NaOH
was also examined and was found to be less efficient in the reaction. Only a moderate yield was
obtained (Table 1, entry 5). In the absence of amine (entry 6) or water (entry 7), the reaction either
could not be performed or proceeded very slowly. The best results, with respect to yield, were obtained
by performing the reaction with the combined promoting effects of both H2O and Et2NH.
It is well known that the rate for organic reactions conducted in aqueous media require either
hydrogen bonding activation of functional groups by water or the repulsive hydrophobic interactions of
the reactants [39–41]. We thus envisioned that hydrogen bonding activation in the presence of amine as
a base generates an enolate, the catalyst of choice for the Michael strategy (Scheme 1).

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Table 1. Screening of conditions for the Michael addition reaction of the model substrate a.
1152
Entry
Condition
Et2NH/H2O
iPr2NH/H2O
(Cyclohexyl)2NH/H2O
Morpholine/H2O
NaOH/H2O
Time
Yield (%) b
1
2
3
4
5
6
7
1
4
99
85
82
78
65
10
0
4
3
6
Et2NH
10
H2O
10
a All reactions were carried out with 1,3-dimethylbarbituric acid 1a (1.5 mmol), nitroalkene
b
2a (1.5 mmol) and amine (1.5 mmol) in water (1.5 mL) for the specified time. Yield of
isolated product.
Scheme 1. A possible mechanistic pathway.
With the optimal reaction conditions in hand, the substrate scope was then investigated. First,
1,3-dimethylbarbituric acid (1a) as C-based nucleophile was reacted with eight different phenyl-type
substituted nitroalkenes as Michael acceptors (Table 2, entries 1–8). The reactions proved to work well
with a range of nitroalkenes bearing either electron-withdrawing or electron-donating groups that
produced the desired products with excellent yields (88%–99%).

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Table 2. Michael addition reaction of barbituric acid derivatives 1 to nitroolefin 2
catalyzed by Et2NH in water at room temperature a.
Entry
1
3
3a
3b
3c
3d
3e
3f
R
Yield (%) b
Ph
99
96
92
91
90
91
89
88
93
96
95
97
94
88
89
85
86
88
92
87
2
p-CH3Ph
p-BrPh
3
4
p-ClPh
5
2,4-Cl2Ph
2,6-Cl2Ph
p-CH3OPh
p-NO2Ph
Ferrocene
CH3
6
7
3g
3h
3i
8
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
Thiophene
Ph
3m
3n
3o
3p
3q
3r
3s
3t
p-CH3Ph
p-BrPh
p-ClPh
2,4-Cl2Ph
2,6-Cl2Ph
p-CH3OPh
Ferrocene
p-NO2Ph
a All reactions were carried out with barbituric acid 1 (1.5 mmol), nitroalkene 2 (1.5 mmol)
and amine (1.5 mmol) in water (1.5 mL) for the specified time. b Yield of isolated product.
Next, we applied the conditions to reactions of barbituric acid (1b) with eight different phenyl-type
substituted nitroalkenes. Interestingly, the Michael product was separated in enol form and not in keto
form in very good to excellent yields (Table 2, entries 13–20). Finally, to show the generality of the
procedure, we tested ferrocene nitroalkene as Michael acceptor and the products were obtained in
very good yields (Table 2, entries 9, 19). A further development has also been achieved by our group.
Thus, Michael addition of barbiturate to either aliphatic nitroalkenes or heteroaromatic nitroalkenes
affords the pyrimidine adduct (Table 2, entries 10, 11) with excellent yields (96% and 95%,
respectively). Thus, the methodology not only suitable for aromatic nitroalkenes, but also aliphatic and
heteroaromatic nitroalkenes.
The X-ray structure of 3a (Figure 1) was obtained by single crystal structure determination from a single
crystal grown from CHCl3/Et2O as a solvent. The structure shows interesting characteristics and also the

Molecules 2014, 19
1154
hydrogen-bonding interactions are listed (see Supporting Information). The packing of the molecules in the
crystal structure is stabilized by C–H⋅ ⋅ ⋅O hydrogen bonds into a three-dimensional framework structure.
Figure 1. ORTEP representation of the structure of 3a.
3. Experimental
3.1. General Information
All the chemicals were purchased from Sigma-Aldrich and Fluka (Seelze, Germany), and were used
without further purification unless otherwise stated. All melting points were measured on a
Gallenkamp melting point apparatus in open glass capillaries and are uncorrected. IR Spectra were
measured as KBr pellets on a Nicolet 6700 FT-IR spectrophotometer (Madison, WI, USA). The NMR
spectra were recorded on a Varian Mercury Jeol-400 NMR spectrometer (Tokyo, Japan).1H-NMR
(400 MHz), and 13C-NMR (100 MHz) were run in either deuterated dimethylsulphoxide (DMSO-d6) or
deuterated chloroform (CDCl3). Chemical shifts (δ) are referred in terms of ppm and J-coupling
constants are given in Hz. Mass spectra were recorded on a Jeol JMS-600 H instrument (Tokyo, Japan).
Elemental analysis was carried out on a Perkin Elmer 2400 Elemental Analyzer (Vernon Hills, Illinois,
IL, USA); CHN mode.
3.2. General Procedure for Synthesis of Nitroalkenes 2a–k
Equimolar amounts of aryl aldehyde and nitromethane (1 equiv.) were dissolved in 95% ethyl
alcohol (100 mL) at room temperature and then a solution of sodium hydroxide (1 equiv.) in ethyl
alcohol (30 mL) was added from a dropping funnel at a rate of 5 mL per minute. The solution of the
nitromethane and aldehyde in alcohol was then vigorously stirred at room temperature for 1 h. As the
reaction proceeded, the insoluble sodium salt of the condensation product precipitated. After all of the
alkali had been added and with the temperature kept below 20 °C, ice water (about 30 mL) was slowly
added until the precipitate just dissolved. This clear, cold solution was slowly added to a solution of
15% HCl (50 mL) and more cold water (300 mL) was added. A fine, light yellow precipitate was
immediately formed and filtered with suction after standing for half an hour. The product thus formed
was quite pure and was found to be satisfactory as a starting product for subsequent preparations
without further purification.

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3.3. General Procedure for Michael Addition for the Synthesis of 3a–t
A mixture of nitroalkene 2a–k (1.5 mmol), barbituric acid derivatives 1a,b (1.5 mmol), and Et2NH
(1.5 mmol) in degassed H2O (1.5 mL) was stirred at room temperature for 1 h until TLC showed
complete disappearance of the reactants. The product either precipitated or was in an oily form. The
reaction mixture was acidified using 1M HCl extract with DCM/10% EtOH then washed with brine
and dried over MgSO4 to afford 3a–t.
1,3-Dimethyl-5-(2-nitro-1-phenylethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3a) According to the
general procedure, 3a was prepared from 1,3-dimethylbarbituric acid (1a) and
(E)-(2-nitrovinyl)benzene (2a) as white crystals (453 mg, 1.48 mmol, 99%); m.p. 85 °C; IR (KBr) ν/cm−1
1738, 1671, 1552, 1372, 1228; 1H-NMR (CDCl3) δ 7.29 (m, 3H, Ph), 7.03 (m, 2H, Ph), 5.28 (dd, 1H,
J = 13.9, 5.8 Hz, CH2NO2), 5.02 (dd, 1H, J 13.9, 5.8, CH2NO2), 4.50 (m, 1H, CHPh), 3.84 (d, 1H,
J = 3.6 Hz, COCHCO), 3.12(s, 3H, CH3), 3.07(s, 3H, CH3); 13C-NMR (CDCl3) δ 166.8, 150.5, 133.7,
129.4, 127.4, 76.5, 51.5, 45.5, 28.5, 28.3; LC/MS (ESI) m/z 305 [M]+; Anal. for C14H15N3O5; calcd: C,
55.08; H, 4.95; N, 13.76; Found: C, 55.10; H, 4.95; N, 13.75.
The structure of 3a was confirmed by X-ray crystal structure analysis (Bruker AXS GmbH,
Karlsruhe, Germany). CCDC-933479 contains the supplementary crystallographic data for this
compound. These data can be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. A colorless cubic crystal of the compound suitable
for X-ray analysis was formed in CHCl3/Et2O at room temperature after 2 days.
1,3-Dimethyl-5-(2-nitro-1-(p-tolyl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3b) According to the
general procedure, 3b was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-methyl-4-(2-
nitrovinyl)benzene (2b) as an oily product (460 mg, 1.44 mmol, 96%). IR (KBr) ν/cm−1 1738, 1671, 1552,
1
1372, 1228; H-NMR (CDCl3) δ 7.08 (d, 2H, J = 8.0 Hz, Ph), 6.91 (d, 2H, J = 8.0 Hz, Ph),
5.25 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.99 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.45 (m, 1H,
CHPh), 3.82 (d, 1H, J = 3.6 Hz, COCHCO), 3.13 (s, 3H, CH3), 3.08 (s, 3H, CH3), 2.28 (s, 3H, CH3);
13C-NMR (CDCl3) δ 166.9, 166.9, 150.6, 139.3, 130.5, 129.9, 127.3, 51.5, 45.3, 28.5, 28.3, 21.1;
LC/MS (ESI): m/z 319 [M]+ Anal. for C15H17N3O5; calcd: C, 56.42; H, 5.37; N, 13.16; Found: C,
;
56.41; H, 5.36; N, 13.17.
5-(1-(4-Bromophenyl)-2-nitroethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (3c) According to
the general procedure, 3c was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-bromo-4-(2-
nitrovinyl) benzene (2c) as a yellow powder (530 mg, 1.38 mmol, 92%); m.p.: 99 °C; IR (KBr) ν/cm−1
1738, 1668, 1552, 1375; 1H-NMR (DMSO-d6) δ 7.51 (d, 2H, J = 7.3 Hz, Ph), 7.07 (d, 2H, J = 7.3 Hz, Ph),
5.40 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.23 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.29 (bs, 1H,
CHPh), 4.17 (bs, 1H, COCHCO), 3.06 (s, 3H, CH3), 2.96 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ 167.8,
167.5, 166.4, 151.3, 135.0, 132.2, 132.1, 131.8, 130.3, 122.1, 76.6, 52.1, 44.0, 28.5, 28.3;
LC/MS (ESI) m/z 384 [M]+ Anal. for C14H14BrN3O5; calcd: C, 43.77; H, 3.67; Br, 20.80; N,
;
10.94;Found: C, 43.79; H, 3.65; Br, 20.81; N, 10.94.

Molecules 2014, 19
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5-(1-(4-Chlorophenyl)-2-nitroethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (3d) According
to the general procedure, 3d was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-chloro-4-(2-
nitrovinyl)benzene (2d) as an oily product (462 mg, 1.36 mmol, 91%). IR (KBr) ν/cm−1 1738, 1669, 1552,
1
1423, 1238; H-NMR (DMSO-d6) δ 7.44 (d, 2H, J = 8.0 Hz, Ph), 7.13 (d, 2H, J = 8.0 Hz, Ph),
5.41 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.23 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.30 (bs, 1H,
CHPh), 4.16 (bs, 1H, COCHCO), 3.06 (s, 3H, CH3), 2.95 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ 167.8,
167.5, 166.4, 151.3, 135.0, 132.2, 132.1, 131.8, 130.3, 122.1, 76.6, 52.1, 44.0, 28.5, 28.3;
LC/MS (ESI) m/z 339 [M]+; Anal. for C14H14ClN3O5; calcd: C, 49.49; H, 4.15; Cl, 10.44; N,
12.37;Found: C, 49.50; H, 4.14; Cl, 10.43; N, 12.36.
5-(1-(2,4-Dichlorophenyl)-2-nitroethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(3e)
According to the general procedure, 3e was prepared from 1,3-dimethylbarbituric acid (1a) and
(E)-2,4-dichloro-1-(2-nitrovinyl) benzene (2e) as a yellow powder (505 mg, 1.35 mmol, 90%);
m.p.: 119 °C; IR (KBr) ν/cm−1 1738, 1667, 1551, 1423, 1221;1H-NMR (DMSO-d6) δ 7.65 (s, 1H, Ph),
7.52 (d, 1H, J = 8.0 Hz, Ph), 7.45(d, 1H, J = 8.0 Hz, Ph), 5.31–5.22 (m, 3H, CH2NO2 and COCHCO),
13
4.83 (bs, 1H, CHPh); C-NMR (DMSO-d6): δ 167.3, 166.4, 151.7, 135.0, 130.9, 129.6, 127.9, 75.7,
51.6, 28.8, 28.7; LC/MS (ESI) m/z 374 [M]+; Anal. for C14H13Cl2N3O5; calcd: C, 44.94; H, 3.50; Cl,
18.95; N, 11.23; Found: C, 44.92; H, 3.51; Cl, 18.90; N, 11.25.
5-(1-(2,6-Dichlorophenyl)-2-nitroethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(3f)
According to the general procedure, 3f was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-2,6-
dichloro-1-(2-nitrovinyl)benzene (2f) as a white powder (510 mg, 1.36 mmol, 91%); m.p.: 140 °C;
1
IR (KBr) ν/cm−1 1738, 1670, 1551, 1423, 1228; H-NMR (DMSO-d6) δ 7.50 (d, 2H, J = 8.0 Hz, Ph),
7.36 (t, 1H, J = 8.0 Hz, Ph), 5.32 (d, 2H, J = 6.6 Hz, CH2NO2), 5.00 (m, 1H, CHPh), 4.11 (d, 1H,
J = 11.0 Hz, COCHCO), 3.08 (s, 3H, CH3), 3.03 (s, 3H, CH3); 13C-NMR (DMSO-d6) δ 167.7, 166.8, 152.0,
134.7, 132.5, 131.2, 130.6, 129.3, 75.6, 50.47, 28.8, 28.7; LC/MS (ESI) m/z 374[M]+; Anal. for
C14H13Cl2N3O5; calcd: C, 44.94; H, 3.50; Cl, 18.95; N, 11.23;Found: C, 44.92; H, 3.51; Cl, 18.90; N, 11.25.
5-(1-(4-Methoxyphenyl)-2-nitroethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (3g) According
to the general procedure, 3g was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-methoxy-4-
(2-nitrovinyl) benzene (2g) as an oily product (447 mg, 1.33 mmol, 89%). IR (KBr) ν/cm−1 1738, 1670,
1
1551, 1423, 1228; H-NMR (DMSO-d6) δ 6.96 (d, 2H, J = 8.0 Hz, Ph), 6.85 (d, 2H, J = 8.0 Hz, Ph),
5.41 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.16 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.21 (m, 1H,
CHPh), 4.04 (d, 1H, J = 2.9 Hz, COCHCO), 3.69 (s, 3H, CH3), 2.99 (s, 3H, CH3), 2.93 (s, 3H, CH3);
13C-NMR (DMSO-d6) δ 168.2, 167.7, 159.6, 151.3, 129.1, 126.6, 114.6, 77.0, 55.6,52.4, 44.7,28.4,
28.3 ; LC/MS (ESI) m/z 335[M]+; Anal. for C15H17N3O6; calcd: C, 53.73; H, 5.11; N, 12.53; Found: C,
53.74; H, 5.10; N, 12.52.
1,3-Dimethyl-5-(2-nitro-1-(4-nitrophenyl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3h) According to
the general procedure, 3h was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-nitro-4-(2-
nitrovinyl)benzene (2h) as a dark brown powder (462 mg, 1.32 mmol, 88%); m.p.: 170 °C; IR (KBr)
1
ν/cm−1 1738, 1646, 1551, 1366, 1217; H-NMR (DMSO-d6) δ 7.50 (d, 2H, J = 8.0 Hz, Ph),
7.38 (d, 2H, J = 8.0 Hz, Ph), 5.32 (d, 2H, J = 6.6 Hz, CH2NO2), 5.00 (m, 1H, CHPh), 4.11 (d, 1H,

Molecules 2014, 19
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13
J = 11 Hz, COCHCO), 3.08 (s, 3H, CH3), 3.03 (s, 3H, CH3); C-NMR (DMSO-d6) δ 167.7, 166.8,
152.0, 136.7, 134.7, 132.5, 131.2, 130.6, 129.3, 75.6, 50.4, 28.8, 28.7; LC/MS (ESI) m/z 350[M]+; Anal.
for C14H14N4O7; calcd: C, 48.00; H, 4.03; N, 15.99; Found: C, 48.01; H, 4.01; N, 16.01.
1,3-Dimethyl-5-(2-ferrocenyl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3i) According to the general
procedure, 3i was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-ferrocenyl-2-nitroethene (2i)
as a dark purple powder (595 mg, 1.39 mmol, 93%); m.p.: 139 °C; IR (KBr) ν/cm−1 1738, 1671, 1551,
1423, 1367, 1228; 1H-NMR (DMSO-d6) δ 5.17 (d, 2H, J = 7.3 Hz, CH2NO2), 4.21 (bs, 5H, ferrocene),
4.00 (m, 1H, CH-ferrocene), 3.92 (d, 1H, J = 2.9 Hz, COCHCO), 3.38 (bs, 4H, ferrocene),
13
3.03 (s, 3H, CH3), 2.88 (s, 3H, CH3), 2.93 (s, 3H, CH3); C-NMR (DMSO-d6) δ 168.4, 167.6, 151.4,
83.2, 76.7, 69.4, 69.3, 68.7, 68.3, 67.7, 66.0, 52.2, 28.5, 28.2 ; LC/MS (ESI) m/z 427[M]+; Anal. for
C19H21FeN3O5; calcd: C, 53.41; H, 4.95; N, 9.84; Found: C, 53.42; H, 4.94; N, 9.85.
1,3-Dimethyl-5-(1-nitropropan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (3j) According to the general
procedure, 3j was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-1-nitroprop-1-ene (2j) as a
yellowish oily product (350 mg, 1.44 mmol, 96%). IR (KBr) ν/cm−1 1745, 1665, 1325, 1225;
1H-NMR (DMSO-d6) δ 4.93 (dd, H, J = 11.2, 5.2 Hz, CH2NO2), 4.70 (dd, H, J = 11.2, 5.2 Hz, CH2NO2),
3.98 (d, 1H, J = 2.4, COCHCO), 3.23 (m, 1H, CH), 3.20 (s, 3H, CH3), 3.02 (s, 3H, CH3), 0.95 (d, 3H,
J = 5.6, CH3); 13C-NMR (DMSO-d6) δ 167.4, 167.3, 165.8, 151.4, 78.4, 50.3, 28.2, 27.7, 13.6; LC/MS
(ESI) m/z 244[M]+; Anal. for C9H13N3O5; calcd: C, 44.44; H, 5.39; N, 17.28; Found: C, 44.46; H, 5.40;
N, 17.31.
1,3-Dimethyl-5-(2-nitro-1-(thiophen-2-yl)ethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (3k) According to
the general procedure, 3k was prepared from 1,3-dimethylbarbituric acid (1a) and (E)-2-(2-
nitrovinyl)thiophene (2k) as a brown semisolid product (443 mg, 1.42 mmol, 95%). IR (KBr) ν/cm−1
1767, 1680, 1558, 1343, 1225;1H-NMR (DMSO-d6) δ 7.45 (brs, 1H, thiophene), 6.95 (brs, 1H, thiophene),
6.89 (brs, 1H, thiophene), 5.45 (d, 1H, J = 10.8 Hz, CH2NO2), 5.20 (dd, 1H, J = 16.8, 8.8 Hz,
CH2NO2), 4.66 (brs, 1H, COCHCO), 4.26 (brs, 1H, CHCH2NO2), 3.12 (s, 3H, CH3), 3.05 (s, 3H,
CH3); 13C-NMR (DMSO-d6) δ 169.5, 168.7, 137.9, 135.9, 134.8, 129.8, 79.5, 29.1, 28.5, 27.5;
LC/MS (ESI) m/z 312[M]+; Anal. for C12H13N3O5S; calcd: C, 46.30; H, 4.21; N, 13.50; Found: C,
46.32; H, 4.22; N, 13.48.
6-Hydroxy-5-(2-nitro-1-phenylethyl)pyrimidine-2,4(1H,3H)-dione (3l) According to the general
procedure, 3l was prepared from barbituric acid (1b) and (E)-(2-nitrovinyl)benzene (2a) as a white
powder (401 mg, 1.45 mmol, 97%); m.p.: 165 °C; IR (KBr) ν/cm−1 3204, 3015, 2920, 1740, 1550,
1363, 1217;1H-NMR (DMSO-d6) δ 11.31 (s, 2H, NH), 7.40 (m, 3H, Ph), 7.13 (m, 2H, Ph),
5.44 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.28 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.33 (m, 1H, CHPh);
13C-NMR (DMSO-d6) δ 169.7, 169.5, 150.7, 135.8, 129.3, 128.8, 128.3, 79.7, 77.4, 51.3, 43.6;
LC/MS (ESI) m/z 277 [M]+; Anal. for C12H11N3O5; calcd: C, 51.99; H, 4.00; N, 15.16; Found: C,
52.01; H, 4.02; N, 15.15.
6-Hydroxy-5-(2-nitro-1-(p-tolyl)ethyl)pyrimidine-2,4(1H,3H)-dione compound with diethylamine (1:1)
(3m) According to the general procedure, 3m was prepared from barbituric acid (1b) and

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(E)-1-methyl-4-(2-nitrovinyl)benzene (2b) as a white powder (513 mg, 1.41 mmol, 94%); m.p.: 210 °C;
1
IR (KBr) ν/cm−1 3210, 3015, 1738, 1686, 1574, 1374; H-NMR (DMSO-d6) δ 9.22 (s, 2H, NH), 7.27
(d, 2H, J = 8.0 Hz, Ph), 6.99 (d, 2H, J = 8.0 Hz, Ph), 5.35 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2),
5.09 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.74(m, 1H, CHPh), 2.92 (m, 1H and 4H, COCHCO and
CH3CH2NHCH2CH3), 2.21 (s, 3H, CH3), 1.14 (t, 6H, J = 7.3 Hz, CH3CH2NHCH2CH3);
13C-NMR (DMSO-d6) δ 164.7, 152.5, 141.2, 135.0, 128.7, 128.1, 85.0, 79.5, 41.9, 21.1, 11.5; LC/MS
(ESI) m/z 364[M]+; Anal. for C15H17N3O5; calcd: C, 56.03; H, 6.64; N, 15.38; Found: C, 56.05; H,
6.65; N, 15.39.
5-(1-(4-Bromophenyl)-2-nitroethyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (3n) According to the
general procedure, 3n was prepared from barbituric acid (1b) and (E)-1-bromo-4-(2-nitrovinyl)
benzene (2c) as a yellow powder (566 mg, 1.32 mmol, 88%); m.p.: 130 °C; IR (KBr) ν/cm−1: 3204, 3015,
2920, 1740, 1550, 1363, 1217; 1H-NMR (DMSO-d6) δ 9.22 (s, 2H, NH), 7.42 (d, 2H, J = 8.0 Hz, Ph),
7.18 (d, 2H, J = 8.0 Hz, Ph), 5.42 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.27 (m, 2H, CH2NO2 and CHPh);
13C-NMR (DMSO-d6) δ 169.5, 169.3, 150.7, 135.1, 133.4, 130.3, 129.3, 79.7, 77.1, 51.3, 33.2; LC/MS
(ESI) m/z 356 [M]+; Anal. for C12H10BrN3O5; calcd: C, 40.47; H, 2.83; Br, 22.44; N, 11.80; Found: C,
40.50; H, 2.85; Br, 22.45; N, 11.83.
5-(1-(4-Chlorophenyl)-2-nitroethyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (3o) According to the
general procedure, 3o was prepared from barbituric acid (1b) and (E)-1-chloro-4-(2-nitrovinyl) benzene
(2d) as a white powder (512 mg, 1.33 mmol, 89%); m.p.: 80 °C; IR (KBr) ν/cm−1 3208, 3018, 2980, 1740,
1699, 1555, 1363, 1217; 1H-NMR (DMSO-d6) δ 9.22 (s, 2H, NH), 7.55 (m, 4Ph), 5.37 (dd, 1H, J = 13.9
13
Hz, CH2NO2), 5.07 (dd, 1H, J = 13.9 Hz, CH2NO2), 4.73 (m, 1H, CHPh); C-NMR (DMSO-d6) δ
164.4, 152.3, 143.5, 132.2, 131.8, 131.4, 130.5, 119.2, 84.8, 78.9, 29.4; LC/MS (ESI) m/z 311 [M]+;
Anal. for C12H10ClN3O5; calcd:C, 46.24; H, 3.23; Cl, 11.37; N, 13.48; Found: C, 46.21; H, 3.22; Cl,
11.40; N, 13.45.
5-(1-(2,4-Dichlorophenyl)-2-nitroethyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione
compound
with
diethylamine (1:1) (3p) According to the general procedure, 3p was prepared from barbituric acid (1b) and
(E)-2,4-dichloro-1-(2-nitrovinyl)benzene (2e) as a beige powder (534 mg, 1.27 mmol, 85%); m.p.: 190 °C;
1
IR (KBr) ν/cm−1 3151, 2986, 1697, 1590, 1376; H-NMR (DMSO-d6) δ 9.18 (s, 2H, NH), 8.30 (bs, 1H,
OH), 7.83 (d, 2H, J = 8.8 Hz, Ph), 7.44(s, 1H, Ph), 7.30 (d, 2H, J = 8.8 Hz, Ph), 5.35 (dd, 1H, J = 13.9,
5.8 Hz, CH2NO2), 5.14 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.90 (m, 1H, CHPh), 2.92 (m, 1H and 4H,
COCHCO and CH3CH2NHCH2CH3), 2.21 (s, 3H, CH3), 1.14 (t, 6H, J = 7.3 Hz, CH3CH2NHCH2CH3);
13C-NMR (DMSO-d6) δ 165.0, 152.5, 140.2, 134.1, 132.7, 131.7, 128.5, 127.3, 82.5, 77.3, 41.9, 21.1, 11.5;
LC/MS (ESI) m/z 419 [M]+; Anal. for C16H20Cl2N4O5; calcd: C, 45.84; H, 4.81; Cl, 16.91; N, 13.36;
Found: C, 45.87; H, 4.83; Cl, 16.90; N, 13.35.
5-(1-(2,6-Dichlorophenyl)-2-nitroethyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (3q) According to the
general procedure, 3q was prepared from barbituric acid (1b) and (E)-2,6-dichloro-1-(2-nitrovinyl)
benzene (2f) as a yellow powder (540 mg, 1.29 mmol, 86%); m.p.: 130 °C; IR (KBr) ν/cm−1 3155,
2986, 1740, 1670, 1551, 1423, 1228;1H-NMR (DMSO-d6) δ 11.38 (s, 2H, NH), 7.63 (d, 2H,
J = 8.8 Hz, Ph), 7.46 (s, 1H, Ph), 7.36 (d, 2H, J = 8.8 Hz, Ph), 5.37 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2),

Molecules 2014, 19
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13
5.25 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 5.04 (m, 1H, CHPh); C-NMR (DMSO-d6) δ 169.6, 168.4,
151.3, 133.1, 130.9, 129.8, 129.2, 75.8, 49.2; LC/MS (ESI) m/z 419 [M]+; Anal. for C12H9Cl2N3O5;
calcd: C, 41.64; H, 2.62; Cl, 20.49; N, 12.14; Found: C, 41.65; H, 2.61; Cl, 20.50; N, 12.13.
6-Hydroxy-5-(1-(4-methoxyphenyl)-2-nitroethyl)pyrimidine-2,4(1H,3H)-dione
compound
with
diethylamine (1:1) (3r) According to the general procedure, 3r was prepared from barbituric acid (1b)
and (E)-4-methoxy-1-(2-nitrovinyl)benzene (2g) as a yellow powder (501 mg, 1.32 mmol, 88%);
1
m.p.: 152 °C; IR (KBr) ν/cm−1 3459, 3016, 2970, 1740, 1571, 1365; H-NMR (DMSO-d6) δ 9.07 (s,
2H, NH), 7.32 (d, 2H, J = 8.8 Hz, Ph), 6.75(s, 1H, Ph), 7.30 (d, 2H, J = 8.8 Hz, Ph), 5.31 (dd, 1H,
J = 13.9, 5.8 Hz, CH2NO2), 5.06 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.68 (m, 1H, CHPh), 3.68 (s,
3H, OCH3), 2.93 (m, 1H and 4H, COCHCO and CH3CH2NHCH2CH3), 1.15 (t, 6H, J = 7.3 Hz,
CH3CH2NHCH2CH3); 13C-NMR (DMSO-d6) δ 164.6, 157.9, 152.5, 136.4, 129.3, 113.5, 85.0, 79.8,
55.4, 41.9, 11.6; LC/MS (ESI) m/z 380[M]+; Anal. for C17H24N4O6; calcd: C, 53.68; H, 6.36; N, 14.73;
Found: C, 53.68; H, 6.36; N, 14.73.
5-(2-Ferrocenyl)ethyl)6-Hydroxypyrimidine-2,4(1H,3H)-dione compound with diethylamine (1:1) (3s)
According to the general procedure, 3s was prepared from barbituric acid (1b) and (E)-1-ferrocenyl-2-
nitroethene (2i) as a brown powder (550 mg, 1.38 mmol, 92%); m.p.: 190 °C; IR (KBr) ν/cm−1 3449,
3016, 2970, 1738, 1546, 1365, 1217;1H-NMR (DMSO-d6) δ 8.98 (s, 2H, NH), 5.16 (t, 1H, J = 9.5 Hz,
CH2NO2), 4.89 (dd, 1H, J = 13.9, 5.8 Hz, CH2NO2), 4.53(m, 1H, CHPh), 4.25-3.93 (m, 10H, ferrocene
and COCHCO), 2.92 (bs, 4H, CH3CH2NHCH2CH3), 1.15 (bs, 6H, CH3CH2NHCH2CH3);
13C-NMR (DMSO-d6) δ 164.5, 152.5, 92.3, 84.7, 79.6, 69.3, 68.8, 67.8, 66.7, 66.4, 41.8, 34.7, 11.6;
LC/MS (ESI) m/z 399 [M]+; Anal. for C17H17FeN3O5; calcd: C, 51.15; H, 4.29; N, 10.53; Found: C,
51.17; H, 4.30; N, 10.54.
6-Hydroxy-5-(2-nitro-1-(4-nitrophenyl)ethyl)pyrimidine-2,4(1H,3H)-dione
compound
with
diethylamine (1:1) (3t). According to the general procedure, 3t was prepared from barbituric acid (1b)
and (E)-4-nitro-1-(2-nitrovinyl)benzene (2h) as a yellow powder (515 mg, 1.3 mmol, 87%); m.p.: 185 °C;
IR (KBr) ν/cm−1 3445, 3015, 2970, 1738, 1575, 1373, 1216;1H-NMR (DMSO-d6) δ 9.18 (s, 2H, NH),
8.13(d, 1H, J = 7.3 Hz, Ph), 7.70(d, 1H, J = 8.0 Hz, Ph), 7.56(t, 1H, J = 8.0 Hz, Ph), 7.36(t, 1H, J = 7.3
Hz, Ph), 5.57(dd, 1H, J = 11.7, 8.0 Hz, CH2NO2), 5.11 (t, 1H, J = 8.0 Hz, COCHCO), 5.06 (dd, 1H,
J = 11.7, 8.0 Hz, CH2NO2), 3.37 (bs, 1H, CHPh), 2.90 (q, J = 7.3 Hz, 4H, CH3CH2NHCH2CH3),
1.13 (t, 6H, J = 7.3 Hz, CH3CH2NHCH2CH3); 13C-NMR (DMSO-d6) δ 164.9, 152.5, 149.5, 138.6,
133.0, 131.4, 127.6, 123.6, 84.5, 78.0, 41.9, 35.1, 11.5; LC/MS (ESI) m/z 395[M]+; Anal. for
C16H21N5O7; calcd: C, 48.61; H, 5.35; N, 17.71; Found: C, 48.59; H, 5.34; N, 17.68.
4. Conclusions
A very convenient procedure for the syntheses of pyrimidine derivatives by Michael addition of
cyclic 1,3-dicarbonyl compounds to a range of nitroalkenes using a simple NHEt2/H2O medium has
been developed. The reaction scope is substantial and a number of substituted barbituric acids and
nitroalkenes could be successfully applied to give multifunctional pyrimidine derivatives. These
reactions gave high yields of products in short periods of time. The study of the full scope of this

Molecules 2014, 19
1160
asymmetric transformation and its application in the synthesis of biologically active molecules are
currently underway in our laboratory.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/19/1/1150/s1.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for funding the work through the research group project Number RGP-VPP-257.
Author Contributions
A.B. proposed the subject, designed the study. H.J.A.-N. and M.W. carried out the synthesis of all
the products. A.M.A.-M. and Y.N.M. monitor progress of the ongoing research of the proposed
project, helped in the results and discussion. H.G. and H.-K.F. carried out the X-ray crystallography part.
A.B. prepared draft the manuscript. All the authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 3a–t are available from the authors.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).