Novel multicomponent reactions of primary amines and alkyl propiolates with alloxan derivatives in water

Article abstract of DOI:10.1016/j.tet.2008.08.039

A water-accelerated multicomponent synthesis of organic target molecules has been used as a key method for the preparation of novel barbiturate derivatives. The three-component condensation reactions of primary amines with alkyl propiolates in the presence of alloxan derivatives in water are developed as efficient and clean green synthetic procedures for the high-yielding preparation of alkyl 2-(5-hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-(alkyl or arylamino)-2-propenoates. The above synthetic protocol provides rapid access to novel and diversely substituted barbiturate derivatives.

Full text of DOI:10.1016/j.tet.2008.08.039

Tetrahedron 64 (2008) 10425–10430
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel multicomponent reactions of primary amines and alkyl propiolates
with alloxan derivatives in water
,
b
c
Mohammad Bagher Teimouri a , Tayyebeh Abbasi , Houri Mivehchi
*
a Petrochemical Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran
b Department of Chemistry, University of Zanjan, PO Box 45195-313, Zanjan, Iran
c Novel Drug Delivery Systems Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 June 2008
Received in revised form 28 July 2008
Accepted 14 August 2008
Available online 16 August 2008
A water-accelerated multicomponent synthesis of organic target molecules has been used as a key
method for the preparation of novel barbiturate derivatives. The three-component condensation re-
actions of primary amines with alkyl propiolates in the presence of alloxan derivatives in water are
developed as efficient and clean green synthetic procedures for the high-yielding preparation of alkyl
2-(5-hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-(alkyl or arylamino)-2-propenoates. The above
synthetic protocol provides rapid access to novel and diversely substituted barbiturate derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Amine
Alkyl propiolate
Alloxan
Barbiturate
Multicomponent reaction
1. Introduction
bearing animals5 and, more recently, to induce apoptosis in the
tumour cells.6,7
Barbiturates have attracted the attention of pharmaceutical
community for more than a century due to their therapeutic value.1
Barbiturate derivatives are widely used as sedative hypnotic drugs
under a variety of conditions and are also employed for anaesthe-
sia.2 For example, barbiturates like phenobarbital (Luminal) 1 and
pentobarbital (Nembutal) 2 were long used as anxiolytics and
hypnotics (Fig. 1). Moreover, phenobarbital is the most widely used
anticonvulsant worldwide and the oldest still in use. Slight struc-
tural modifications in many depressant barbiturates produce
compounds with excitatory or convulsant activity, e.g., 5-benzyl-5-
ethylbarbituric acid 3, a homologue of phenobarbital. The structure
and conformation of the C-5 side chains of the barbiturates have
been suggested to be determinants of the different biological
activities. Many 5,5-disubstituted barbituric acid derivatives have
been synthesized in an effort to develop a structure–activity
relationship for these compounds. For instance, Ro 28-2653 43
belongs to a new barbiturate class of matrix metalloproteinase
(MMP) inhibitors with high selectivity for the gelatinases A and B
(MMP-2 and MMP-9), which have been implicated in tumour
growth and metastasis.3,4 Preclinically, Ro 28-2653 has been shown
to reduce tumour growth and extend survival time of tumour-
One of the powerful tools used to combine economic aspects
with the environmental concerns is performing organic reactions in
water; this strategy consists of two or more synthetic steps, which
are carried out in water as a cheap, nontoxic, environmentally
friendly solvent, in a one-step reaction, without isolation of any
intermediate thus reducing time, saving money, energy and raw
materials.8 Although, production of a contaminated aqueous waste
stream can have significant economic impacts, for example, con-
centration of contaminated water streams by distillation is very
energy intensive compared to say concentration of propanol waste
stream.9 However, the development and implementation of pro-
cesses using water as solvent may serve as one avenue for lowering
NO2
N
N
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
N
N
N
N
N
N
N
N
H
O
O
O
O
4
1
2
3
* Corresponding author. Tel.: þ98 21 44580000; fax: þ98 21 44580032.
E-mail address: m.teimouri@ippi.ac.ir (M.B. Teimouri).
Figure 1. Selected examples of biologically active barbiturates.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.039

10426
M.B. Teimouri et al. / Tetrahedron 64 (2008) 10425–10430
Table 1
Table 1 (continued)
Three-component condensation reactions of primary amines, alkyl propiolates and
alloxan derivatives
Entry
R
R0
R00
Product
Yielda (%)
H O
OR'
N
H
O
-Pr
n
N
OEt
OH
R
O
CO2R'
O
H
O
O
H
H
H2O
r.t., 30 min.
O
O
9
n-Propyl
Ethyl
H
O
O
88
R
NH2
+
+
N
N
R"
R"
N
N
N
N
R"
R"
H
8i
H
O
H
O
8
O
5
6
7
H
O
Entry
R
R0
R00
Product
Yielda (%)
-
1
Ada
N
OEt
OH
H
O
-
i
H
Bu
N
OMe
OH
10
11
12
13
14
15
1-Adamantyl
Ethyl
Ethyl
Ethyl
H
H
H
O
O
81
95
76
80
89
90
H
N
N
1
iso-Butyl
Methyl
Methyl
Methyl
Methyl
H
H
H
H
O
O
82
H
8j
H
O
N
N
H
8a
H
O
H
O
H
O
Allyl
N
OEt
OH
Bn
N
OMe
OH
H
H
Allyl
O
O
O
O
2
3
4
Benzyl
85
91
77
N
N
N
N
H
8k
H
H
8b
H
O
O
O
H
n-Hex
N
OMe
OH
H
O
N
OEt
OH
C6H5
H
n-Hexyl
O
O
H
H
Phenyl
Benzyl
n-Hexyl
Allyl
O
O
N
N
H
8c
N
N
O
H
8l
H
O
H
O
N
OMe
OH
C6H5
H
H
O
O
O
Phenyl
Bn
N
OMe
OH
N
N
H
8d
H
H
Methyl Methyl
Methyl Methyl
Methyl Methyl
O
O
O
N
N
Me
8m
Me
H
O
O
N
OMe
OH
4-OH-C6H4
H
5
6
7
4-Hydroxyphenyl Methyl
H
H
H
O
O
H
84
79
93
H
O
N
N
n
-Hex
N
OMe
OH
H
8e
O
H
O
O
H
O
i-Bu
N
N
N
OEt
OH
Me
8n
Me
O
H
iso-Butyl
Ethyl
O
O
N
N
H
8f
H
H
O
O
Allyl
N
OMe
OH
H
O
H
Bn
N
OEt
O
O
OH
N
N
H
Me
8o
Benzyl
Ethyl
O
Me
O
N
N
H
8g
H
O
H
O
H
O
-Bu
i
n-Hex
N
OEt
OH
N
H
OEt
OH
H
O
O
16
iso-Butyl
Ethyl
Methyl
75
O
O
H
8
n-Hexyl
Ethyl
H
90
N
N
N
N
Me
8p
Me
H
8h
O
O

M.B. Teimouri et al. / Tetrahedron 64 (2008) 10425–10430
10427
Table 1 (continued )
indicated the formation of these novel hydroxy barbiturates 8. All
the products were characterized by FTIR, 1H and 13C NMR spectra,
and elemental analysis. The reaction can be represented as in
Table 1.
Entry
R
R0
R00
Product
Yielda (%)
H
O
Bn
N
OEt
OH
The scope and limitations of this simple process were explored
by using two alkyl propiolates, two alloxan derivatives and a wide
range of primary amines. A variety of structurally diverse amines
underwent the one-pot reaction smoothly without using any cat-
alyst to afford the corresponding barbiturate derivatives in good to
high yields. As shown in Table 1, the allylic, benzylic, hindered and
unhindered primary amines are used in this protocol with excellent
results. Moreover, aromatic primary amines give the corresponding
barbiturates in good yields. Thus, a diverse set of biologically useful
barbiturate products can be potentially prepared in one step by this
method. However, secondary amines such as morpholine and thio-
morpholine have not participated in the reaction. We also tried to
take advantage of 25% aqueous ammonia, 50% aqueous hydroxyl-
amine and phenylhydrazine as the amine component. Un-
fortunately, the reaction of alloxan and methyl propiolate with each
of these NH2-containing compounds did not afford the desired
barbiturate under the same reaction conditions.
Although the mechanism of the reaction between a primary
amine and alkyl propiolate in the presence of alloxan has not yet
been established experimentally, a plausible explanation is depic-
ted in Figure 2. On the basis of the well established chemistry of
trivalent nitrogen nucleophiles, the successful nucleophilic attack
by amines on a carbon atom is facilitated when the latter is con-
jugated with a carbonyl group or when it is part of an unsaturated
bond otherwise activated. Therefore, the first step may involve
nucleophilic addition of the primary amine to the alkyl propiolate
H
17
Benzyl
Ethyl
Methyl
O
O
84
N
N
Me
8q
Me
O
H
O
N
OEt
OH
C6H5
H
18
Phenyl
Ethyl
Methyl
O
O
72
N
N
Me
8r
Me
O
a
Refers to purified yield. Compound purity is >95% as determined by 1H NMR.
both the environmental impact of the chemical industry and the
hundred billion dollar costs associated with environmental regu-
lation compliance.10 Moreover, multicomponent condensation re-
actions due to their productivity, simple procedures, convergence
and facile execution are one of the important strategies in combi-
natorial chemistry.11 Therefore, the discovery and development of
novel multicomponent reactions have attracted great attention
from research groups working in various areas such as drug dis-
covery, organic synthesis and material science. As a result, one-pot
multicomponent reactions in organic chemistry have expanded
rapidly.12
Continuing our efforts directed towards the straightforward
preparation of biologically active target molecules through multi-
component reactions,13 we performed the synthesis of some novel
barbiturates via a three-component reaction of primary amines,
alkyl propiolates and alloxan derivatives at room temperature by
employing water as the reaction medium. In fact, as clearly stated
by Sheldon, it is generally recognized that ‘‘the best solvent is no
solvent and if a solvent (diluent) is needed then water is pre-
fered’’.14 The use of water as a reaction medium represents re-
markable benefits since this green solvent is highly polar and
therefore immiscible with most organic compounds; moreover, the
water-soluble by-products reside and separation of the organic
materials is thus easy. A further advantage is that many organic
reactions exhibit rate enhancement in water.15
and formation of the
b-aminoacrylate 9 as an electron-rich en-
amine.16 The central carbonyl groups of the cyclic vicinal triones
such as alloxan derivatives possess outstanding electrophilic
(electron-pair-accepting) properties.17 The polar reactions with
carbanion-like (electron rich) species such as enamines give rise to
nucleophilic addition reactions to carbonyl groups under exclusive
C–C bond formation.18 Subsequent nucleophilic attack of
b-ami-
noacrylate 9 to the central carbonyl group of the alloxan 7 would
yield iminium-oxyanion intermediate 10 that can be tautomerized
to product 8.
The key step in the synthesis is an efficient component reaction
of a primary amine with an alkyl propiolate to give a b-amino-
acrylate derivative, which then reacts with alloxans. In order to
confirm the route mechanism of the reaction in Figure 2, via the
formation of
reaction, 3-isobutylaminomethylacrylate 9a as a representative
-aminoacrylate was synthesized separately by the condensation of
b-aminoacrylate intermediate in the first stage of the
2. Results and discussion
b
isobutylamine and methyl propiolate. Then, we examined the re-
action of the isolated 3-isobutylaminomethylacrylate with 1 equiv
of alloxan in water and we obtained the product 8a in 85%.
In conclusion, we have developed a novel one-pot, three-com-
ponent reaction for the preparation of barbiturates of potential
synthetic and pharmacological interest. Excellent yields, a simple
purification process, short reaction times, one pot, 100% atom
In the present investigation, a mixture of primary amine 5, alkyl
propiolate 6 and alloxan derivative 7 in a 1:1:1 molar ratio in water
was vigorously stirred at room temperature for 30 min. After
completion of the reaction (TLC analysis), the mixture was filtered
to afford the corresponding alkyl 2-(5-hydroxy-2,4,6-trioxohexa-
hydro-5-pyrimidinyl)-3-(alkyl or arylamino)-2-propenoates 8 in
high yields. 1H and 13C NMR spectra of the crude products clearly
O
O
O
H O
N
N
H
R
N
OR'
CO2R'
R"
R"
..
iminium-enamine
tautomrization
O
RNH
H
7
..
O
H
8
R
NH2
O
O
+
H
CO2R'
9
N
N
5
H
6
R"
R"
10
O
Figure 2. Possible mechanism for the formation of products 8.

10428
M.B. Teimouri et al. / Tetrahedron 64 (2008) 10425–10430
efficiency and finally using water as a cheap, nontoxic, environ-
mentally friendly solvent are the main advantages of this method.
This method appears to have broad scope with respect to variations
of primary amines, alkyl propiolates and alloxan derivatives, and
presents a straightforward procedure for the efficient synthesis of
novel biologically active barbiturates.
NHCONH); dC (100.7 MHz, DMSO-d6) 172.3, 167.1, 151.7, 150.6, 91.1,
71.9, 50.6, 49.0, 31.4, 26.1, 22.5, 14.4. Anal. Calcd for C14H21N3O6
(327.33): C, 51.37; H, 6.47; N, 12.84%. Found: C, 51.42; H, 6.44; N,
12.87%.
3.2.3. Methyl 3-(phenylamino)-2-(5-hydroxyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8d)
3. Experimental
3.1. General
White powder (0.246 g, 77%); mp 208–210 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3400 (O–H), 3225, 3110 (N–H), 1766, 1729, 1667 (C]O); dH
(400.1 MHz, DMSO-d6) 3.58 (3H, s, OCH3), 6.99–7.34 (5H, m, C6H5),
7.49 (1H, s, OH), 7.75 (1H, d, J 13.4 Hz, ]CH–NH), 9.48 (1H, d, J
13.4 Hz, ]CH–NH/O]C), 11.32 (2H, s, NHCONH); dC (100.7 MHz,
DMSO-d6) 171.3, 166.9, 150.5, 142.4, 141.2, 130.1, 123.2, 116.3, 97.6,
72.1, 51.5. Anal. Calcd for C14H13N3O6 (319.27): C, 52.67; H, 4.10; N,
13.16%. Found: C, 52.74; H, 4.01; N, 13.20%.
Melting points were measured on a Bu¨chi 535 apparatus and are
uncorrected. Elemental analyses were performed using a Heraeus
CHN-O-Rapid analyzer. FTIR spectra were recorded on a Bruker
Equinox-55 spectrometer. 1H and 13C NMR spectra were recorded
on
a Bruker DRX-400 Avance spectrometer at 400.13 and
100.77 MHz, respectively, with CDCl3, CD3COCD3 or CD3SOCD3 as
solvent and calibrated using residual undeuterated solvent as an
internal reference. Analytical TLC was carried out on precoated
plates (Merck silica gel 60, F254) and visualized with UV light. All
chemical reagents were obtained from Aldrich, Merck, Fluka or
Acros, and were used without further purification.
3.2.4. Methyl 3-(4-hydroxyanilino)-2-(5-hydroxyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8e)
White powder (0.281 g, 84%); mp 200–202 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3335, 3308 (O–H), 3294 (N–H), 1719, 1701, 1678 (C]O); dH
(400.1 MHz, DMSO-d6) 3.55 (3H, s, OCH3), 6.73 and 7.02 (4H, 2d, J
8.8 Hz, C6H4OH), 7.36 (1H, s, OH), 7.60 (1H, d, J 13.6 Hz, ]CH–NH),
9.23 (1H, s, C6H4OH), 9.35 (1H, d, J 13.6 Hz, ]CH–NH/O]C), 11.30
(2H, s, NHCONH); dC (100.7 MHz, DMSO-d6) 171.8, 166.9, 153.9,
150.5, 143.8, 133.4, 118.2, 116.5, 95.7, 72.1, 51.3. Anal. Calcd for
3.2. Typical procedure for the preparation of methyl 2-(5-
hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-
(isobutylamino)-2-propenoate (8a)
C14H13N3O7 (335.27): C, 50.15; H, 3.91; N,12.53%. Found: C, 50.10; H,
3.90; N, 12.58%.
To a magnetically stirred solution of isobutylamine (0.073 g,
1.0 mmol) and methyl propiolate (0.084 g, 1.0 mmol) in water
(5 mL) was added alloxan (0.160 g, 1.0 mmol) at room temperature
(25 ꢀC) and stirring was continued for about 30 min. The comple-
tion of reaction was confirmed by TLC (EtOAc–hexane 2:1). The
resulting solid was removed by filtration, washed with water
(5 mL) and diethylether (1 mL) and dried at 80 ꢀC in air to give 8a as
a white powder (0.327 g, 72%). The dried product thus obtained
showed a single spot on TLC and was pure enough for all analytical
purposes.
3.2.5. Ethyl 2-(5-hydroxy-2,4,6-trioxohexahydro-5-pyrimidinyl)-3-
(isobutylamino)-2-propenoate (8f)
White powder (0.248 g, 79%); mp 179–181 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3265 (O–H), 3100 (N–H), 1728, 1705, 1630 (C]O); dH
(400.1 MHz, DMSO-d6) 1.36 (6H, d, J 6.7 Hz, CH(CH3)2), 1.56 (3H, t, J
7.1 Hz, OCH2CH3), 2.22–2.26 (1H, m, CH(CH3)2), 3.59 (2H, dd, J 5.7,
6.9 Hz, N–CH2), 4.39 (2H, q, J 6.7 Hz, OCH2), 7.11 (1H, s, OH), 7.72
(1H, d, J 13.6 Hz, ]CH–NH), 8.42 (1H, br d, ]CH–NH/O]C), 11.16
(2H, s, NHCONH); dC (100.7 MHz, DMSO-d6þacetone-d6) 172.3,
167.2, 153.2, 150.5, 92.0, 72.5, 59.2, 56.8, 30.4, 19.6, 13.9. Anal. Calcd
for C13H19N3O6 (313.30): C, 49.84; H, 6.11; N, 13.41%. Found: C,
49.90; H, 6.07; N, 13.48%.
White powder (0.188 g, 82%); mp 200–202 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3335 (O–H), 3300, 3240, 3115 (N–H), 1768, 1704, 1646
(C]O); dH (400.1 MHz, CDCl3) 0.85 (6H, d, J 5.2 Hz, CH(CH3)2), 1.67–
1.72 (1H, m, CH(CH3)2), 3.02 (2H, dd, J 5.5, 5.6 Hz, N–CH2), 3.44 (3H,
s, OCH3), 7.10 (1H, s, OH), 7.12 (1H, d, J 17.1 Hz, ]CH–NH), 7.72 (1H,
br d, ]CH–NH/O]C), 11.15 (2H, s, NHCONH); dC (100.7 MHz,
CDCl3) 171.8, 167.2, 152.3, 150.6, 91.0, 71.8, 56.5, 50.7, 30.0, 20.5.
Anal. Calcd for C12H17N3O6 (229.28): C, 48.16; H, 5.73; N, 14.04%.
Found: C, 48.24; H, 5.70; N, 13.97%.
3.2.6. Ethyl 3-(benzylamino)-2-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8g)
White powder (0.323 g, 93%); mp 170–172 ꢀC; FTIR (KBr)
(
nmax, cmꢁ1): 3323 (O–H), 3212 (N–H), 1723, 1698, 1677 (C]O);
dH (400.1 MHz, DMSO-d6) 1.10 (3H, t, J 7.0 Hz, OCH2CH3), 3.96
(2H, q, J 6.6 Hz, OCH2), 4.52 (2H, d, J 6.0 Hz, N–CH2), 7.27–7.41
(6H, m, OHþC6H5), 7.43 (1H, d, J 13.6 Hz, ]CH–NH), 8.23–8.24
(1H, m, ]CH–NH/O]C), 10.84 (2H, s, NHCONH); dC (100.7 MHz,
DMSO-d6þacetone-d6) 171.8, 166.7, 152.3, 150.2, 139.7, 128.5,
127.5, 127.2, 92.6, 72.0, 58.8, 52.2, 13.9. Anal. Calcd for
3.2.1. Methyl 3-(benzylamino)-2-(5-hydroxy-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8b)
White powder (0.283 g, 85%); mp 180–182 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3277 (O–H), 3113 (N–H), 1769, 1703, 1670 (C]O); dH
(400.1 MHz, DMSO-d6) 3.39 (3H, s, OCH3), 4.41 (2H, d, J 5.6 Hz, N–
CH2), 7.17 (1H, s, OH), 7.24–7.58 (6H, m, ]CH–NH and C6H5), 8.00–
8.05 (1H, m, ]CH–NH/O]C), 11.19 (2H, s, NHCONH); dC
(100.7 MHz, DMSO-d6) 172.3, 167.2, 151.6, 150.6, 140.1, 129.0, 127.8,
127.5, 92.1, 71.9, 52.2, 50.8. Anal. Calcd for C15H15N3O6 (333.29): C,
54.06; H, 4.54; N, 12.61%. Found: C, 53.97; H, 4.60; N, 12.58%.
C16H17N3O6 (347.32): C, 55.33; H, 4.93; N, 12.10%. Found: C,
55.40; H, 4.95; N, 12.05%.
3.2.7. Ethyl 3-(hexylamino)-2-(5-hydroxy-2,4,6-trioxohexahydro-
5-pyrimidinyl)-2-propenoate (8h)
White powder (0.307 g, 90%); mp 172–174 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3313 (O–H), 3210 (N–H), 1720, 1694, 1661 (C]O); dH
(400.1 MHz, DMSO-d6) 0.82 (3H, br s, CH2CH3), 1.01 (3H, t, J 7.0 Hz,
OCH2CH3), 1.22–1.26 and 1.43–1.47 (8H, 2 m, 4CH2), 3.17–3.19 (2H,
m, N–CH2), 3.86 (2H, q, J 7.0 Hz, OCH2CH3), 7.06 (1H, s, OH), 7.13 (1H,
d, J 13.7 Hz, ]CH–NH), 7.75–7.79 (1H, br m, ]CH–NH/O]C), 11.16
(2H, s, NHCONH); dC (100.7 MHz, DMSO-d6) 172.5, 166.6, 152.2,
150.6, 91.1, 71.7, 59.1, 48.9, 31.4, 31.3, 26.1, 22.5, 14.3, 14.1. Anal. Calcd
for C15H23N3O6 (341.36): C, 52.78; H, 6.79; N, 12.31%. Found: C,
52.70; H, 6.73; N, 12.38%.
3.2.2. Methyl 3-(hexylamino)-2-(5-hydroxy-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8c)
White powder (0.298 g, 91%); mp 149–151 ꢀC; FTIR (KBr)
(
nmax, cmꢁ1): 3354 (O–H), 3249 (N–H), 1770, 1714, 1670 (C]O); dH
(400.1 MHz, DMSO-d6) 0.84 (3H, t, J 7.0 Hz, CH2CH3), 1.20–1.25
and 1.43–1.48 (8H, 2m, 4CH2), 3.18 (2H, dt, J 6.5, 6.4 Hz, N–CH2),
3.40 (3H, s, OCH3), 7.10 (1H, s, OH), 7.13 (1H, d, J 14.0 Hz, ]CH–
NH), 7.62–7.66 (1H, br m, ]CH–NH/O]C), 11.15 (2H, s,

M.B. Teimouri et al. / Tetrahedron 64 (2008) 10425–10430
10429
3.2.8. Ethyl 3-(propylamino)-2-(5-hydroxy-2,4,6-trioxohexahydro-
5-pyrimidinyl)-2-propenoate (8i)
CDCl3) 0.85 (3H, t, J 5.0 Hz, CH2CH3), 1.26–1.30 and 1.53–1.58 (8H,
2m, 4CH2), 3.20–3.24 (2H, m, N–CH2), 3.29 (6H, s, 2NCH3), 3.55 (3H,
s, OCH3), 7.24 (1H, s, OH), 7.50 (1H, d, J 13.9 Hz, ]CH–NH), 7.96–
8.02 (1H, m, ]CH–NH/O]C); dC (100.7 MHz, CDCl3) 170.8, 166.8,
153.3, 151.2, 92.1, 72.3, 51.1, 49.6, 31.4, 31.0, 29.0, 26.2, 22.5, 14.0.
Anal. Calcd for C16H25N3O6 (355.38): C, 54.08; H, 7.09; N, 11.82%.
Found: C, 54.05; H, 7.14; N, 11.77%.
White powder (0.263 g, 88%); mp 171–175 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3360 (O–H), 3239 (N–H), 1703, 1655 (C]O); dH (400.1 MHz,
DMSO–d6) 0.84 (3H, t, J 7.3 Hz, CH2CH3), 1.01 (3H, t, J 7.0 Hz,
OCH2CH3), 1.47–1.51 (2H, m, CH2CH3), 3.15–3.19 (2H, m, N–CH2),
3.88 (3H, q, J 7.0 Hz, OCH2CH3), 7.08 (1H, s, OH), 7.15 (1H, d, J
13.9 Hz, ]CH–NH), 7.79–7.83 (1H, br m, ]CH–NH/O]C), 11.18
(2H, s, NHCONH); dC (100.7 MHz, DMSO-d6) 172.5, 166.6, 152.3,
150.6, 91.1, 79.6, 71.6, 59.1, 50.6, 24.6, 14.2, 11.4. Anal. Calcd for
3.2.14. Methyl 3-(allylamino)-2-(5-hydroxyl-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8o)
C
12H17N3O6 (299.28): C, 48.16; H, 5.73; N, 14.04%. Found: C, 48.22;
White powder (0.280 g, 90%); mp 126–128 ꢀC; FTIR (KBr) (nmax
,
H, 5.66; N, 13.98%.
cmꢁ1): 3563 (O–H), 3460 (N–H), 1730, 1704, 1666 (C]O); dH
(400.1 MHz, acetone-d6) 3.20 (6H, s, 2NCH3), 3.49 (3H, s, OCH3),
3.93–3.96 (2H, m, N–CH2), 5.14 and 5.24 (2H, 2dd, J 17.1, 10.2, 1.5 Hz,
–CH]CH2), 5.77 (1H, s, OH), 5.92–5.96 (1H, m, –CH]CH2), 7.39 (1H,
d, J 13.8 Hz, ]CH–NH), 7.84–7.88 (1H, br m, ]CH–NH/O]C); dC
(100.7 MHz, DMSO-d6þacetone-d6) 170.4, 152.5, 151.8, 135.8, 115.7,
115.4, 50.8, 50.7, 50.5, 50.0, 28.0. Anal. Calcd for C13H17N3O6
(311.29): C, 50.16; H, 5.50; N, 13.50%. Found: C, 50.21; H, 5.53; N,
13.46%.
3.2.9. Ethyl 3-(adamantylamino)-2-(5-hydroxyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8j)
White powder (0.317 g, 81%); mp 232–234 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3344 (O–H), 3235 (N–H), 1730, 1703, 1655 (C]O); dH
(400.1 MHz, DMSO-d6) 1.02 (3H, t, J 7.0 Hz, OCH2CH3), 1.62 and 1.73
(12H, 2br s, 2CH2 of adamantyl), 2.07 (3H, br s, 3CH of adamantyl),
3.86 (3H, q, J 7.0 Hz, OCH2CH3), 7.10 (1H, s, OH), 7.38 (1H, d, J
14.0 Hz, ]CH–NH), 7.93–7.96 (1H, m, ]CH–NH/O]C), 11.18 (2H,
s, NHCONH); dC (100.7 MHz, DMSO-d6) 172.4, 166.6, 150.6, 146.7,
91.4, 71.8, 59.2, 52.1, 43.3, 35.9, 29.3,14.1. Anal. Calcd for C19H25N3O6
(391.42): C, 58.30; H, 6.44; N, 10.74%. Found: C, 58.37; H, 6.40; N,
10.80%.
3.2.15. Ethyl 2-(5-hydroxy-1,3-dimethyl-2,4,6-trioxohexahydro-5-
pyrimidinyl)-3-(isobutylamino)-2-propenoate (8p)
White powder (0.256 g, 75%); mp 106–108 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3337 (O–H), 1700, 1672, 1609 (C]O); dH (400.1 MHz, DMSO-
d6) 0.84 (6H, d, J 6.6 Hz, CH(CH3)2), 0.92 (3H, t, J 7.1 Hz, OCH2CH3),
1.68–1.73 (1H, m, CH(CH3)2), 3.04 (2H, dd, J 5.7, 5.9 Hz, N–CH2), 3.13
(6H, s, 2NCH3), 3.82 (2H, q, J 6.6 Hz, OCH2), 7.15 (1H, s, OH), 7.22 (1H,
d, J 13.9 Hz, ]CH–NH), 7.90 (1H, br d, J 6.4 Hz, ]CH–NH/O]C); dC
(100.7 MHz, DMSO-d6) 170.5, 167.0, 152.9, 151.5, 91.7, 72.0, 59.1,
59.0, 30.0, 28.9, 19.9, 14.3. Anal. Calcd for C15H23N3O6 (341.36): C,
52.78; H, 6.79; N, 12.31%. Found: C, 52.81; H, 6.83; N, 12.27%.
3.2.10. Ethyl 3-(allylamino)-2-(5-hydroxyl-2,4,6-trioxohexahydro-
5-pyrimidinyl)-2-propenoate (8k)
White powder (0.283 g, 95%); mp 162–164 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3371 (O–H), 3280 (N–H), 1720, 1700, 1682 (C]O); dH
(400.1 MHz, DMSO-d6) 1.02 (3H, t, J 7.0 Hz, OCH2CH3), 3.84–3.90
(4H, m, OCH2CH3 and NCH2), 5.12 and 5.17 (2H, 2dd, J 17.2, 10.2,
1.6 Hz, –CH]CH2), 5.85–5.89 (1H, m, –CH]CH2), 7.11 (1H, s, OH),
7.15 (1H, d, J 13.8 Hz, ]CH–NH), 7.80–7.84 (1H, m, ]CH–NH/
O]C), 11.18 (2H, s, NHCONH); dC (100.7 MHz, DMSO-d6) 172.4,
166.6, 151.9, 150.6, 136.5, 116.6, 92.1, 71.7, 59.2, 50.7, 14.2. Anal. Calcd
for C12H15N3O6 (297.26): C, 48.49; H, 5.09; N, 14.14%. Found: C,
48.55; H, 5.02; N, 14.18%.
3.2.16. Ethyl 3-(benzylamino)-2-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8q)
White powder (0.316 g, 84%); mp 143–145 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3409 (O–H), 3295 (N–H), 1693, 1665, 1629 (C]O); dH
(400.1 MHz, CDCl3) 1.06 (3H, t, J 7.0 Hz, CH2CH3), 3.27 (6H, s,
2NCH3), 3.97 (2H, q, J 7.0 Hz, OCH2CH3), 4.41 (2H, d, J 5.7 Hz, N–
CH2), 7.22–7.33 (6H, m, C6H5 and OH), 7.60 (1H, d, J 13.6 Hz, ]CH–
NH), 8.35–8.41 (1H, br m, ]CH–NH/O]C); dC (100.7 MHz, CDCl3)
170.8, 166.4, 153.2, 151.0, 137.7, 128.8, 127.8, 127.2, 93.1, 72.2, 59.6,
53.2, 28.9, 14.2. Anal. Calcd for C18H21N3O6 (375.37): C, 57.59; H,
5.64; N, 11.19%. Found: C, 57.64; H, 5.67; N, 11.24%.
3.2.11. Ethyl 3-(phenylamino)-2-(5-hydroxyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8l)
White powder (0.253 g, 76%); mp 190–192 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3393 (O–H), 3300, 3203, 3094 (N–H), 1764, 1733, 1632
(C]O); dH (400.1 MHz, DMSO-d6) 1.08–1.12 (3H, m, CH3), 3.96–4.02
(2H, m, OCH2), 6.98–7.33 (5H, m, C6H5), 7.46 (1H, s, OH), 7.78 (1H, d,
J 13.1 Hz, ]CH–NH), 9.68 (1H, d, J 13.1 Hz, ]CH–NH/O]C), 11.39
(2H, s, NHCONH); dC (100.7 MHz, DMSO-d6) 171.3, 167.1, 150.5,
142.9, 141.0, 130.1, 123.2, 116.1, 97.6, 71.9, 60.1, 14.0. Anal. Calcd for
3.2.17. Ethyl 3-(phenylamino)-2-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8r)
White powder (0.260 g, 72%); mp 124–126 ꢀC; FTIR (KBr) (nmax
,
C
15H15N3O6 (333.29): C, 54.06; H, 4.54; N, 12.61%. Found: C, 53.97;
cmꢁ1): 3377 (O–H), 1705, 1668 (C]O), 1599 (C]C); dH (400.1 MHz,
CDCl3) 1.05 (3H, t, J 7.0 Hz, CH2CH3), 3.27 (6H, s, 2NCH3), 3.97 (2H, q,
J 7.0 Hz, OCH2CH3), 6.98–7.34 (6H, m, C6H5 and OH), 8.06 (1H, d, J
13.4 Hz, ]CH–NH), 9.90 (1H, d, J 13.4 Hz, ]CH–NH/O]C); dC
(100.7 MHz, CDCl3) 170.50, 166.11, 150.84, 144.72, 140.00, 129.60,
123.56, 116.20, 96.78, 72.24, 60.16, 29.00, 14.06. Anal. Calcd for
H, 4.47; N, 12.54%.
3.2.12. Methyl 3-(benzylamino)-2-(5-hydroxy-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8m)
White powder (0.289 g, 80%); mp 140–142 ꢀC; FTIR (KBr) (nmax
,
cmꢁ1): 3354 (O–H), 1749, 1705, 1669 (C]O); dH (400.1 MHz, DMSO-
d6) 3.12 (6H, s, 2NCH3), 3.40 (3H, s, OCH3), 4.39 (2H, d, J 5.9 Hz, N–
CH2), 7.23–7.36 (5H, m, C6H5), 7.41 (1H, s, OH), 7.56 (1H, d, J 14.0 Hz,
]CH–NH), 7.64–7.70 (1H, m, ]CH–NH/O]C); dC (100.7 MHz,
DMSO-d6) 170.5, 167.6, 152.7, 151.5, 140.1, 129.0, 127.7, 127.6, 93.8,
75.3, 51.9, 51.0, 28.9. Anal. Calcd for C17H19N3O6 (361.35): C, 56.51;
H, 5.30; N, 11.63%. Found: C, 56.60; H, 5.35; N, 11.60%.
C17H19N3O6 (361.35): C, 56.51; H, 5.30; N,11.63%. Found: C, 56.46; H,
5.34; N, 11.68%.
Acknowledgements
We would like to thank Iran Polymer and Petrochemical
Institute (IPPI) research council for the financial support.
3.2.13. Methyl 3-(hexylamino)-2-(5-hydroxy-1,3-dimethyl-2,4,6-
Supplementary data
trioxohexahydro-5-pyrimidinyl)-2-propenoate (8n)
White powder (0.316 g, 89%); mp 86–88 ꢀC; FTIR (KBr) (nmax
,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.08.039.
cmꢁ1): 3561 (O–H), 3475 (N–H), 1683, 1610 (C]O); dH (400.1 MHz,

10430
M.B. Teimouri et al. / Tetrahedron 64 (2008) 10425–10430
10. Bezdek, R. H.; Wendling, R. M.; DiPerna, P. J. Environ. Manage. 2008, 86,
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