Multicomponent tandem synthesis of oxospirobicyclic butenolidobarbiturates

Article abstract of DOI:10.3184/030823410X12746990145128

Novel oxospirobicyclic γ-butenolides containing barbiturate moiety have been synthesised by the Michael-addition of primary amines to dialkyl acetylenedicarboxylates followed by aldol-like reaction with alloxan derivatives, and then ?-lactonisation. Subsequent 1,4-addition of water and elimination of the amine group completes the sequence. This tandem reaction sequence represents a rapid and unprecedented route to the described biologically interesting molecules.

Full text of DOI:10.3184/030823410X12746990145128

310 RESEARCH PAPER
JUNE, 310–314
JOURNAL OF CHEMICAL RESEARCH 2010
Multicomponent tandem synthesis of oxospirobicyclic
butenolidobarbiturates
Mohammad Bagher Teimouria*, Tayyebeh Abbasib and Hamid Reza Khavasic
aPetrochemical Department, Iran Polymer and Petrochemical Institute, PO Box 14965-115, Tehran, Iran
bDepartment of Chemistry, University of Zanjan, PO Box 45195-313, Zanjan, Iran
cDepartment of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Novel oxospirobicyclic γ-butenolides containing barbiturate moiety have been synthesised by the Michael-addition
of primary amines to dialkyl acetylenedicarboxylates followed by aldol-like reaction with alloxan derivatives, and
then γ-lactonisation. Subsequent 1,4-addition of water and elimination of the amine group completes the sequence.
This tandem reaction sequence represents a rapid and unprecedented route to the described biologically interesting
molecules.
Keywords: amine, acetylenic ester, alloxan, barbiturate, γ-butenolide, multicomponent reaction
γ-Butenolides are ubiquitous integral parts of numerous
pharmacologically relevant natural products.1 This includes,
for example, chlorotricolide,2 securinine,3 kallolide A,4 pseu-
dopterolide,5 dysidiolide,6 tonkinecin,7 ( )-differolide.8 The
activity of these natural products has been attributed to the
butenolide moiety.
temperature for 3 h. After completion of the reaction (TLC
analysis), the solvent was removed under reduced pressure,
the residue was washed with diethyl ether and recrystallised
from ethanol to afford corresponding alkyl or arylammonium
4-(alkoxycarbonyl)-2,6,8,10-tetraoxo-1-oxa-7,9-diazaspiro
[4.5]dec-3-ene-3-olates 4 in excellent yields (Scheme 1,
Table 1). Compounds 4a–q are stable solids whose structures
were established by FT-IR, 1H and 13C NMR spectroscopy and
by elemental analysis. The structure of 4m was confirmed by a
single-crystal X-ray analysis. (Fig. 1).
The scope and limitations of this simple process were
explored by using two dialkyl acetylenedicarboxylates, 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 catalyst to afford the cor-
responding spirocyclic butenolide derivatives in high yields.
3-Hydroxy-4-alkoxycarbonyl-γ-butenolides have been pre-
viously prepared mainly by base-mediated cyclisation reac-
tions, namely, the reactions of pyruvates with aldehydes,9
benzaldehyde with dimethyl methoxyfumarate,10 acetophe-
nones with formaldehyde and diethyl oxalate,11 and by
DABCO-mediated dimerisation of methyl 2,4-dioxopentano-
ate.12 A different approach relies on the phosphine-mediated
reaction of ketones with methyl acetoxypropynoate.13 Also,
the synthesis of spiro 3-methoxy-4-methoxycarbonyl-γ-
butenolides based on PPh3 mediated reactions of 1,2-quinones
in refluxing benzene has been reported.14 5-Alkylidene-3-
hydroxy-4-alkoxycarbonyl-butenolides have been prepared by
cyclisation of 1,3-dicarbonyl compounds with oxalyl chlo-
ride.15 Sonoda et al. reported the synthesis of 2,3-dioxo-2,3-
dihydrofurans by cyclisation of acetophenone-derived silyl
enol ethers with oxalyl chloride.16 Although, there are many
ways to synthesise the γ-butenolide moiety, to the best of our
knowledge only two one-pot multicomponent approaches have
been published.14,17
Indeed, our group has long had an interest in developing
new reactions as well as expanding the scope of existing mul-
ticomponent reactions to rapidly access drug-like motifs. Our
recent interest aimed at the development of efficient protocols
for the preparation of biologically active heterocycles via mul-
ticomponent reactions,18–21 has been guided by the observation
that the presence of two or more different heterocyclic moi-
eties in a single molecule often enhances the biological profile
remarkably. In this report the facile synthesis of some novel
oxospirobicyclic γ-butenolides containing a barbiturate moiety
is described.
Table 1 Three-component
condensation
reactions
of
primary amines, dialkyl acetylenedicarboxylates, and alloxan
derivatives
Entry R1
R2
R3
Product Yielda
/%
1
2
Allyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
80
96
91
89
78
86
70
90
90
89
87
97
92
91
97
98
95
1-Adamantyl
N–Hexyl
Isobutyl
Benzyl
3
4
5
6
1-Adamantyl
n-Propyl
Allyl
Allyl
Isobutyl
Phenyl
1-Adamantyl
Isobutyl
4-Hydroxyphenyl Ethyl
Benzyl
7
Ethyl
8
Ethyl
9
Methyl Methyl
Methyl Methyl
Methyl Methyl
Methyl Methyl
10
11
12
13
14
15
16
17
Ethyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
Ethyl
Ethyl
n-Propyl
Phenyl
In the present investigation, a mixture of primary amine 1,
dialkyl acetylenedicarboxylates 2 and alloxan derivative 3 in
a 1:1:1 molar ratio in water was vigorously stirred at room
a Purified yield, which is >95% as determined by 1H NMR.
Scheme 1
* Correspondent. E-mail: m.teimouri@ippi.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2010 311
Fig. 1 ORTEP representation of compound 4m.
As shown in Table 1, the allylic, benzylic, hindered, and unhin-
dered primary amines were used in this protocol with excellent
results. Moreover, the aromatic primary amines give the cor-
responding barbiturates in good yields. Thus, a diverse set of
biologically useful barbiturate products can be potentially pre-
pared in one step by this method. However, secondary amines
such as diethylamine, morpholine and thiomorpholine did
not participate in the reaction. We also tried to take advantage
of 25% aqueous ammonia, 50% aqueous hydroxylamine and
phenylhydrazine as the amine component. Unfortunately, the
reaction of alloxan and dimethyl acetylenedicarboxylate with
each of these NH2-containing compounds did not afford the
desired barbiturate under the same reaction conditions.
Various reaction pathways are possible by mixing these
polyfunctionalised starting materials; the thus-observed clean
reaction is remarkable. The reaction might be explained by the
mechanism shown in Scheme 2 in which a tandem sequence
has been invoked to account for the generation of the buteno-
lide and barbiturate moieties. The nucleophilic addition of
amines to acetylenic esters has also been employed to afford
enaminones.22,23 Therefore, the first step may involve Michael
addition of the primary amine to the acetylenic ester and for-
mation of the aminobutendioate 5 as an electron-rich enami-
none.24 The central carbonyl groups of cyclic vicinal triones
such as alloxan derivatives possess outstanding electrophilic
properties.25 The polar reactions with carbanion-like (electron
rich) species such as enaminones give rise to nucleophilic
addition reactions of carbonyl groups with exclusive C–C bond
formation.26 Subsequent nucleophilic (aldol-type) attack of
aminobutendioate 5 to the central carbonyl group of the alloxan
3 would yield the iminium-oxyanion intermediate 6, that can
be tautomerised to hydroxy barbiturates 7. γ-Lactonisation of
Z-7 (compound 7 with Z- configuration around the C=C double
bond), would produce the spiro 3-aminobutenolide 8. Indeed,
the 3-alkylaminobutenolide 8 is an enaminone. Enaminones
react with a variety of O-, N-, and C-nucleophiles to give
the alkylamine substitution products. A typical reaction with
an O-nucleophile is hydrolysis of (alkylamino)alkenoates
to hydroxyalkenoates, these reactions are acid-catalysed and,
probably proceed by an addition–elimination mechanism. The
latter, after expulsion of the amine unit by 1,4-addition of
water to 8 would provide the spiro 3-hydroxybutenolide 9. The
hydroxy group in compound 9 is very acidic because it is an
enol form of a cyclic β-ketoester compound and especially
augmented by the vicinal carbonyl group. The acid–base reac-
tion between the enol 9 and the amine in reaction mixture leads
to corresponding ammonium salt 4.
As shown in Scheme 2, at least five distinct reactions occur
in this one-pot process. All these steps take place in an ordered
manner to provide the final compound with concomitant
Scheme 2

312 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
creation of three bonds. Three irreversible steps (the formation
of eneminone, lactonisation and the final acid–base reaction)
cause the observed reaction sequence to be a unique and
productive process.
In solution, 2-aminobutenedioates 5 can exist in (Z)- and/or
(E)- isomeric forms. In most cases, the substituent at C-2 (e.g.,
the alkyl or arylamino group) was found to be oriented trans
with respect to the ester group or analogous structural element
at C-4. So far, only a few examples of 2-aminobutenedioates
with the opposite configuration around the C=C double bond,
where the substituent at C-2 and the ester group are cis
oriented, have been found.27
To our surprise, we found that the product of the reaction
was dependent on the nature of the precursors. In some cases
with alloxan (3, R3 = H) as starting material, we obtained
hydroxy barbiturates 7 (E-isomer) instead of spirocyclic
butenolides 4 (Scheme 3, Table 2). The formation of hydroxy
barbiturates 7 (in which the reaction stopped at the E-7
production stage in some cases) is highly informative and
provides clear-cut evidence for the existence of this type of
intermediate in the reaction pathway.
3-hydroxy-4-alkoxycarbonyl-γ-butenolides containing two
different pharmacophoric subunits, by a sequence of a 1,4-
Michael addition, aldol-like reaction, lactonisation, 1,4-
addition-elimination and an acid–base reaction. The one-pot
multicomponent protocol has several distinct advantages over
sequential multi-step procedures. These include superior atom
economy, simplified workup procedures, greater efficiency
and superior overall yields.
Experimental
Melting points were measured on a Büchi 535 apparatus and are
uncorrected. Elemental analyses were performed using an elementar
vario EL III instrument. FT-IR 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 or CD3SOCD3 as solvents and calibrated
using residual undeuterated solvent as an internal reference. Chemical
shifts are reported in parts per million (ppm) relative to TMS as inter-
nal reference. Analytical TLC was carried out on precoated plates
(Merck silica gel 60, F254) and visualised with UV light. All chemical
reagents were obtained from Aldrich, Merck, Fluka or Acros and were
used without further purification.
The configuration of the C=C bond in the 2-aminobutene-
dioate moiety is the most significant factor that dictates the
outcome of a given γ-lactonisation. In the (E) configuration,
the direction of ester group is opposite to hydroxy group and
this arrangement is not suitable for γ-lactonisation because a
trans C=C bond contained within a five-membered ring is not
energetically feasible. Our efforts to effect the cyclisation of
hydroxy barbiturates 7 failed because of their E-configuration.
In contrast, in the Z-configuration of 7, the formation of spiro
γ-butenolide 8 is highly favourable.
Some pieces of evidence are available to contribute towards
a discussion of the mechanism of the tandem reaction. The key
step in the synthesis is an efficient reaction of a primary amine
with a dialkyl acetylenedicarboxylate to give a 2-alkylamino-
2-butendioate derivative, which then reacts with an alloxan
derivative. In order to confirm the mechanism outlined in
Scheme 2, involving initial formation of a 2-alkylamino-2-
butendioate intermediate, diethyl 2-(isobutylamino)-2-
butendioate 5m, a representative 2-alkylamino-2-butendioate,
was synthesised separately by the condensation of isobutyl-
amine and diethyl acetylenedicarboxylate. We then, examined
the reaction of the product, diethyl 2-(isobutylamino)-2-
butendioate, with one equivalent of 1,3-dimethylalloxan in
water, and we obtained the product 4m with 90% yield.
In conclusion, we have reported a new multicomponent
reaction, yielding pharmacologically relevant oxospirocyclic
Typical procedure for the preparation of 4a
To a magnetically stirred solution of allylamine (0.057 g, 1.0 mmol)
and dimethyl acetylenedicarboxylate (0.143 g, 1.0 mmol) in water
(5 mL) was added alloxan monohydrate (0.160 g, 1.0 mmol) at room
temperature (25 °C) and stirring was continued for about 3 h. The
completion of reaction was confirmed by TLC (EtOH/EtOAc 1:2).
The solvent was removed under vacuum and the solid residue was
washed with diethylether (3 mL) and was recrystallised from ethanol
to give white powders (0.262 g, 80%). The dried product thus obtained
showed a single spot on TLC and was pure enough for all analytical
purposes.
Prop-2-en-1-ylammonium 4-(methoxycarbonyl)-2,6,8,10-tetraoxo-1-
oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4a): M.p. 157–159 °C; IR
(KBr) (νmax, cm−1): 3209, 3101 (N–H), 1792, 1746, 1717, 1690, 1615
1
(C=O); H NMR (400.1 MHz, DMSO-d6): δH 3.34 (3 H, s, OCH3),
3.42–3.49 (2 H, m, NCH2), 5.25 (1 H, d, 3JHH = 10.4 Hz, =CH2), 5.33
(1 H, d, 3JHH = 17.4 Hz, =CH2), 5.78–5.87 (1 H, m, CH2=CH–NCH2),
8.07 (3 H, br s, –NH3+), 11.57 (2 H, br s, NHCONH); 13C NMR (100.7
MHz, DMSO-d6): δC 171.6, 169.2, 164.3, 160.1, 150.2, 131.4, 120.2,
100.9, 77.1, 50.3, 41.5; Anal. Calcd for C12H13N3O8 (327.24): C,
44.04; H, 4.00; N, 12.84. Found: C, 43.84; H, 4.03; N, 12.74%.
Adamantan-1-ylammonium 4-(methoxycarbonyl)-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4b): White powder
(0.405 g, 96%); M.p. 202–204 °C; IR (KBr) (νmax, cm−1): 3524, 3381,
1
3215 (N–H), 1778, 1730, 1717, 1687, 1636 (C=O); H NMR (400.1
MHz, DMSO-d6): δH 1.54 and 1.62 (6 H, AB-system, 3JHH = 12.0 Hz,
3 × CH2), 1.74 (6 H, s, 3 × CH2), 2.05 (3 H, s, 3 × CH), 3.45 (3 H, s,
OCH3), 8.50–10.50 (5 H, br s, –NH3+ and NHCONH); 13C NMR
(100.7 MHz, DMSO-d6): δC 171.6, 169.3, 164.3, 160.1, 150.2, 100.6,
77.2, 56.5, 51.3, 50.2, 35.5, 28.9;Anal. Calcd for C19H23N3O8 (421.40):
C, 54.15; H, 5.50; N, 9.97. Found: C, 53.96; H, 5.54; N, 9.92%.
Hexan-1-ylammonium 4-(methoxycarbonyl)-2,6,8,10-tetraoxo-1-oxa-
7,9-diazaspiro[4.5]dec-3-en-3-olate (4c): White powder (0.338 g,
91%); M.p. 191–193 °C; IR (KBr) (νmax, cm−1): 3214, 3112 (N–H),
1792, 1769, 1728, 1708, 1682 (C=O); 1H NMR (400.1 MHz, DMSO-
Table 2 Three-component reactions of primary amines,
dialkyl acetylenedicarboxylates, and alloxan in water
Entry
R1
R2
Product
Yielda /%
1
2
3
4
4-Hydroxyphenyl
4-Hydroxyphenyl
Phenyl
Methyl
Ethyl
Ethyl
Ethyl
E-7a
E-7b
E-7c
E-7d
92
89
81
95
3
d6): δH 0.83 (3 H, t, JHH = 7.0 Hz, CH2CH3), 1.23–1.30 (6 H, m,
3
CH2CH2CH2), 1.45–1.53 (2 H, m, CH2CH3), 2.74 (2 H, t, JHH = 7.5
Isobutyl
Hz, NCH2), 3.30 (3 H, s, OCH3), 7.74 (3 H, br s, –NH3+),11.52 (2 H,
s, NHCONH); 13C NMR (100.7 MHz, DMSO-d6): δC 171.6, 169.3,
a Purified yield, which is >95% as determined by 1H NMR.

JOURNAL OF CHEMICAL RESEARCH 2010 313
165.3., 160.1, 150.2, 100.5, 77.2, 50.2, 39.4, 31.2, 27.4, 25.9, 22.3,
14.3; Anal. Calcd for C15H21N3O8 (371.34): C, 48.52; H, 5.70; N,
11.32. Found: C, 48.83; H, 5.74; N, 11.41%.
50.4, 46.3, 29.1, 26.9, 20.3; Anal. Calcd for C15H21N3O8 (371.34):
C, 48.52; H, 5.70; N, 11.32. Found: C, 48.30; H, 5.64; N, 11.24%.
Phenylammonium 4-(methoxycarbonyl)-7,9-dimethyl-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4k):White powder (0.340
g, 87%); M.p 174–176 °C; IR (KBr) (νmax, cm−1): 3249, 3174 (N–H),
Isobutylammonium 4-(methoxycarbonyl)-2,6,8,10-tetraoxo-1-oxa-
7,9-diazaspiro[4.5]dec-3-en-3-olate (4d): White powder (0.305 g,
89%); M.p. 167–169 °C (dec); IR (KBr) (νmax, cm−1): 3220, 3198, 3150
(N–H), 1794, 1731, 1722, 1648, 1618 (C=O); 1H NMR (400.1 MHz,
DMSO-d6): δH 0.88 (6 H, d, 3JHH = 6.2 Hz, CH(CH3)2), 1.80-1.83 (1 H,
1
1790, 1700, 1692, 1601 (C=O); H NMR (400.1 MHz, DMSO-d6):
δH 3.14 (6 H, s, 2 NCH3), 3.46 (3 H, s, OCH3), 6.88 (3 H, br s, –NH3+),
7.15–7.18 and 7.33–7.37 (5 H, 2 m, C6H5); 13C NMR (100.7 MHz,
DMSO-d6): 170.5, 167.3, 163.7, 157.9, 151.1, 136.5, 130.0, 125.6,
121.4, 104.8, 77.7, 51.0, 29.2; Anal. Calcd for C17H17N3O8 (391.33):
C, 52.18; H, 4.38; N, 10.74. Found: C, 52.47; H, 4.35; N, 10.67%.
Adamantan-1-ylammonium 4-(methoxycarbonyl)-7,9-dimethyl-2,6,8,10-
tetraoxo-1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4l): White
powder (0.436 g, 97%); M.p. 199–201 °C; IR (KBr) (νmax, cm−1): 3150
(N–H), 1772, 1700, 1688, (C=O); 1H NMR (400.1 MHz, DMSO-d6):
δH 1.54 and 1.62 (6 H, AB-system, 2JHH = 12.0 Hz, 3 CH2 of adaman-
tyl), 1.74 (6 H, s, 3 CH2 of adamantyl), 2.05 (3 H, s, 3CH of adaman-
tyl), 3.13 (6 H, s, 2 NCH3), 3.43 (3 H, s, OCH3), 7.87 (3 H, br s,
–NH3+); 13C NMR 100.7 MHz, DMSO-d6): δC 171.3, 168.3, 164.3,
160.1, 151.3, 101.3, 77.8, 51.3, 50.3, 40.4, 35.5, 29.1, 28.8; Anal.
Calcd for C21H27N3O8 (449.45): C, 56.12; H, 6.05; N, 9.35. Found:
C, 56.22; H, 6.01; N, 9.29%.
3
m, CH(CH3)2), 2.61 (2 H, d, JHH = 6.4 Hz, NCH2CH), 3.47 (3 H, s,
OCH3), 8.10–10.50 (5 H, br s, –NH3+ and NHCONH); 13C NMR
(100.7 MHz, DMSO-d6): δC 171.6, 169.0, 164.2, 160.1, 150.2, 101.4,
77.1, 50.4, 46.3, 26.9, 20.2; Anal. Calcd for C13H17N3O8 (343.28):
C, 45.48; H, 4.99; N, 12.24. Found: C, 45.76; H, 5.02; N, 12.29%.
Benzylammonium 4-(methoxycarbonyl)-2,6,8,10-tetraoxo-1-oxa-7,9-
diazaspiro[4.5]dec-3-en-3-olate (4e): White powder (0.294 g, 78%);
M.p. 176–179 °C; IR (KBr) (νmax, cm−1): 3495, 3205, 3103 (N–H),
1792, 1750, 1715, 1683, 1619 (C=O); 1H NMR (400.1 MHz, DMSO-
d6): δH 3.43 (3 H, s, OCH3), 4.01 (2 H, s, NCH2), 7.35–7.44 (5 H, m,
C6H5), 8.11 (3 H, br s, –NH3+), 11.50 (2 H, br s, NHCONH); 13C NMR
(100.7 MHz, DMSO-d6): δC 171.6, 169.3, 164.3, 160.1, 150.2, 134.5,
129.3, 129.1, 128.9, 100.9, 77.2, 50.3, 42.9;Anal. CalcdforC16H15N3O8
(377.30): C, 50.93; H, 4.01; N, 11.14. Found: C, 51.16; H, 4.03; N,
11.18%.
Isobutylammonium 4-(ethoxycarbonyl)-7,9-dimethyl-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4m): White powder
(0.355 g, 92%); M.p. 162–164 °C; IR (KBr) (νmax, cm−1): 3256, 3230
(N–H), 1789, 1718, 1678, 1627 (C=O); 1H NMR (400.1 MHz, DMSO-
d6): δH 0.88 (6 H, d, 3JHH = 6.7 Hz, CH(CH3)2), 1.00 (3 H, t, 3JHH = 7.1
Hz, OCH2CH3), 1.82 (1 H, m, CH(CH3)2), 2.62 (2 H, d, 3JHH = 6.9 Hz,
NCH2CH), 3.14 (6 H, s, 2 NCH3), 3.87 (2 H, q, 3JHH = 7.1 Hz, OCH2),
7.89 (3H, s, –NH3+); 13C NMR (100.7 MHz, DMSO-d6): δC 171.1,
168.2, 163.1, 160.9, 151.2, 101.6, 77.7, 58.4, 46.3, 29.1, 26.9, 20.2,
14.7; Anal. Calcd for C16H23N3O8 (385.36): C, 49.87; H, 6.02; N,
10.90. Found: C, 50.16; H, 5.98; N, 10.96%.
Adamantan-1-ylammonium 4-(ethoxycarbonyl)-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4f): White powder (0.374
g, 86%); M.p. 255–254 °C (dec); IR (KBr) (νmax, cm−1): 3360, 3250,
1
3180 (N–H), 1802, 1750, 1737, 1712. 1620 (C=O); H NMR (400.1
MHz, DMSO-d6): δH 1.06 (3 H, t, 3JHH = 7.1 Hz, CH2CH3), 1.53 and
2
1.61 (6 H, AB-system, JHH = 12.0 Hz, 3 × CH2), 1.75 (6 H, s, 3 ×
CH2), 2.03 (3 H, s, 3 × CH), 3.91 (2 H, q, 3JHH = 7.1 Hz, OCH2), 7.90
(3 H, br s, –NH3+), 11.59 (2 H, br s, NHCONH); 13C NMR (100.7
MHz, DMSO-d6): δC 171.5, 169.2, 163.3, 160.6, 150.2, 101.2, 77.1,
58.5, 51.2, 40.3, 35.6, 28.8, 14.7;Anal. Calcd for C20H25N3O8 (435.42):
C, 55.17; H, 5.79; N, 9.65. Found: C, 55.50; H, 5.84; N, 9.59%.
Propan-1-ylammonium 4-(ethoxycarbonyl)-2,6,8,10-tetraoxo-1-oxa-
7,9-diazaspiro[4.5]dec-3-en-3-olate (4g): White powder (0.240 g,
70%); M.p. 178–180 °C; IR (KBr) (νmax, cm−1): 3272, 3190, 3124
(N–H), 1788, 1742, 1722, 1647, 1610 (C=O); 1H NMR (400.1 MHz,
(4-Hydroxyphenyl)ammonium 4-(ethoxycarbonyl)-7,9-dimethyl-2,6,8,10-
tetraoxo-1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4n): White
powder (0.384 g, 91%); M.p. 170–172 °C; IR (KBr) (νmax, cm−1): 3241,
1
3100 (N–H), 1792, 1709, 1664, 1641 (C=O); H NMR (400.1 MHz,
3
DMSO-d6): δH 0.98 (3 H, t, JHH = 7.1 Hz, OCH2CH3), 3.14 (6 H, s,
3
DMSO-d6): δH 0.86 (3 H, t, JHH = 7.4 Hz, CH2CH3), 1.06 (3 H, t,
2 NCH3), 3.86 (2 H, q, 3JHH = 7.1 Hz, OCH2), 6.79 and 7.12 (4 H, 2 d,
3JHH = 7.0 Hz, OCH2CH3), 1.47–1.55 (2 H, m, CH2CH3), 2.74 (2 H, t,
3JHH = 7.4 Hz, NCH2), 3.91 (2 H, q, 3JHH = 7.0 Hz, OCH2), 8.00–11.00
(5 H, br s, –NH3+ and NHCONH); 13C NMR (100.7 MHz, DMSO-d6):
δC 158.3, 157.1, 149.5, 145.6, 79.4, 79.0, 30.4, 27.3, 27.3, 25.0, 24.8;
Anal. Calcd for C13H17N3O8 (343.28): C, 45.48; H, 4.99; N, 12.24.
Found: C, 45.60; H, 5.03; N, 12.35%.
3JHH = 8.7 Hz, C6H4OH), 9.00–10.50 (4 H, br s, –NH3+ and OH); 13
C
NMR (100.7 MHz, DMSO-d6): δC 170.9, 168.0, 163.0, 160.4, 157.2,
151.2, 124.5, 123.8, 116.5, 102.5, 77.7, 58.6, 29.1, 14.7; Anal. Calcd
for C18H19N3O9 (421.35): C, 51.31; H, 4.55; N, 9.97. Found: C, 51.23;
H, 4.57; N, 10.04%.
Benzylammonium 4-(ethoxycarbonyl)-7,9-dimethyl-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4o): White powder
(0.407 g, 97%); M.p. 179–181 °C; IR (KBr) (νmax, cm−1): 3258 (N–H),
Prop-2-en-1-ylammonium 4-(ethoxycarbonyl)-2,6,8,10-tetraoxo-1-
oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4h): White powder (0.307
g, 90%); M.p. 154–156 °C; IR (KBr) (νmax, cm−1): 3289, 3163 (N–H),
1798, 1740, 1713, 1679, 1624 (C=O); 1H NMR (400.1 MHz, DMSO-
1
1776, 1713, 1698, 1619 (C=O); H NMR (400.1 MHz, DMSO-d6):
δH 0.99 (3 H, t, 3JHH = 7.1 Hz, OCH2CH3), 3.14 (6 H, s, 2 NCH3), 3.85
(2 H, q, 3JHH = 7.1 Hz, OCH2), 4.02 (2 H, s, NCH2), 7.34–7.44 (5 H, m,
C6H5), 8.32 (3 H, br s, –NH3+); 13C NMR (100.7 MHz, DMSO-d6):
δC 171.1, 168.3, 163.2, 160.9, 151.2, 134.5, 129.3, 129.0, 128.9, 101.3,
77.8, 58.3, 42.9, 29.1, 14.5; Anal. Calcd for C19H21N3O8 (419.38):
C, 54.41; H, 5.05; N, 10.02. Found: C, 54.20; H, 5.00; N, 9.97%.
Propan-1-ylammonium 4-(ethoxycarbonyl)-7,9-dimethyl-2,6,8,10-
tetraoxo-1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4p): White
powder (0.364 g, 98%); M.p. 173–175 °C; IR (KBr) (νmax, cm−1): 3447,
3
3
d6): δH 1.07 (3 H, t, JHH = 7.0 Hz, CH3CH2), 3.43 (2 H, d, JHH
=
3
5.9 Hz, NCH2), 3.90 (2 H, t, JHH = 7.0 Hz, OCH2), 5.26 (1 H, d,
3JHH = 9.4 Hz, =CHAHB), 5.33 (1 H, d, JHH = 16.1 Hz, =CHAHB),
3
5.80–5.85 (1 H, m, -CH=CH2), 8.50–11.00 (5 H, br s, –NH3+ and
NHCONH); 13C NMR (100.7 MHz, DMSO-d6): δC 171.5, 169.3,
163.4, 160.7, 150.2, 131.5, 120.2, 100.8, 77.1, 58.4, 41.5, 14.7; Anal.
Calcd for C13H15N3O8 (341.27): C, 45.75; H, 4.43; N, 12.31. Found: C,
45.65; H, 4.46; N, 12.24%.
1
Prop-2-en-1-ylammonium 4-(methoxycarbonyl)-7,9-dimethyl-2,6,8,10-
tetraoxo-1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4i): White
powder (0.320 g, 90%); M.p 178–180 °C; IR (KBr) (νmax, cm−1): 3255
(N–H), 1780, 1700, 1679, 1631 (C=O); 1H NMR (400.1 MHz, DMSO-
3241 (N–H), 1785, 1706, 1677, 1623 (C=O); H NMR (400.1 MHz,
DMSO-d6): δH 0.86 (3 H, t, 3JHH = 7.4 Hz, CH2CH3), 1.00 (3 H, t, 3JHH
= 7.1 Hz, OCH2CH3), 1.53 (2 H, m, CH2CH3), 2.73 (2 H, t, 3JHH = 7.4
Hz, NCH2), 3.14 (6 H, s, 2 NCH3), 3.87 (2 H, q, 3JHH = 7.1 Hz, OCH2),
7.90 (3 H, br s, –NH3+);13C NMR (100.7 MHz, DMSO-d6): δC 171.1,
168.2, 163.1, 161.0, 151.2, 101.7, 77.7, 58.5, 41.1, 29.1, 20.91, 14.70.
11.3; Anal. Calcd for C15H21N3O8 (371.34): C, 48.52; H, 5.70; N,
11.32. Found: C, 48.23; H, 5.67; N, 11.27%.
d6): δH 3.34 (3 H, s, OCH3), 3.43 (6 H, s, 2 NCH3), 5.27 (1 H, d, 3JHH
=
10.4 Hz, =CHAHB), 5.34 (1 H, d, 3JHH = 17.4 Hz, =CHAHB), 5.80-5.87
(1 H, m, CH2=CH–), 8.04 (3 H, br s, –NH3+); 13C NMR (100.7 MHz,
DMSO-d6): δC 171.3, 168.3, 164.3, 160.2, 151.3, 131.4, 120.3, 101.2,
77.9, 50.3, 41.5, 29.1; Anal. Calcd for C14H17N3O8 (355.30): C, 47.33;
H, 4.82; N, 11.83. Found: C, 47.15; H, 4.79; N, 11.77%.
Phenylammonium 4-(ethoxycarbonyl)-7,9-dimethyl-2,6,8,10-tetraoxo-
1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4q):White powder (0.385
g, 95%); M.p 168–170 °C; IR (KBr) (νmax, cm−1): 3229 (N–H), 1790,
1692, 1670, 1622 (C=O); 1H NMR (400.1 MHz, DMSO-d6): δH 1.00
Isobutylammonium 4-(methoxycarbonyl)-7,9-dimethyl-2,6,8,10-
tetraoxo-1-oxa-7,9-diazaspiro[4.5]dec-3-en-3-olate (4j): White
powder (0.330 g, 89%); M.p. 175–177 °C; IR (KBr) (νmax, cm−1): 3254
(N–H), 1780, 1700, 1680, 1632 (C=O); 1H NMR (400.1 MHz, DMSO-
3
(3 H, t, JHH = 6.3, CH2CH3), 3.16 (6 H, s, 2 NCH3), 3.91 (2 H, q,
3JHH = 6.5, OCH2), 5.98 (3 H, br s, –NH3+), 7.16-7.17 and 7.32–7.34
(5 H, 2 m, C6H5); 13C NMR (100.7 MHz, DMSO-d6): δC 170.3, 167.3,
162.6, 158.6, 151.0, 136.6, 129.9, 125.5, 121.5, 105.1, 77.6, 59.3,
29.2, 14.5; Anal. Calcd for C18H19N3O8 (405.35): C, 53.33; H, 4.72;
N, 10.37. Found: C, 53.56; H, 4.70; N, 10.31%.
3
d6): δH 0.88 (6 H, d, JHH = 6.7 Hz, CH(CH3)2), 1.80–1.83 ( 1 H, m,
3
CH(CH3)2), 2.62 (2 H, d, JHH = 5.4 Hz, NCH2CH), 3.13 (6 H, s, 2
NCH3), 3.42 (3 H, s, OCH3), 7.91 (3 H, br s, –NH3+); 13C NMR (100.7
MHz, DMSO-d6): δC 171.3, 168.1, 164.2, 160.1, 151.2, 101.7, 77.8,

314 JOURNAL OF CHEMICAL RESEARCH 2010
Preparation of E–7a; typical procedure
NHCONH); 13C NMR (100.7 MHz, DMSO-d6): δC 171.4, 169.1,
163.3, 160.8, 150.2, 101.3, 77.1, 65.4, 58.6, 46.4, 26.8, 20.2, 15.6,
14.6; Anal. Calcd for C16H23N3O8 (385.37): C, 49.87; H, 6.02; N,
10.90. Found: C, 49.93; H, 5.98; N, 10.86%.
To a magnetically stirred solution of 4-aminophenol (0.110 g,
1.0 mmol) and dimethyl acetylenedicarboxylate (0.143 g, 1.0 mmol)
in water (5 mL) was added alloxan (0.160 g, 1.0 mmol) at room tem-
perature (25 °C) and stirring was continued for about 3 h. The com-
pletion of reaction was confirmed by TLC (EtOAc-hexane 2:1). The
resulting solid was removed by filtration, washed with water (5 mL)
and diethylether (3 mL) and dried at 80 °C in air to give E-7a as
a white powder (0.362 g, 92%). The dried product thus obtained
showed a single spot on TLC and was pure enough for all analytical
purposes.
Dimethyl (2E)-2-[(4-hydroxyphenyl)amino]-3-(5-hydroxy-2,4,6-
trioxohexahydroprimidin-5-yl)but-2-enedioate (E-7a): M.p. 158–
160 °C; IR (KBr) (νmax, cm−1): 3544, 3434, 3324 (N–H and O–H),
1767, 1743, 1707, 1676, 1627 (C=O); 1H NMR (400.1 MHz, DMSO-
d6): δH 3.63 and 3.67 (6 H, 2 s, 2 OCH3), 6.80 and 6.99 (4 H, 2 d, 3JHH
= 8.7 Hz, C6H4OH), 7.44 (2 H, br s, 2 OH), 7.98 (1 H, s, C6H4NH);
9.13 and 9.93 (2 H, 2 s, NHCONH); 13C NMR (100.7 MHz, DMSO-
d6): δC 173.7, 168.5, 161.1, 160.7, 158.5, 152.2, 150.2, 128.4, 123.8,
116.5, 110.0, 78.4, 53.9, 52.4; Anal. Calcd for C16H15N3O9 (393.30):
C, 48.86; H, 3.84; N, 10.68. Found: C, 49.07; H, 3.86; N, 10.73%.
Diethyl (2E)-2-[(4-hydroxyphenyl)amino]-3-(5-hydroxy-2,4,6-tri-
oxohexahydroprimidin-5-yl)but-2-enedioate (E-7b): White powder
(0.375 g, 89%); M.p. 189–191 °C (dec); IR (KBr) (νmax, cm−1): 3430,
3380, 3306 (N–H and O–H),1749, 1737, 1707, 1687, 1652 (C=O); 1H
NMR (400.1 MHz, DMSO-d6): δH 1.03 (3 H, t, 3JHH = 7.1 Hz, CH2CH3
), 1.12 (3 H, t, 3JHH = 7.1 Hz, CH2CH3), 4.02-4.15 (4 H, 2 q, 3JHH = 7.1
Hz, 2 OCH2), 6.82 and 6.99 (4 H, 2 d, 3JHH = 8.7 Hz, C6H4OH), 7.42
and 7.47 (2 H, 2 s, 2 OH), 7.97 (1 H, s, C6H6NH), 9.07 and 9.92 (2 H,
2 s, NHCONH); 13C NMR (100.7 MHz, DMSO-d6): δC 173.8, 168.7,
160.5, 160.1, 158.6, 152.2, 150.1, 128.7, 123.8, 116.4, 109.9, 78.4,
63.1, 66.9, 14.2, 13.9; Anal. Calcd for C18H19N3O9 (421.35): C, 51.31;
H, 4.55; N, 9.97. Found: C, 51.04; H, 4.51; N, 9.93%.
We would like to thank Iran Polymer and Petrochemical
Institute (IPPI) Research Council for the financial support.
Received 20 March 2010; accepted 5 May 2010
Paper 1000015 doi: 10.3184/030823410X12746990145128
Published online: 2 July 2010
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Diethyl (2E)-2-anilino-3-(5-hydroxy-2,4,6-trioxohexahydroprimi-
din-5-yl)but-2-enedioate (E-7c): White powder (0.328 g, 81%); M.p.
177–179 °C; IR (KBr) (νmax, cm−1): 3549, 3384, 3316 (N–H and O–H),
1800, 1726, 1711, 1668, 1635 (C=O); 1H NMR (400.1 MHz, DMSO-
d6): δH 1.01 (3 H, t, 3JHH = 7.0 Hz, CH2CH3), 1.12 (3 H, t, 3JHH = 7.0 Hz,
CH2CH3), 4.02–4.14 (4 H, m, 2 OCH2), 6.64 and 6.63–7.51 (5 H, m,
C6H5), 8.03 (1 H, s, OH), 9.12 (1 H, br s, C6H5NH), 11.36 (1 H, s,
NHCONH), 11.92 (1 H, br s, NHCONH); 13C NMR (100.7 MHz,
DMSO-d6): δC 173.3, 168.9, 160.5, 160.0, 152.2, 150.4, 133.0, 130.1,
126.9, 115.6, 110.8, 78.6, 63.2, 61.1, 14.2, 13.8; Anal. Calcd for
C18H19N3O8 (405.38): C, 53.33; H, 4.72; N, 10.37. Found: C, 53.59;
H, 4.68; N, 10.30%.
Diethyl (2E)-2-(5-hydroxy-2,4,6-trioxohexahydropyrimidin-5-yl)-3-
(isobutylamino)but-2-enedioate (E-7d): White powder (0.366 g,
95%); M.p. 176–178 °C (dec); IR (KBr) (νmax, cm−1): 3220, 3104
1
(N–H and O–H), 1797, 1723, 1706 (C=O); H NMR (400.1 MHz,
DMSO- d6): δH 0.88 (6 H, d, 3JHH = 6.7 Hz, CH(CH3)2), 1.06 (3 H, t,
3JHH = 6.8 Hz, OCH2CH3), 1.80–1.84 (1 H, m, CH(CH3)2), 2.61 (2 H,
d, 3JHH = 7.0 Hz, CH2CH), 3.34 (2 H, q, 3JHH = 7.1 Hz, OCH2), 3.91
3
(2 H, q, JHH = 7.1 Hz, OCH2), 7.00–10.00 (4 H, br s, O–H, NH and
27 A. Ziyaei-Halimehjani and M.R. Saidi, Tetrahedron Lett., 2008, 49, 1244.

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