Urotropine-bromine promoted synthesis of functionalized oxaspirotricyclic furopyrimidines via a domino Knoevenagel condensation/Michael addition/α-bromination/Williamson cycloetherification sequence in water

Article abstract of DOI:10.1016/j.tet.2013.06.030

An efficient, safe and facile route to functionalized spiro[furo[2,3-d] pyrimidine-6,5′-pyrimidine] derivatives has been developed by a one-pot pseudo three-component domino coupling of aromatic aldehydes and (thio)barbituric acids in the presence of urot

Full text of DOI:10.1016/j.tet.2013.06.030

Tetrahedron 69 (2013) 6804e6809
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Urotropineebromine promoted synthesis of functionalized
oxaspirotricyclic furopyrimidines via a domino Knoevenagel
condensation/Michael addition/a-bromination/Williamson
cycloetherification sequence in water
,
b
Mohammad Bagher Teimouri a , Peyman Akbari-Moghaddam ,
*
Mahnaz Motaghinezhad c
a Faculty of Chemistry, Kharazmi University, Mofateh Ave., Tehran, Iran
b Chemistry and Chemical Engineering Research Center of Iran (CCERCI), PO Box 14335-186, Tehran, Iran
c Faculty of Chemistry, Omidiyeh Branch, Islamic Azad University, Omidiyeh, Iran
a r t i c l e i n f o
a b s t r a c t
An efficient, safe and facile route to functionalized spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]
derivatives has been developed by a one-pot pseudo three-component domino coupling of aromatic
aldehydes and (thio)barbituric acids in the presence of urotropineebromine (UB) complex in water at
room temperature. The reaction sequence consists of an initial Knoevenagel condensation of aromatic
aldehydes with (thio)barbituric acids, followed by Michael addition of the second equivalent of (thio)
barbituric acid derivatives, and then UB-catalyzed Williamson cycloetherification to afford the products.
Ó 2013 Elsevier Ltd. All rights reserved.
Article history:
Received 12 January 2013
Received in revised form 29 May 2013
Accepted 10 June 2013
Available online 14 June 2013
Keywords:
Benzaldehydes
Urotropineebromine
Spiro compound
Thiobarbituric acids
1. Introduction
numerous pharmacological and agrochemical applications viz. an-
timalarials,7 antifolates,8e12 and antivirus,13 as well as potential ra-
The strategy of "green chemistry" calls for the development of
new chemical reactivities and reaction conditions that can poten-
tially provide benefits for chemical syntheses in terms of resource
efficiency, energy efficiency, product selectivity, operational sim-
plicity, and health and environmental safety.1 Nowadays, domino
reactions, particularly those performed in water, have become an
increasingly useful tool for the synthesis of chemically and bi-
ologically important compounds because of their convergence,
atom economy, bond-forming efficiency and other suitable char-
acteristics from the point of view of green chemistry.2,3 These re-
actions are powerful for expediently building up molecular
complexity and diversity4 through the facile formation of several
new bonds in a one-pot transformation, quite closely approaching
the concept of an ideal synthesis, and are particularly well adapted
for combinatorial synthesis.5
diation protection agents.14 Due to their biological importance, furo
[2,3-d]pyrimidine derivatives have become synthetic targets for
many organic and medicinal chemists.15e21 Very recently, Elinson
and co-workers reported the synthesis of spiro-derivatives of furo
[2,3-d]pyrimidine-(6,50-pyrimidine)pentone via cascade assembly of
1,3-dialkylbarbituric acids and benzaldehydes in the presence of
molecular bromine.22 Later, they also prepared the same products by
electrocatalytic methods.23 It should be noted that although syn-
thesis of furo[2,3-d]pyrimidine-6,50pyrimidine)pentones have been
reported in the literature,22,23 no attempts were made to utilize 2-
thiobarbituric acid derivatives and also unsubstituted barbituric
acid to furnish thio-analogues of the products. Notably, one of the
drawbacks of the previously described methods for the synthesis of
furo[2,3-d]pyrimidine-6,50pyrimidine)pentones was the use of mo-
lecular bromine as avolatile, hazardous and strong corrosive oxidant.
To expand and improve this type of domino process, herein, we
utilized thio-analogues of barbituric acid and unsubstituted barbi-
turic acid and also UB complex as a safe source of active bromine in
water to produce novel spiro[furo[2,3-d]pyrimidine-6,50-pyrimi-
dine] derivatives.
The furo[2,3-d]pyrimidines, because of a formal isoelectronic
relationship with purine, are of special biological interest.6 It has
* Corresponding author. Tel./fax: þ98 26 34551023; e-mail addresses: teimouri@
khu.ac.ir, mbteimouri@yahoo.com (M.B. Teimouri).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.030

M.B. Teimouri et al. / Tetrahedron 69 (2013) 6804e6809
6805
The urotropineebromine (UB) complex is a non-hygroscopic,
readily handled and storable solid, which was first reported as
a synthetic oxidant for the selective oxidation of primary and sec-
ondary alcohols to aldehydes and ketones, respectively.24 It is not
affected by ordinary exposure to light, air or water and has no of-
fensive odour of bromine or amine. Hence, it is a safe and convenient
source of active bromine in comparison to molecular bromine, which
is a highly toxic, volatile and corrosive oxidant. Furthermore, the
measurement of stoichiometric amounts of molecular bromine for
small scale reactions is difficult and there is therefore a high risk of
forming brominated side products. The use of UB complex as a ver-
satile reagent and safe alternative to liquid bromine in many various
reactions has been reported,25e30 in which these disadvantages are
eliminated. Also, the UB complex is transformed during reaction into
easily removable products and presents a convenient alternative to
other N-bromo reagents, such as N-bromosuccinimide.
of the p-nitrophenyl group (dH 7.51 and 8.18 ppm, 3JHH¼8.4 Hz) and four
resonances for the NH protons at dH 10.92,11.11,11.70 and 12.77 ppm as
a sharp, a fairly sharp, a fairly broad and a completely broad singlet,
respectively. The 1H decoupled 13C NMR spectrum of 3a showed 13
distinct resonances, which confirmed the proposed structure.
Encouraged by the remarkable results obtained with the above
reaction conditions, and in order to show the generality and scope of
this new protocol, we used ten substituted benzaldehydes and four
barbituric acid derivatives. Four derivatives of barbituric acids
(2-thiobarbituric acid, 1,3-diethyl-2-thiobarbituric acid, barbituric
acid, 1,3-dimethylbarbituric acid) afforded oxaspirotricyclic
furobarbiturate in good to excellent isolated yields. Also, the results
showed that substituted benzaldehydes containing electron-
withdrawing groups (o- and p-NO2, p-CN, o- and p-Cl, p-Br, p-F)
and electron-donatinggroupsatmetaposition(m-OH)all toleratethe
reaction conditions with excellent yields. We also continued our task
to explore the reactivity of different aliphatic aldehydes with barbi-
turic acids under similar reaction conditions. The reaction system did
not work well with aliphatic aldehydes, such as butyraldehyde, ac-
etaldehyde and formaldehyde, to generate the corresponding desired
products, but only an intractable mixture was obtained in each case.
The proposed mechanism for the synthesis of spiro[furo[2,3-d]
pyrimidine-6,50-pyrimidine] derivatives is illustrated in Scheme 2.
The reaction is thought to proceed in a stepwise manner. Firstly, we
assumed that the reaction occurs via a Knoevenagel condensation
In connection with our recent interest aimed at the development
of efficient protocols for the preparation of biologically active het-
31e33
erocycles via multicomponent reactions in aqueous medium
and in continuation of our interest on the chemistry of the UB
complex,27e29 in this article, we describe a novel use of the UB
complex for the synthesis of oxaspirotricyclic furobarbiturates via
a domino Knoevenagel condensation/Michael addition/a-bromina-
tion/Williamson cycloetherification sequence of aromatic aldehydes
with (thio)barbituric acid derivatives (Scheme 1).
R
O
R
O
R
O
Ar
N
N
N
N
O
UB, H2O
rt
N
N
X
X
2
+
X
Ar
H
O
R
R
O
2
R
O
3
1
Ar-CHO = Benzaldehyde derivatives
R = Me, H
X = O, S
Scheme 1. Synthesis of spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine] derivatives.
2. Results and discussion
between barbituric acid 1 and aromatic aldehyde 2 to form the
arylidenebarbituric acid 4, which suffers immediate Michael addi-
tion of the second barbituric acid molecule 1 to produce arylbis(-
In a pilot experiment, a mixture of 2-thiobarbituric acid
(2 mmol) and p-nitrobenzaldehyde (1 mmol) was stirred in water
(15 mL) at room temperature. After 20 min, UB complex (containing
1 mmol active bromine) was added to the reaction mixture. Then,
the reaction was stirred for 4 h and the precipitated product was
separated by filtration and washed with distilled water (2ꢀ10 mL).
The crude product crystallized from EtOH/THF (1:1) and the pure
product 3a was obtained as a white solid in 91% yield. To evaluate
the use of this interesting approach, a variety of (thio)barbituric
acid derivatives and various benzaldehydes were examined. Nota-
bly, the reaction is straightforward and proceeds cleanly at room
temperature in water to produce the corresponding products 3aer
in good to excellent yields, and no undesirable side reactions were
observed. All the products were easily isolated simply by filtration
and washing with water. Representative structures and yields of
the products are shown in Fig. 1, which clearly demonstrates that
the UB complex is an excellent catalyst for this one-pot reaction in
water. The structures of the new products 3aeo were established
by their satisfactory elemental analyses and spectral (1H, 13C
NMR and IR) studies, and by comparison with known compounds
3p, 3q and 3r reported in the literature.22
barbitur-5-yl)methane 5. Subsequently,
a-bromination of the
Michael-adduct 5 gives substituted 5-bromo-5-[aryl(barbitur-5-yl)
methyl]pyrimidine 6. Finally, intramolecular Williamson cyclo-
etherification of 6 in a 5-exo-tet fashion gives the oxaspirotricyclic
furobarbiturate 3. It is reasonable to assume that the three basic
nitrogen atoms of the UB complex can promote all stages of the re-
action (base-catalyzed Knoevenagel condensation, Michael addition,
a-bromination, enolization and Williamson cycloetherification).
When the pseudo three-component reaction of 2-thibarbituric
acid and 4-nitrobenzaldehyde in water was examined without
any catalyst at room temperature, it was found that no desired
product 3a was observed by TLC analysis even after 24 h, while
undesired Knoevenagel condensation and also Michael addition
adducts were formed under the above conditions. Subsequently,
the addition of the UB complex to the above reaction mixture
resulted in 5-(4-nitrophenyl)-2,20-dithioxo-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-
trione 3a in excellent yield.
In order to gain an insight into the possible reaction mechanism, the
5-(4-nitrobenzylidene)thiobarbituric acid as a representative Knoeve-
nagel condensation adduct was synthesized separately by the conden-
sation of 4-nitrobenzaldehyde and 2-thiobarbituric acid.34 Then we
examined the reaction of the isolated 5-(4-nitrobenzylidene)thio-
barbituric acid with 1 equiv of 2-thiobarbituric acid in the presence of UB
The elucidation of the structure of 3 using 1H and 13C NMR spec-
troscopic data is discussed with 3a as an example. The 1H NMR spec-
trum of 3a consisted of a singlet for the methine proton of the furan
moiety (dH 5.07 ppm), two apparent doublets for the aromatic protons

6806
M.B. Teimouri et al. / Tetrahedron 69 (2013) 6804e6809
H
N
H
N
H3C
O
H
N
CH3
S
S
S
S
H
H
H
O
O
O
O
O
O
N
O
O
O
O
N
N
N
N
N
N
N
S
S
N
S
N
N
S
H
H
N
H
N
H
H
H
O
Cl
O
O
O
CH3
O
CH3
3a (91%)
3b (86%)
3c (89%)
3d (81%)
NO2
H3C
Cl
H3C
O
H
H
CH3
CH3
O
N
O
N
S
N
S
N
H
H
O
O
O
O
O
O
O
O
O
N
N
N
N
O
N
N
O
O
N
H
N
H
S
S
N
N
N
N
O
H
H
O
O
O
O
CH3
CH3
O
O
CH3
CH3
HO
3h (85%)
3e (80%)
3f (82%)
3g (90%)
NO2
Cl
H
N
H
H
H
N
O
O
N
O
N
O
H
H
H
H
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
O
O
O
O
N
N
N
H
N
H
H
H
N
O
O
H
H
H
H
O
O
O
O
3j (86%)
3k (88%)
3l (92%)
3i (90%)
O2N
Cl
F
Br
H3C
N
H3C
H3C
H3C
O
O
O
O
N
N
N
H3C
H3C
H3C
H3C
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
O2N
O
O
O
N
N
O
N
N
CH3
CH3
CH3
CH3
O
O
O
H3C
H3C
H3C
H3C
O
O
O
O
3p (91%)
3m (84%)
3o (90%)
3n (86%)
CN
F
H3C
N
H3C
N
O
O
H3C
H3C
O
O
O
O
O
N
N
N
N
O
O
N
N
CH3
CH3
O
H3C
H3C
O
O
3q (89%)
3r (92%)
Cl
NO2
Fig. 1. The structures of products 3aer.
Scheme 2. A possible mechanism for the synthesis of oxaspirotricyclic furobarbiturate 3.

M.B. Teimouri et al. / Tetrahedron 69 (2013) 6804e6809
6807
complex containing 1 equiv of active bromine in water at room tem-
perature, and we obtained the product 3a in excellent yield within 4 h.
When the reactions were performed using substituted benzal-
dehydes containing electron-donating groups at ortho and/or para
positions (2,4-dimethoxybenzaldehyde, 4-hydroxybenzaldehyde
and 4-phenylbenzaldehyde) and barbituric acid derivatives (2-
thiobarbituric acid and 1,3-dimethylbarbituric acid) under similar
reaction conditions, 1H NMR and 13C NMR spectroscopic analyses of
the isolated product indicated the formation of the corresponding
substituted arylidenebarbituric acid derivatives 7e10 in quantita-
tive yields and a half amount of each barbituric acid derivative
remaining unreacted (Scheme 3).
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 DMSO-d6 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 internal reference. Analytical
TLC was carried out on pre-coated plates (Merck silica gel 60,
F254) and visualized with UV light. All chemical reagents were
obtained from Merck, Fluka or Acros and were used without
further purification.
It has been shown that the electrophilicity of Knoevenagel ad-
ducts, and hence reactivity towards Michael addition, increases
4.1.1. General procedure for the synthesis of 5-aryl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine] derivatives (3aer). A
O
H
R"
X
X
O
R
O
R
O
R
X
R
O
R
O
UB
N
N
N
N
N
H
+
+
R'
2
H2O
r.t.
N
R
O
R'
R''
Unreacted
R' = OMe, OH, C6H5
R" = OMe, H
R = Me, H
X = O, S
7 X = O, R = Me, R' = R" = OMe
8 X = S, R = H, R' = R" = OMe
9 X = O, R = Me, R' = OH, R" = H
10 X = O, R = Me, R' = C6H5, R" = H
Scheme 3. Reactions of barbituric acids with benzaldehydes containing electron-donating groups in water at room temperature.
when electron-withdrawing substituents are added or when mol-
mixture of the appropriate benzaldehyde (1.0 mmol), (thio)barbituric
acid derivative (2.0 mmol) and distilled water (15 mL), was charged in
a 50 mL round bottom flask. The mixture was stirred at room tem-
perature (25 ꢁC) for 20 min. Then, the UB complex (0.235 g, 1 mmol
active bromine) was added to the reaction and stirring was continued
for 4 h. After completion of the reaction (monitored by TLC using
EtOAc/hexane 1:1 as eluent), the precipitated product was separated
by filtration and washed with distilled water (2ꢀ10 mL). The crude
product was then purified by recrystallization from a mixture of EtOH/
THF.
ecules become more planar.35 The strongly electron-donating 2,4-
dimethoxy and 4-hydroxy substituents in 7, 8 and 9 will stabilize
the vinyl group and render it less susceptible to nucleophilic attack.
Although the phenyl group is moderately electron-donating, it
clearly stabilizes the Knoevenagel product 10 sufficiently to prevent
further reaction.
The hydroxy group at ortho- or para-position acts as a strongly
electron-donating by resonance, but at meta-position it can be con-
sidered as a strongly inductive electron-withdrawing substituent so
it will enhance the electrophilicity of the corresponding Knoevenagel
adduct leading to the formation of the 3-hydroxyphenylbis(barbitur-
5-yl)methane Michael product.
4.1.2. 5-(4-Nitrophenyl)-2,20-dithioxo-1,5-dihydro-2H,20H-spiro[furo[2,3-
d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-trione
(3a). White
powder (0.382 g, 91%); mp 275e277 ꢁC; IR (KBr) (nmax, cmꢂ1): 3370 and
3. Conclusions
3200 (NeH), 1778, 1723 and 1666 (C]O); 1H NMR (400.2 MHz, DMSO-
3
d6): dH 5.07 (1H, s, CH), 7.51 (2H, d, JHH¼8.4 Hz, arom.), 8.18 (2H, d,
In summary, a simple and efficient synthetic procedure has been
developed for the synthesis of functionalized 5-aryl-1,5-dihydro-
2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine] derivatives
from (thio)barbituric acids and aromatic aldehydes by using the UB
complex as a safe bromine source in water. The merit of this cascade
reaction is highlighted by its mild reaction conditions, easy work-
up, excellent yields, high bond-efficiency of producing three new
bonds (two CeC and one CeO), and one stereocenter in a single
operation. The protocol avoids the use of expensive catalysts, toxic
solvents, anhydrous condition and chromatographic separation.
The pharmaceutical relevance of the pyrimidine-2-thione scaffold
coupled with the structural diversity that is accessible via this
method will allow for widespread application of this methodology.
3JHH¼8.4 Hz, arom.), 10.92, 11.11 and 11.70 (3H, 3s, 3NH), 12.77 (1H, br s,
NH); 13C NMR (100.6 MHz, DMSO-d6): dC 166.9, 165.3, 164.2, 160.3,
151.3, 149.7, 148.0, 143.3, 131.0, 123.6, 89.3, 85.9, 54.5; Anal. Calcd for
C15H9N5O6S2 (419.39): C, 42.96; H, 2.16; N, 16.70%. Found: C, 43.09; H,
2.15; N, 16.64%.
4.1.3. 5-(2-Chlorophenyl)-2,20-dithioxo-1,5-dihydro-2H,20H-spiro[furo
[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-trione (3b). Pale
yellow powder (0.352 g, 86%); mp 263e265 ꢁC; IR (KBr) (nmax, cmꢂ1):
3380, 3233 and 3150 (NeH), 1734, 1706 and 1648 (C]O); 1H NMR
(400.2 MHz, DMSO-d6): dH 5.10 (1H, s, CH), 7.17e7.48 (4H, m, arom.),
10.94, 11.27 and 11.76 (3H, 3s, 3NH), 12.77 (1H, br s, NH); 13C NMR
(100.6 MHz, DMSO-d6): dC 167.3, 165.0, 164.1, 160.2, 151.2, 150.0, 133.8,
132.6, 132.0, 130.6, 129.5, 127.7, 88.4, 86.1, 51.7; Anal. Calcd for
C15H9ClN4O4S2 (408.84): C, 44.07; H, 2.22; N, 13.70%. Found: C, 43.91;
H, 2.25; N, 13.66%.
4. Experimental section
4.1. General
4.1.4. 5-(4-Chlorophenyl)-2,20-dithioxo-1,5-dihydro-2H,20H-spiro[furo
[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-trione
(3c). White powder (0.364 g, 89%); mp 271e273 ꢁC; IR (KBr) (nmax
,
€
Melting points were measured on a Buchi 535 apparatus and
are uncorrected. Elemental analyses were performed using an

6808
M.B. Teimouri et al. / Tetrahedron 69 (2013) 6804e6809
cmꢂ1): 3616, 3467 and 3217 (NeH), 1717 and 1675 (C]O); 1H NMR
(400.2 MHz, DMSO-d6): dH 4.86 (1H, s, CH), 7.20 (2H, d,
CH), 6.46e7.05 (4H, m, arom.), 9.35 (1H, s, OH), 10.84, 11.09 and
11.57 (3H, 3s, 3NH), 12.65 (1H, br s, NH); 13C NMR (100.6 MHz,
DMSO-d6): dC 168.3, 165.6, 165.0, 161.1, 158.4, 152.1, 150.6, 137.2,
130.3, 120.9, 116.7, 90.5, 87.0, 56.9; Anal. Calcd for C15H10N4O7
(358.26): C, 50.29; H, 2.81; N, 15.64%. Found: C, 50.17; H, 2.79;
N, 15.58%.
3
3JHH¼8.4 Hz, arom.), 7.37 (2H, d, JHH¼8.4 Hz, arom.), 10.90, 11.12
and 11.65 (3H, 3s, 3NH), 12.72 (1H, br s, NH); 13C NMR (100.6 MHz,
DMSO-d6): dC 167.2, 164.3, 162.1, 160.3, 153.4, 149.8, 135.2, 133.6,
131.2, 128.6, 89.5, 86.0, 54.9; Anal. Calcd for C15H9ClN4O4S2
(408.84): C, 44.07; H, 2.22; N, 13.70%. Found: C, 44.15; H, 2.20; N,
13.75%.
4.1.10. 5-(4-Bromophenyl)-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimi-
dine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3i). White pow-
der (0.379 g, 90%); mp 296e298 ꢁC; IR (KBr) (nmax, cmꢂ1): 3353 and
3248 (NeH),1715,1668 and 1649 (C]O); 1H NMR (400.1 MHz, DMSO-
4.1.5. 1,10,3,30-Tetraethyl-5-phenyl-2,20-dithioxo-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-trione
3
(3d). Yellow powder (0.395 g, 81%); mp 196e198 ꢁC; IR (KBr) (nmax
,
d6): dH 4.79 (1H, s, CH), 7.08 (2H, d, JHH¼8.3 Hz, arom.), 7.45 (2H, d,
cmꢂ1): 1723, 1689 and 1659 (C]O); 1H NMR (400.1 MHz, CDCl3): dH
0.70 (3H, t, 3JHH¼7.1 Hz, Me), 1.24 (3H, t, 3JHH¼7.0 Hz, Me), 1.35 (3H, t,
3JHH¼7.0 Hz, Me), 1.48 (3H, t, 3JHH¼7.1 Hz, Me), 3.31e3.83 (2H, ABX3
system, CH2), 4.43e4.62 (6H, 3ABX3 system overlapping, 3ꢀ CH2),
4.85 (1H, s, CH), 7.03e7.29 (5H, m, arom.); 13C NMR (100.6 MHz,
CDCl3): dC 177.9, 176.6, 164.4, 162.7, 162.0, 157.9, 133.0, 130.4, 129.8,
129.3, 91.3, 90.6, 59.7, 46.0, 45.0, 44.8, 44.4, 13.3, 13.2, 12.5, 12.3; Anal.
Calcd for C23H26N4O4S2 (486.60): C, 56.77; H, 5.39; N, 11.51%. Found:
C, 56.94; H, 5.41; N, 11.48%.
3JHH¼8.3 Hz, arom.), 10.84, 11.08 and 11.59 (3H, 3s, 3NH), 12.67 (1H, br
s, NH); 13C NMR (100.6 MHz, DMSO-d6): dC 168.0, 165.8, 165.1, 161.1,
152.0, 150.6, 135.6, 132.4, 132.3, 123.1, 90.3, 86.8, 55.8; Anal. Calcd for
C15H9BrN4O6 (421.15): C, 42.78; H, 2.15; N, 13.30%. Found: C, 42.92; H,
2.16; N, 13.25%.
4.1.11. 5-(4-Chlorophenyl)-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimi-
dine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3j). White pow-
der (0.324 g, 86%); mp 290e292 ꢁC; IR (KBr) (nmax, cmꢂ1): 3559, 3505
and 3210 (NeH), 1746, 1710 and 1664 (C]O); 1H NMR (400.1 MHz,
3
4.1.6. 5-(4-Chlorophenyl)-1,10,3,30-tetraethyl-2,20-dithioxo-1,5-dihydro-
2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-
trione (3e). Yellow powder (0.417 g, 80%); mp 174e176 ꢁC; IR (KBr)
DMSO-d6): dH 4.81 (1H, s, CH), 7.15 (2H, d, JHH¼7.8 Hz, arom.), 7.32
(2H, d, 3JHH¼7.8 Hz, arom.), 10.83, 11.07 and 11.59 (3H, 3s, 3NH), 12.66
(1H, br s, NH); 13C NMR (100.6 MHz, DMSO-d6): dC 168.0, 165.7, 165.1,
161.1, 152.0,150.5, 135.2, 134.4, 132.0,129.4, 90.3, 86.8, 55.8; Anal. Calcd
for C15H9ClN4O6 (376.70): C, 47.82; H, 2.41; N, 14.87%. Found: C, 47.63;
H, 2.44; N, 14.91%.
(
nmax, cmꢂ1): 1726, 1689 and 1664 (C]O); 1H NMR (400.1 MHz,
CDCl3): dH 0.75 (3H, t, 3JHH¼7.0 Hz, Me), 1.23 (3H, t, 3JHH¼6.9 Hz, Me),
1.34 (3H, t, 3JHH¼6.9 Hz, Me), 1.47 (3H, t, 3JHH¼7.0 Hz, Me), 3.42e3.90
(2H, ABX3 system, CH2), 4.41e4.61 (6H, 3ABX3 system overlapping, 3ꢀ
3
CH2), 4.81 (1H, s, CH), 6.99 (2H, d, JHH¼8.2 Hz, arom.), 7.27 (2H, d,
4.1.12. 5-(4-Fluorophenyl)-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimi-
dine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3k). White pow-
der (0.317 g, 88%); mp 330e332 ꢁC; IR (KBr) (nmax, cmꢂ1): 3351,
3307, 3251 and 3200 (NeH), 1776, 1717 and 1685 (C]O); 1H NMR
(400.1 MHz, DMSO-d6): dH 4.82 (1H, s, CH), 7.08e7.18 (4H, m,
arom.), 10.82, 11.06, 11.60 and 12.64 (4H, 4br s, 4NH); 13C NMR
(100.6 MHz, CDCl3): dC 166.8, 164.5, 163.9, 162.1 (d, 1JCF¼244.3 Hz,
3JHH¼8.2 Hz, arom.); 13C NMR (100.6 MHz, CDCl3): dC 177.8, 176.6,
164.2, 162.8, 161.8, 157.8, 136.5, 131.6, 130.7, 130.0, 91.0, 90.2, 58.9, 46.0,
45.0, 44.8, 44.4, 13.3, 12.8, 12.4, 12.3; Anal. Calcd for C23H25ClN4O4S2
(521.05): C, 53.02; H, 4.84; N, 10.75%. Found: C, 53.21; H, 4.81; N,
10.72%.
4.1.7. 1,10,3,30-Tetraethyl-5-(4-nitrophenyl)-2,20-dithioxo-1,5-dihydro-
2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-4,40,60(10H,3H,30H)-
trione (3f). Pale yellow powder (0.436 g, 82%); mp 234e236 ꢁC; IR
(KBr) (nmax, cmꢂ1): 1734, 1701, 1682 and 1659 (C]O); 1H NMR
C
ipsoeF), 159.8, 150.8, 149.3, 131.1 (d, 3JCF¼3.2 Hz, CparaeF), 130.9 (d,
2
3JCF¼8.4 Hz, CmetaeF), 114.9 (d, JCF¼21.6 Hz, CorthoeF), 89.1, 85.6,
54.6; Anal. Calcd for C15H9FN4O6 (360.25): C, 50.01; H, 2.52; N,
15.55%. Found: C, 49.74; H, 2.50; N, 15.58%.
3
(400.1 MHz, DMSO-d6): dH 0.57 (3H, t, JHH¼6.8 Hz, Me), 1.11 (3H, t,
3JHH¼6.8 Hz, Me), 1.19 (3H, t, 3JHH¼6.9 Hz, Me),1.38 (3H, t, 3JHH¼6.9 Hz,
Me), 3.19e3.73 (2H, ABX3 system, CH2), 4.20e4.56 (6H, 3ABX3 system
overlapping, 3ꢀ CH2), 5.42 (1H, s, CH), 7.44 (2H, d, 3JHH¼8.4 Hz, arom.),
8.12 (2H, d, 3JHH¼8.4 Hz, arom.); 13C NMR (100.6 MHz, DMSO-d6): dC
179.4, 176.6, 164.7, 163.0, 162.3, 157.5, 149.0, 142.3, 131.8, 124.6, 91.8,
90.6, 55.9, 46.1, 45.2, 44.3, 44.0, 13.4, 13.1, 12.6, 12.3; Anal. Calcd for
C23H25N5O6S2 (531.60): C, 51.96; H, 4.74; N, 13.17%. Found: C, 52.14; H,
4.77; N, 13.22%.
4.1.13. 5-(3-Nitrophenyl)-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimi-
dine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3l). Cream pow-
der (0.356 g, 92%); mp 346e348 ꢁC; IR (KBr) (nmax, cmꢂ1): 3200 and
3108 (NeH), 1774, 1717 and 1647 (C]O); 1H NMR (400.1 MHz, DMSO-
d6): dH 5.11 (1H, s, CH), 7.56e8.17 (4H, m, arom.), 10.90, 11.06 and 11.64
(3H, 3s, 3NH),12.76 (1H, br s, NH); 13C NMR (100.6 MHz, DMSO-d6): dC
167.6, 166.2, 165.1, 161.1, 152.1, 150.5, 148.7, 138.8, 137.1, 131.0, 124.8,
124.7, 90.1, 86.5, 55.0; Anal. Calcd for C15H9N5O8 (387.26): C, 46.52; H,
2.34; N, 18.08%. Found: C, 46.70; H, 2.32; N, 18.13%.
4.1.8. 5-Phenyl-1,5-dihydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-
pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3g). White powder
(0.308 g, 90%); mp 304e306 ꢁC; IR (KBr) (nmax, cmꢂ1): 3572, 3460,
3442 and 3425 (NeH), 1714 and 1661 (C]O); 1H NMR (400.1 MHz,
DMSO-d6): dH 4.74 (1H, s, CH), 7.09e7.26 (5H, m, arom.), 10.81,
11.02 and 11.58 (3H, 3s, 3NH), 12.63 (1H, br s, NH); 13C NMR
(100.6 MHz, DMSO-d6): dC 168.3, 165.7, 165.1, 161.1, 152.1, 150.6,
136.0, 130.1, 129.7, 129.4, 90.5, 86.9, 56.9; Anal. Calcd for
C15H10N4O6 (342.26): C, 52.64; H, 2.94; N, 16.37%. Found: C, 52.44;
H, 2.93; N, 16.31%.
4.1.14. 4-(1,10,3,30-Tetramethyl-2,20,4,40,60-pentaoxo-1,10,3,30,4,40,5,60-
octahydro-2H,20H-spiro[furo[2,3-d]pyrimidine-6,50-pyrimidin]-5-yl)
benzonitrile (3m). White powder (0.356 g, 84%); mp 265e267 ꢁC;
IR (KBr) (nmax, cmꢂ1): 2233 (C^N), 1720, 1700 and 1674 (C]O); 1H
NMR (400.2 MHz, DMSO-d6): dH 2.47, 3.13, 3.22 and 3.41 (12H, 4s,
4Me), 5.29 (1H, s, CH), 7.44 (2H, d, 3JHH¼8.4 Hz, arom.), 7.80 (2H, d,
3JHH¼8.4 Hz, arom.); 13C NMR (100.6 MHz, DMSO-d6): dC 165.6,
163.3, 163.2, 158.7, 151.3, 150.4, 140.9, 132.4, 130.4, 119.0, 111.8, 90.1,
85.5, 55.3, 30.3, 29.6, 28.3, 28.2; Anal. Calcd for C20H17N5O6
(423.37): C, 56.74; H, 4.05; N, 16.54%. Found: C, 56.59; H, 4.08; N,
16.48%.
4.1.9. 5-(3-Hydroxyphenyl)-1,5-dihydro-2H,20H-spiro[furo[2,3-d]py-
rimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-pentone (3h). White
powder (0.305 g, 85%); mp 317e319 ꢁC; IR (KBr) (nmax, cmꢂ1):
3350, 3280, 3120 and 3077 (NeH and OeH), 1708, 1682 and
1646 (C]O); 1H NMR (400.1 MHz, DMSO-d6): dH 4.61 (1H, s,
4.1.15. 1,10,3,30-Tetramethyl-5-(2-nitrophenyl)-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3n). Cream powder (0.381 g, 86%); mp 284e286 ꢁC; IR

M.B. Teimouri et al. / Tetrahedron 69 (2013) 6804e6809
6809
(KBr) (nmax, cmꢂ1): 1673 and 1665 (C]O); 1H NMR (400.1 MHz,
DMSO-d6): dH 2.52, 3.06, 3.19 and 3.36 (12H, 4s, 4 Me), 5.33 (1H, s,
CH), 7.48e7.99 (4H, m, arom.); 13C NMR (100.6 MHz, DMSO-d6): dC
166.7, 164.1, 163.9, 159.2, 152.1, 151.3, 149.6, 134.8, 133.9, 131.5, 129.7,
125.9, 89.6, 87.1, 51.9, 31.1, 30.1, 29.3, 29.0; Anal. Calcd for C19H17N5O8
(443.36): C, 51.47; H, 3.86; N, 15.80%. Found: C, 51.29; H, 3.90; N,
15.73%.
C19H16N2O3 (320.34): C, 71.24; H, 5.03; N, 8.74%. Found: C, 71.51; H,
5.06; N, 8.70%.
Acknowledgements
The authors thank the Kharazmi University Research Council
(Project No. 4/296) for financial support of this research.
4.1.16. 5-(4-Fluorophenyl)-1,10,3,30-tetramethyl-1,5-dihydro-2H,20H-
spiro[furo[2,3-d]pyrimidine-6,50-pyrimidine]-2,20,4,40,60(10H,3H,30H)-
pentone (3o). Cream powder (0.375 g, 90%); mp 275e277 ꢁC; IR (KBr)
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.030.
(
nmax, cmꢂ1): 1716, 1697, 1670 and 1659 (C]O); 1H NMR (400.2 MHz,
CDCl3): dH 2.66, 3.30, 3.44 and 3.53 (12H, 4s, 4 Me), 4.91 (1H, s, CH),
7.04e7.06 (4H, m, arom.); 13C NMR (100.6 MHz, CDCl3): dC 165.3,
164.8, 162.8, 162.6, 160.0 (d, 1JCF¼222.1 Hz, CipsoeF), 151.1, 149.5, 130.0
References and notes
3
2
(d, JCF¼8.4 Hz, CmetaeF), 128.6 (s, CparaeF), 115.9 (d, JCF¼21.8 Hz,
1. Anastas, P. T.; Warner, J. C. Green Chemistry Theory and Practice; Oxford Uni-
versity: New York, NY.
C
orthoeF), 89.9, 85.4, 58.3, 29.9, 29.5, 28.4, 28.1; Anal. Calcd for
2. (a) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304e322; (b) Padwa, A.; Bur, S.
K. Tetrahedron 2007, 63, 5341e5378; (c) Ganem, B. Acc. Chem. Res. 2009, 42,
463e472; (d) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072e3081.
3. (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68e82; (b) Hailes, H. C. Org. Process
Res. Dev. 2007, 11, 114e120; (c) Herrerías, C. I.; Yao, X.; Li, Z.; Li, C.-J. Chem. Rev.
2007, 107, 2546e2562.
4. (a) Sunderhaus, J. D.; Martin, S. F. Chem.dEur. J. 2009, 15, 1300e1308; Akrito-
poulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324e331; (b) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29,
123e131.
C19H17FN4O6 (416.36): C, 54.81; H, 4.12; N, 13.46%. Found: C, 54.52; H,
4.10; N, 13.43%.
4.1.17. 5-(2,4-Dimethoxybenzylidene)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (7). Yellow powder (0.243 g, 80%); mp
200e202 ꢁC; IR (KBr) (nmax, cmꢂ1): 1721 and 1659 (C]O), 1601
(C]C); 1H NMR (400.2 MHz, DMSO-d6): dH 3.20 and 3.23 (6H, 2s, 2
NMe), 3.90 and 3.93 (6H, 2s, 2 OMe), 6.63e6.70 (2H, m, arom. H),
5. (a) Syamala, M. Org. Prep. Proced. Int. 2009, 41, 1e68; (b) Weber, L.; Illgen, K.;
Almstetter, M. Synlett 1999, 366e374; (c) Kappe, C. O.; Stadler, A. Methods
Enzymol. 2003, 369, 197e223; (d) Dax, S. L.; McNally, J. J.; Yougman, M. A. Curr.
Med. Chem. 1999, 6, 255e270.
3
8.47 (1H, d, JHH¼8.8 Hz, arom. H), 8.68 (1H, s, ]CH); 13C NMR
(100.6 MHz, DMSO-d6): dC 166.3, 163.2, 162.9, 161.2, 151.6, 150.5,
135.7, 114.9, 114.8, 106.3, 97.8, 56.7, 56.3, 29.0, 28.4; Anal. Calcd for
C15H16N2O5 (304.29): C, 59.21; H, 5.30; N, 9.21%. Found: C, 58.98;
H, 5.27; N, 9.17%.
6. De Clercq, E. Med. Res. Rev. 2003, 23, 253e274.
7. Campaigne, E.; Ellis, R. L.; Bradford, M.; Ho, J. J. Med. Chem. 1969, 12, 339e342.
8. Gangjee, A.; Devraj, R.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F.; Barrews, L. R.
J. Med. Chem. 1994, 37, 1169e1176.
9. Gangjee,A.;Devraj,R.;McGuire,J.J.;Kisliuk, R.L.J.Med.Chem.1995, 38, 3798e3805.
10. Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2002, 45,
1942e1948.
4.1.18. 5-(2,4-Dimethoxybenzylidene)-2-thioxodihydropyrimidine-
4,6(1H,5H)-dione (8). Yellow powder (0.255 g, 87%); mp
255e257 ꢁC; IR (KBr) (nmax, cmꢂ1): 3280 and 3194 (NeH), 1757 and
1673 (C]O), 1610 (C]C); 1H NMR (400.2 MHz, DMSO-d6): dH 3.89
and 3.92 (6H, 2s, 2 OMe), 6.64e8.57 (3H, m, arom), 8.63 (1H, s, ]
CH), 11.09 and 11.25 (2H, 2s, 2NH); 13C NMR (100.6 MHz, DMSO-d6):
dC 166.3, 164.6, 162.9, 162.6, 150.7, 149.5, 136.0, 115.0, 114.7, 106.3,
97.9, 56.7, 56.3; Anal. Calcd for C13H12N2O4S (292.31): C, 53.42; H,
4.14; N, 9.58%. Found: C, 53.29; H, 4.10; N, 9.54%.
11. Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein, F.; Kisliuk, R. L. J. Med. Chem.
2004, 47, 6893e6901.
12. Gangjee, A.; Zeng, Y.; McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2005, 48, 5329e5336.
13. Janeba, Z.; Balzarini, J.; Andrei, G.; Snoeck, R.; De Clercq, E.; Robins, M. J. J. Med.
Chem. 2005, 48, 4690e4696.
14. Furukawa, S.; Takada, M.; Castle, H. N. J. Heterocycl. Chem. 1981, 18, 581e585.
ꢀ
15. Martin-Kohler, A.; Widmer, J.; Bold, G.; Meyer, T.; Sequin, U.; Traxler, P. Helv.
Chim. Acta 2004, 87, 956e975.
16. Otter, B. A.; Saluja, S. S.; Fox, J. J. J. Org. Chem. 1972, 37, 2858e2863.
17. Kawahara, N.; Nakajima, T.; Itoh, T.; Ogura, H. Heterocycles 1984, 22, 2217e2220.
18. Figueroa-Villar, J. D.; Carneiro, C. L.; Cruz, E. R. Heterocycles 1992, 34, 891e894.
19. Kajikawa, S.; Nishino, H.; Kurosawa, K. Heterocycles 2001, 54, 171e183.
20. Kidwai,M.;Rastogi, S.;Venkataramanan, R.Bull.Chem. Soc. Jpn. 2003, 76, 203e204.
21. Jursic, B. S.; Stevens, E. D. Synth. Commun. 2004, 34, 3915e3923.
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I. Tetrahedron Lett. 2010, 51, 6598e6601.
4.1.19. 5-(4-Hydroxybenzylidene)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (9). Yellow powder (0.193 g, 74%); mp
295e297 ꢁC; IR (KBr) (nmax, cmꢂ1): 3200 (OeH), 1638 (C]O), 1600
(C]C); 1H NMR (400.1 MHz, DMSO-d6): dH 3.16 and 3.18 (6H, 2s, 2 Me),
6.85 (2H, d, 3JHH¼8.0 Hz, arom. H), 8.23e8.27 (3H, m, ]CHþarom. H),
10.77 (1H, s, OH); 13C NMR (100.6 MHz, DMSO-d6): dC 164.4, 164.0,
162.1, 157.6, 152.4, 139.5, 125.1, 116.8, 115.2, 29.9, 29.2; Anal. Calcd for
C13H12N2O4 (260.24): C, 60.00; H, 4.65; N, 10.76%. Found: C, 60.13; H,
4.62; N, 10.80%.
23. Vereshchagin, A. N.; Elinson, M. N.; Dorofeeva, E. O.; Zaimovskaya, T. A.; Ste-
panov, N. O.; Gorbunov, S. V.; Belyakov, P. A.; Nikishin, G. I. Tetrahedron 2012,
68, 1198e1206.
24. Yavari, I.; Shaabani, A. J. Chem. Res., Synop. 1994, 274e276.
25. Gangwani, H.; Sharma, P. K.; Banerji, K. K. J. Chem. Res., Synop. 1999, 180e181.
26. Bandgar, B. P.; Admane, S. B.; Jare, S. S. J. Chem. Res., Synop. 1998, 154e155.
27. Shaabani, A.; Teimouri, M. B.; Safaei, H. R. Synth. Commun. 2000, 30, 265e271.
28. Shaabani, A.; Teimouri, M. B.; Bazgir, A. Indian J. Chem., Sect. B 2002, 41,1975e1977.
29. Teimouri, M. B.; Mivehchi, H. Synth. Commun. 2005, 35, 1835e1843.
30. Heravi, M.; Abdolhosseini, N.; Oskooie, H. A. Tetrahedron Lett. 2005, 46,
8959e8963.
31. Teimouri, M. B.; Abbasi, T.; Mivehchi, H. Tetrahedron 2008, 64, 10425e10430.
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J. Chem. Soc., Perkin Trans. 1 1999, 2483e2488.
4.1.20. 5-(Biphenyl-4-ylmethylene)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (10). Yellow powder (0.259 g, 81%); mp
162e164 ꢁC; IR (KBr) (nmax, cmꢂ1): 1726 and 1658 (C]O), 1564 (C]
C); 1H NMR (400.1 MHz, DMSO-d6): dH 3.17 and 3.21 (6H, 2s, 2 Me),
7.38e8.17 (9H, m, arom), 8.35 (1H, s, CH); 13C NMR (100.6 MHz,
DMSO-d6): dC 163.5, 161.7, 156.3, 152.4, 145.0, 140.1, 135.3, 133.1,
130.4, 129.7, 128.2, 127.4, 119.7, 29.9, 29.3; Anal. Calcd for