One-pot new barbituric acid derivatives derived from the reaction of barbituric acids with BrCN and ketones

Article abstract of DOI:10.1002/jccs.201190031

Reaction of cyclic β-dicarbonyl compounds such as pyrimidine-(1 H,3H,5H)-2,4,6-trione (BA), 1,3-dimethyl pyrimidine-(1 H,3H,5H)-2,4,6-trione (DMBA) and 2-thioxo-pyrimidine-(1 H,3H,5H)-4,6-dione (TBA) with cyanogen bromide in acetone and 2-butanone in the presence of triethylamine afforded a new class of stable heterocyclic spiro[furo[2,3-d]pyrimidine-6,5′-pyrimidine]2, 2′,4,4′,6′(3H,3′H,5H)-penta-ones (dimeric forms of barbiturate) at 0 °C and ambient temperature. Structure elucidation was carried out by X-ray crystallographic, ¹H NMR, ¹³C NMR, two dimensional NMR, FT-IR spectra, mass spectrometry and elemental analysis. The mechanism of product formation is discussed. The reaction of DMBA with cyanogen bromide in the presence of triethylamine also afforded trimeric form of barbiturate of uracil derivatives in good yield. The reaction of selected acyclic β-dicarbonyl compounds with cyanogen bromide in the presence of triethylamine in acetone and/or diethyl ether has also been investigated under the same condition. Diethyl malonate and ethyl cyanoacetate brominated and also ethyl acetocetate both bro-minated and cyanated on active methylene via cyanogen bromide.

Full text of DOI:10.1002/jccs.201190031

Journal of the Chinese Chemical Society, 2011, 58, 309-318
309
One-pot New Barbituric Acid Derivatives Derived from the Reaction of
Barbituric Acids with BrCN and Ketones
Yaser Hosseini,a Saeed Rastgar,a Zerrin Heren,b Orhan Büyükgüngörc and Nader Noroozi Pesyana*
aDepartment of Chemistry, Faculty of Science, Urmia University, 57159, Urmia, Iran
bDepartment of Chemistry, Ondokuz Mayis University, TR-55139, Samsun, Turkey
cDepartment of Physics, Ondokuz Mayis University, TR-55139, Samsun, Turkey
Received September 12, 2010; Accepted January 29, 2011; Published Online February 25, 2011
Reaction of cyclic b-dicarbonyl compounds such as pyrimidine-(1H,3H,5H)-2,4,6-trione (BA), 1,3-
dimethyl pyrimidine-(1H,3H,5H)-2,4,6-trione (DMBA) and 2-thioxo-pyrimidine-(1H,3H,5H)-4,6-dione
(TBA) with cyanogen bromide in acetone and 2-butanone in the presence of triethylamine afforded a new
class of stable heterocyclic spiro[furo[2,3-d]pyrimidine-6,5¢-pyrimidine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-penta-
ones (dimeric forms of barbiturate) at 0 °C and ambient temperature. Structure elucidation was carried out
by X-ray crystallographic, 1H NMR, 13C NMR, two dimensional NMR, FT-IR spectra, mass spectrometry
and elemental analysis. The mechanism of product formation is discussed. The reaction of DMBA with
cyanogen bromide in the presence of triethylamine also afforded trimeric form of barbiturate of uracil de-
rivatives in good yield. The reaction of selected acyclic b-dicarbonyl compounds with cyanogen bromide
in the presence of triethylamine in acetone and/or diethyl ether has also been investigated under the same
condition. Diethyl malonate and ethyl cyanoacetate brominated and also ethyl acetocetate both bro-
minated and cyanated on active methylene via cyanogen bromide.
Keywords: Barbituric acid; Teriethylammonium-5-bromo-2,4,6-trioxohexahydropyrimidin-5-ide;
Uracil.
INTRODUCTION
Heterocyclic furo[2,3-d]pyrimidines,1 pyrido[2,3-
d]pyrimidines,1f spirobarbituric acids,2 5-alkylated and
benzylated barbituric acids and other derivatives3 are well
known as pharmaceutical and biological effects.
spiro barbituric deoxyribonucleoside13 and to form spiro-
linked condensed [1,2-a]quinolines.14 Nitta15 and co-work-
ers recently have reported p-conjugated systems contain-
ing barbituric acid and 1,3-dimethyl barbituric acid deriv-
atives.
The reaction of cyanogen bromide4 with varieties of
tertiary amines give N-cyanoammonium bromides in the
von Braun reaction.5 Reaction of barbituric acid with
cyanogen bromide in the presence of pyridine derivatives
is known as König reaction. In this reaction, the pyridine
derivative reacts with cyanogen bromide and is afterwards
coupled with an activated methylene to give a polymethine
dye.6 For example; determination of niketamide7 and nia-
cinamide8 by the reaction of barbituric acid and cyanogen
bromide has been used.
Cyanogen bromide is a very useful reagent for the
synthesis of cyanamides,16 cyanates,17 and also is utilized
in a selective cleavage of the methionyl peptide bonds in
ribonuclease18 and etc. Cyanogen bromide also is a useful
brominating agent such as; the bromination and cyanation
of imidazoles,19 free radical reaction with alkanes (bro-
mination of alkanes)20 and a-bromination of b-amino-
enones.21 Based on these concepts, we have investigated
the reaction of cyclic b-dicarbonyl compounds such as bar-
bituric, 1,3-dimethylbarbituric and thiobarbituric acid with
cyanogen bromide and some ketones and also acyclic b-
dicarbonyls such as diethyl malonate, ethyl cyanoecetate
and ethyl acetoacetate with cyanogen bromide in the pres-
ence of triethylamine.
Barbituric acids can act as a nucleophile to attack var-
ious electrophiles e.g. carbodiimides,9 benzophenone de-
rivatives,10 2,2¢-bipyridil to form 5,5¢-(2-pyrilidine)bisbar-
bituric acid,11 C60 molecules,12 erythrolactol to obtain
* Corresponding author. Tel: (+98) 441 2972147; Fax: (+98) 441 2776707; E-mail: n.noroozi@urmia.ac.ir or pesyan@gmail.com

310 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Hosseini et al.
RESULTS AND DISCUSSION
duce the salts of 6a-c in good yields in acetone at room
temperature.
Cyanogen halides such as cyanogen bromide (BrCN)
like 1-cyanobenzotriazole is a convenient source of NC+,
strongly electrophilic and is a common reagent for cyana-
tion of various compouds.22 In this research, unsuccessful
attempts were made to synthesize and isolate the 2,4,6-
trioxohexahydropyrimidine-5-carbonitrile (11a), 1,3-di-
methyl-2,4,6-trioxohexahydropyrimidine-5-carbonitrile
(11b) and 4,6-dioxo-2-thioxohexahydropyrimidine-5-car-
bonitrile (11c). Instead, representatively, the reaction of
1a-c with cyanogen bromide and acetone (2) in the pres-
ence of triethylamine afforded the salts of triethylammo-
nium-5-bromo-2,4,6-trioxohexahydropyrimidin-5-ide
(6a), 1,3-dimethyl triethylammonium-5-bromo-2,4,6-tri-
oxohexahydropyrimidin-5-ide (6b), triethylammonium-
5-bromo-4,6-dioxo-2-thioxohexahydropyrimidin-5-ide
(6c) and a new class of stable heterocyclic compounds 5,5-
dimethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-pyrim-
idine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone (7a), 1,1¢,3,3¢,5,5¢-
hexamethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-pyr-
imidine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone (7b) and 5,5-
dimethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-pyr-
imidine]2,2¢-dithioxo-4,4¢,6¢(3H,3¢H,5H)-trione (7c) in
moderate yield, respectively (Scheme I).
The different schematic mechanisms for the reaction
between barbituric acid and cyanogen bromide are de-
picted in Scheme II. On the basis of the well established
chemistry of barbituric acid23 it is reasonable to assume that
the enol form of barbituric acid 1a reacts directly with
cyanogen bromide to form intermediate A (path a). Intra-
molecular rearrangement of this intermediate produces 5-
bromo-1,3-dimethylpyrimidine-(1H,3H,5H)-2,4,6-trione
(13a) followed by loss of HCN, then to form the salt of tri-
ethylammonium-5-bromo-2,4,6-trioxohexahydropyrimi-
din-5-ide, 6a similar to bromination of 1-alkyl-imidazoles
via BrCN.19 An alternative mechanism is presented
through path b. In this case, the enol form of 1a reacts di-
rectly with cyanogen bromide to form 11a. Next, inter-
molecular attack by the bromide ion to nitrile group in 11a
produces intermediate B then intramolecularly rearrange to
C followed by loss of HCN to form the salt of 6a (path c).
No triethylammonium-5-cyano-2,4,6-trioxohexahydro-
pyrimidin-5-ide (12a) was observed. Therefore, it seems
that the path b is improbable.
Proposed mechanism for the preparation of
Scheme II
6a as representative
Reaction of cyclic b-dicarbonyls (1a-e)
with cyanogen bromide and ketones (2-5)
in the presence of triethylamine
Scheme I
As a part of our current studies on barbituric acids and
its reaction with cyanogen bromide and our interest in the
chemistry of cyanogen bromide we discovered unexpected
bromination by cyanogen bromide. The cyanation of some
compounds via cyanogen bromide is well-known.16,17 Here
in, we report smooth bromination of barbituric acids by
cyanogen bromide in the presence of triethylamine to pro-
1
The structures of the 6a-c were deduced by IR, H
NMR, 13C NMR spectra, elemental analysis and GC-Mass
spectroscopy. The 1H NMR spectrum of 6a consists of a
triplet (three equivalent methyl protons at d = 1.16 ppm), a
quartet (for three equivalent methylene protons at d = 3.08

One-pot New Barbituric Acid Derivatives
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 311
ppm), a broad singlet (for ammonium proton at d = 8.93
ppm) and a singlet for two equivalent amidic protons at d =
9.38 ppm on barbituric acid ring moiety. The IR spectrum
ethylammonium hydrobromide salt (Scheme III). Com-
pound 13b was reported to react with another unsaturated
carbon-carbon double bond to form 5-spirobarbiturate sys-
tem under basic condition.12,26 Attempts to synthesize 7 in
acetonitrile and/or in diethyl ether gave the salts of 6 and
triethylammonium hydrobromide in good yield (No 7 was
observed).
of 6a indicated no CN bond stretching absorption. The 13
C
NMR spectrum of 6a shows five distinct peaks. The peak at
d = 9.09 and 46.19 ppm are of methyl and methylene car-
bons in triethylammonium salt moiety. The peak at 72.27
ppm corresponds to C-5 on barbituric acid ring. Two peaks
at d = 152.02 and 161.26 ppm correspond to the two un-
equivalent carbonyl groups on barbituric acid ring moiety,
respectively (see experimental). Other evidence for the for-
mation of 6a-c (the existence of bromine atom in these mol-
ecules) was performed by mass analysis and also Beilstein
test and the wet silver nitrate test24 (precipitate of pale
yellow silver bromide).
According to Scheme II, cyanogen bromide plays the
major role in formation of 6 via intermediate A and 13. In
other words, compound 6 is the key reagent for the synthe-
sis of 7. No 6 and 7 were observed in the absence of cyano-
gen bromide under the same condition!
The structures of 7a-c were characterized by IR, 1H
NMR, 13C NMR, 1H-1H COSY, 1H-13C HETCOR spectra,
mass analysis and X-ray crystallography (for 7b). Re-
cently, we have reported the crystal structure of compound
7b27 (Fig. 2a). 1H-1H COSY spectrum of 7a shows no cor-
relation between those three N–H signals. 1H-13C HETCOR
spectrum of 7a shows correlation of carbon signal at d
23.75 ppm with the proton at d 1.30 ppm which identifies
The proposed mechanism for the formation of 7b is
shown in Scheme III. First, the Knoevenagel condensation
of 1b25 with acetone afforded 1,3-dimethyl-5-(propan-2-
ylidene)pyrimidine-(1H,3H,5H)-2,4,6-trione (14b). Then
Michael addition of 1,3-dimethyl triethylammonium-5-
bromo-2,4,6-trioxohexahydropyrimidin-5-ide salt, 6b to
b-carbon position of 14b as an a,b-unsaturated carbonyl
compound gave an intermediate (15b). Unfortunately, all
attempts failed to separate or characterize 15b. Finally,
intramolecular nucleophilic attack of oxygen anion to the
carbon atom produced 7b (moderate yield) and also tri-
1
the two geminal methyl protons. H-13C HETCOR spec-
trum of 7b shows correlation of carbon signal at d 23.33
ppm with the proton at d 1.40 ppm. The carbon signals at d
27.85, 29.08 and 29.63 ppm correlate with proton signals at
d 3.28, 3.36 and 3.43 ppm, respectively.
Compound 5,6-dihydro-1,3-dimethyl-5,6-bis-[l¢,3¢-
dimethyl-2¢,4¢,6¢-trioxo-pyrimid(5¢,5¢)yl]furo[2,3-d]uracil
(16b) was prepared from the reaction of 1b with cyanogen
bromide and ketones 2-5 in the presence of Et3N (a trimeric
form of 1,3-dimethylbarbituric acid, Scheme IV). Previ-
ously, Dryhurst et al reported the synthesis of 16b by elec-
trochemical method.28 Barba et al reported the synthesis of
16e by cathodic reduction of 2,2-dibromo-1,3-indandione
in dichloromethane-Bu4NBF4 (Fig. 1).29 Here in, we report
a chemical method for the synthesis of 16b for first time.
Knoevenagel condensation, Michael ad-
dition and cyclization mechanism for the
formation of 7b as representative
Scheme III
Reaction of 1b with cyanogen bromide in
various ketones (2-5) in the presence of
triethylamine for the synthesis of 16b
Scheme IV

312 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Hosseini et al.
methyl barbituric acid 1b.28,31 Knoevenagel condensation
of 1b with 17b produced 1,3,1¢,3¢-tetramethyl-[5,5¢]-bi-
pyrimidinylidene-2,4,6,2¢,4¢,6¢-hexaone (18b). Of course,
the alloxan derivative can also be prepared from the oxida-
tion of barbituric acid and its derivatives e.g. 5-hydroxy
barbituric acid (HB), 5-alkylidene and/or arylidene barbi-
turic acids.31 The conversion of HB to alloxan by electro-
chemical method has also been reported.31g 5-Hydroxy bar-
bituric acid can also be prepared from 5-bromo barbituric
acid under alkali condition.31h,i a-Diketo compounds e.g.
isatin has been condensed with barbituric acids by
Knoevenagel condensation reaction.32,33 Therefore, like
isatin, 1,3-dimethyl alloxan, 17b can be condensed with 1b
to obtain 18b. The Michael addition of 6b with 18b formed
intermediate 19b. Then intramolecular nucleophilic attack
of oxygen anion to C5 atom of barbituric acid ring moiety
(pushing the bromide ion out) to form 16b and triethyl-
ammonium hydrobromide salt (Scheme VI). Unfortu-
Fig. 1. Structure of 16e.
This compound was obtained from ketone and/or another
reactant containing a minimum of 5% water (water has im-
portant role in the formation of 16b). Formation of trimeric
form of 1,3-dimethyl barbituric acid (16b) also depends on
the steric hindrance of R1 and R2 of the ketones. No 16a and
16c-e were obtained from the reaction of 1a and 1c-e under
the same condition, respectively. These results indicate that
the salt of 6b plays an important role due to stronger nu-
cleophilicity in compare to 6a and 6c. Both 6a and 6c have
aromatic nature while 6b does not. The aromaticity of py-
rimidine ring moiety reduces the nucleophilicity (Scheme
V). The 1H NMR spectrum of 16b consisted of two singlets
for two unequivalent methyl groups at d = 3.41 and 3.14
ppm, respectively, a singlet for two equivalent methyl pro-
tons at d = 3.09 ppm and a singlet at d = 3.02 ppm for an-
other two equivalent methyl protons. 13C NMR spectrum of
16b consisted of fourteen distinct peaks that confirms the
structure of 16b (see experimental and Fig. 2b).
Scheme V Tautomeric and mesomeric forms of 6a-c
The formation of the barbituric acid trimer may be in-
volve in oxidation of the enol form and then radical cou-
pling.30 The proposed mechanism of the formation of 16b
by chemical method is shown in Scheme VI. The 1,3-di-
methyl pyrimidine-2,4,5,6(1H,3H)-tetraone (1,3-dimethyl
alloxan, 17b) was formed from the oxidation of 1,3-di-
Fig. 2. X-ray crystal structure of 7b27 (a) and 16b (b)
synthesized by chemical method.

One-pot New Barbituric Acid Derivatives
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 313
conclude that the existence of trace amount of water con-
verts 6b to 17b through intermediate 20b (Scheme VII).
Compound 17b is a reactive compound which easily con-
densed with 1b prior to Knoevenagel condensation of 1b
with ketones 2-5 (especially with hindrance and bulky ke-
tones such as 4 and 5). The formation of 16b is a competing
reaction parallel with the formation of 7b and 8b. We per-
formed the reaction of 5,5-dimethylcyclohexane-1,3-dione
(dimedone, 1d) and 1,3-indandion (1e) with cyanogen bro-
mide in 2-5 in the presence of triethylamine under the same
condition. No 7d-10d and 7e-10e were obtained by the
chemical method.
Proposed mechanism for the formation of
16b via chemical method
Scheme VI
The sulfur analogues of the compounds 7c-10c may
have two tautomeric forms. For 7c, this phenomenon arose
from the strong nucleophilicity of the sulfur in thiocar-
bonyl group of the thiouracil ring moiety, which tauto-
merized to thiol functional group [lactim-thiolactim form
(7c[II])] on pyrimidine ring moiety (resulting a tautomeric
equilibrium mixture). In other words, a mixture of lactam-
thiolactam (7c[I]) and lactim-thiolactim (7c[II]) exist in an
equilibrium mixtures (Scheme VIII).34 Another interesting
observed phenomenon was the equilibrium mixture of two
tautomers of 8a. The 1H and 13C NMR spectra of 8a show
two distinct tautomers (existence of more than four NH
peaks in 1H NMR and the number of 13C NMR peaks). This
indicates the equilibrium mixture of lactam and lactim
forms and has enough lifetimes in NMR time scale (Fig. 3).
nately, all attempts failed to separate and characterize 17b,
18b and 19b. We concluded that 1,3-dimethyl triethyl-
ammonium-5-bromo-2,4,6-trioxohexahydropyrimidin-5-
ide, 6b was hydrolyzed to 5-hydroxy-1,3-dimethylbarbitu-
ric acid (20b) by the small amount of water and then oxi-
dized to 1,3-dimethyl alloxan, 17b (Scheme VII). We ex-
amined the reaction of 1b in extra pure acetone (» 99.5 to
99.9%) under the same condition. No 16b was observed
but only 6b and 7b were obtained. Compounds 8a-c and
16b were obtained from the reaction of 1a-c with 2-buta-
none (3) and cyanogen bromide under the same condition,
respectively. In contrast, the reaction of 4-nitro acetophe-
none (4) and cyclohexanone (5) with 1b only produced the
trimeric form (16b) under the same condition. Thus, we
Scheme VIII Tautomeric forms of 7c as representa-
tive
Proposed mechanism for the formation of
Scheme VII
1,3-dimethyl alloxan 17b
Furthermore, the reaction of some acyclic b-dicar-
bonyl compounds with cyanogen bromide in acetone in the
presence of triethylamine were also examined. Reaction of
diethyl malonate (DEM) (21a), ethyl cyanoacetate (ECA)
(21b) and ethyl acetoacetate (EAA) (21c) with cyanogen
bromide in acetone formed diethyl bromomalonate (22a)
and ethyl bromoacetoacetate (22c) in moderate yield, re-
spectively. Triethylammonium hydrobromide salt was ob-

314 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Hosseini et al.
served in all reaction products (Schemes I and IX).
Cyanation and bromination of 21 via cy-
anogen bromide and formation of 27b
from 21b
Scheme IX
1
The H NMR spectrum of diethyl bromomalonate,
22a show a triplet at d 1.31 and a quartet at d 4.29 ppm are
of to equivalent methyl and methylene protons, respec-
tively. A singlet at d 4.82 corresponds to the CHBr proton.
The peak integration ratios 1.0:4.0:6.0 are of methine, two
methylene and two methyl protons, respectively. These ra-
tios are in good agreement with the structure of 22a. The
13C NMR spectrum of 22a show a peak at d 13.85 and 63.21
ppm are of methyl and methylene carbon atoms, at d 42.40
and 164.58 ppm corresponds to the methine and carbonyl
carbon atoms, respectively (see experimental).
Diethyl cyanomalonate, 23a has been synthesized
previously by the reaction of ethyl cyanoacetate, 21b with
ethyl chloroformate in the presence of anhydrous potas-
sium carbonate in acetone.35 We performed the reaction of
21a with cyanogen bromide according to method of refer-
ence 35 (formation of 23a was not observed). In contrast,
our experiments indicated that the reaction of 21a with
cyanogen bromide leads to diethyl bromomalonate, 22a
and N,N-diethylcyanamide (24) in acetone and/or ether
(Scheme IX). Expectedly, triethylamine attacks the NC+ of
cyanogen bromide obtaining triethylcyanoammonium bro-
mide salt (26) (Scheme X). According to Scheme X, the
ethyl bromide and 24 were observed based on von Braun
reaction5 through analyzing the crude reaction mixture by
GC-Mass analyses.
Scheme X Formation of 24 via von Braun reaction5
The reaction of ethyl cyanoacetate, 21b with cyano-
gen bromide in ether indicated no significant product(s). In
contrast, in acetone as a polar aprotic solvent ethyl 2-iso-
propylidenecyanoacetate (27b) was afforded by means of
the condensation of 21b with acetone in 32% yield
(Scheme IX). No 22b and 23b were observed in this reac-
tion. The structure of 27b was characterized by 1H NMR,
Fig. 3. The expanded 1H NMR spectrum (minor tauto-
mer is assigned by *) of the equilibrium mix-
tures of two lactam and lactim forms (a) and 13C
NMR spectrum (b) of 8a.

One-pot New Barbituric Acid Derivatives
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 315
1
13C NMR and GC-Mass analysis. H NMR spectra show
Table 1. The summary of GC-Mass analysis of the reaction
between 21a-c with cyanogen bromide
two singlets at d 2.31 and 2.41 ppm, corresponding to the
two geminal methyl protons on carbon-carbon double
bond. A triplet at d 1.36 and a quartet at 4.27 ppm corre-
Material(s)
Reaction
Solvent
Yield [b]
(%)
Compd.
RT[a]/min obtained from
column elution
spond to methyl and methylene groups, respectively. 13
C
21a
21a
21a
21a
21a
21a
21b
21b
21b
21c
21c
21c
21c
Ether
Ether
Ether
Acetone
Acetone
Acetone
Ether
Acetone
Acetone
Ether
1.11
2.32
3.64
0.85
2.44
3.96
1.62
1.66
3.17
2.71
2.75
2.95
2.56
24
13.5
64.1
20.0
14.3
47.6
38.1
100
39
32
11
20
10
NMR spectrum of 27b shows eight distinct peaks that con-
firms its structure characterization (see experimental).
Interestingly, ethyl bromoacetoacetate, 22c or ethyl
cyanoacetoacetate (23c) were found in the reaction be-
tween ethyl acetoacetate, 21c and cyanogen bromide in
ether as nonpolar aprotic solvent (Scheme IX). Some other
unknown compounds also were observed as by-products
by means of GC-Mass analyzing. The separation of all
products released from 21c was unsuccessful by silica gel
column chromatography. No distinct product(s) were ob-
served in acetone. We characterized the structures of 22c
and 23c (from crude reaction mixture) by means of GC-
Mass analyses. No triethylammonium 2-bromo-1,3-dieth-
oxy-1,3-dioxopropan-2-ide (25a), triethylammonium 1-
bromo-1-cyano-2-ethoxy-2-oxoethan-1-ide (25b) and tri-
ethylammonium 2-bromo-1-ethoxy-1,3-dioxobutan-2-ide
(25c) salts were obtained in the reactions of 21a-c with
cyanogen bromide in presence of triethylamine, respec-
tively. The results from GC-Mass analyses of the obtained
products from 21a-c were summarized in Table 1.
21a
22a
24
21a
22a
21b
21b
27
21c
22c
23c
22c
Ether
Ether
Acetone
trace
[a] Retention time. [b] Yields refer to peak integration.
EXPERIMENTAL
General
Melting points were measured with a digital melting
point apparatus (Electrothermal) and were uncorrected. IR
spectra were determined in the region 4000-400 cm-1 on a
NEXUS 670 FT IR spectrometer by preparing KBr pellets.
The 1H and 13C NMR spectra were recorded on Bruker 300
FT-NMR at 300 and 75 MHz, respectively (Urmia Univer-
sity, Urmia, Iran). 1H and 13C NMR spectra were obtained
on solution in DMSO-d6 and/or in CDCl3 as solvents using
TMS as internal standard. Elemental analyses were per-
formed using a VarioEL III analyzer (Tabriz University,
Tabriz, Iran). The mass analysis performed using mass
spectrometer (Agilent Technology (HP) type, MS Model:
5973 network Mass selective detector Electron Impact (EI)
70 eV), ion source temperature was 230 ºC (Tehran Univer-
sity, Tehran, Iran). The GC-Mass analyses were recorded
on Thermo Finnigan K970 (Urmia University). The com-
pounds 1a-c were synthesized and purified in our labora-
tory as described in literature previously.36 Cyanogen bro-
mide was synthesized based on reported references.4 Com-
pounds 21a-c, triethylamine and used solvents purchased
from Merck and Aldrich without further purification.
Preparation of compound 7a
X-Ray analysis of compound 16b
Crystals of 16b were obtained by slow evaporation
of a solution of 16b in acetone at room temperature. The
data were acquired using a STOE IPDS II diffractometer,
data collection and cell refinement were processed using
STOE X-AREA (Stoe & Cie, 2002) and data reduction
was processed using STOE X-RED (Stoe & Cie, 2002) pro-
gram. Program(s) used to refine structure was SHELXL97
(Sheldrick, 1997, University of Göttingen, Germany, 1997).
Crystal data for 16b: Orthorhombic; C18H18N6O9; M 462.38;
Unit cell parameters at 293(2) K: a = 13.2422(4), b =
15.9176(6), c = 19.5817(6) Å; a = b = g = 90°; V =
4127.5(2) Å3; Z = 8; m = 0.122 mm–1; Total reflection num-
ber 4275; 304 parameters; l = 0.71073 Å; 2916 reflections
with I > 2s(I); Rint = 0.056; qmax = 26.49°; R[F2 > 2s(F2)]
= 0.048; wR(F2) = 0.112; S = 1.02, F000 = 1920. The crystal-
lographic data for 16b were deposited to the Cambridge
Crystallographic Data Center (entry no. CCDC-786144)
and are available free of charge upon request to CCDC, 12
Union Road, Cambridge, UK (fax: +44-1223-336033, e-
mail: deposit@ccdc.cam.ac.uk).
Synthetic Procedure for 5,5-dimethyl-1H,1¢H-
spiro[furo[2,3-d]pyrimidine-6,5¢-pyrimidine]-
2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone 7a
In a round bottom flask equipped with magnetically

316 J. Chin. Chem. Soc., Vol. 58, No. 3, 2011
Hosseini et al.
stirrer, 0.075 g (0.58 mmol) barbituric acid and 0.033 g
(0.58 mmol) acetone were dissolved in 25 mL methanol
and were refluxed for 24 h. The 0.075 g (0.58 mmol) barbi-
turic acid and 0.1 mL (0.75 mmol) triethylamine was added
into previous solution and transferred into a separatory fun-
nel. This solution was added drop wise into the solution of
0.052 g (0.58 mmol) BrCN equipped with an ice-bath and
magnetically stirrer then stirred for 3 hours. (Caution! The
cyanogen bromide is highly toxic. Reactions should be car-
ried out in a well-ventilated hood). Finally, the reaction
mixture perturbed to dark red color. The reaction mixture
was kept overnight at room temperature and white crystal-
line solid precipitated, filtered, washed with cold water and
dried. (0.07 g, 50%), mp 165-166 °C (decomps.). FT-IR
(KBr): 3523, 3245, 2848, 1708, 1655 cm-1. 1H NMR (300
MHz, DMSO-d6, d): 1.30 (s, 6H), 10.77 (s, 1H), 11.68 (s,
2H), 12.43 (bs, 1H). 13C NMR (75 MHz, DMSO-d6, d):
165.7, 162.5, 160.5, 151.0, 150.1, 92.6, 91.0, 50.5, 23.8.
Anal. Calcd for C11H10N4O6 (MW 294.11): C, 44.88; H,
3.43; N, 19.05. Found: C, 41.71; H, 3.44; N, 16.70%. MS
m/z: 294 (M+, 21), 279 (base peak, 100), 236 (15), 219 (5),
193 (40), 167 (20), 150 (25), 122 (10), 108 (8), 82 (10), 56
(35), 44 (15).
72.3, 46.2, 9.1. Anal. Calcd. for C10H18N3O3Br: C, 38.9; N,
13.63; H, 5.84. Found: C, 39.04; N, 13.66; H, 5.92%. MS
m/z: 308 (M+, 0), 154 (7), 128 (base peak, 100), 101 (15),
86 (60), 72 (5), 58 (16), 42 (98).
Triethylammonium-1,3-dimethyl-5-bromo-2,4,6-trioxo-
hexahydropyrimidin-5-ide 6b
White solid (45%), mp 152-154 °C (decomps.).
1
FT-IR (KBr) 3200, 2980, 1670, 526 cm-1. H NMR (300
MHz, DMSO-d6, d): 1.17 (t, 9H), 2.80 (s, 6H), 3.08 (q, 6H),
8.95 (bs, 1H). 13C NMR (75 MHz, DMSO-d6, d): 161.9,
157.1, 73.4, 46.1, 30.2, 9.1. Anal. Calcd. for C12H22N3O3Br:
C, 42.87; N, 12.50; H, 6.60. Found: C, 42.65; N, 12.43; H,
6.52%.
Triethylammonium-5-bromo-4,6-dioxo-2-thioxohexa-
hydropyrimidin-5-ide 6c
White solid (50%); mp 159-161 °C. FT-IR (KBr)
1
3408, 2975, 1648, 1612, 590 cm-1. H NMR (300 MHz,
DMSO-d6, d): 1.16 (t, 9H), 3.07 (q, 6H), 10.17 (bs, 1H),
10.35 (bs, 2H). 13C NMR (75 MHz, DMSO-d6, d): 174.7,
164.3, 79.7, 46.2, 9.1. Anal. Calcd. for C10H18N3O2SBr: C,
37.05; N, 12.97; H, 5.56. Found: C, 37.10; N, 13.05; H,
5.51%.
5-Ethyl-5-methyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-
6,5¢-pyrimidine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-pentaone 8a
White crystalline solid, mp 182 °C (decomps.). FT-IR
(KBr) 3258, 2852, 1762, 1717, 1656 cm-1. 1H NMR (300
MHz, DMSO-d6, d): 1.19 (t, 3H), 3.09 (m, 1H), 3.18 (s,
3H), 3.60 (q, 1H), 10.80 (s, 1H), 11.55 (s, 1H), 11.65 (s,
1H), 12.46 (bs, 1H). 13C NMR (75 MHz, DMSO-d6, d):
167.7, 167.1, 165.0, 163.3, 162.8, 160.8, 160.7, 151.2,
151.1, 150.0, 88.7, 87.9, 84.6, 83.9, 46.2, 45.0, 35.1, 15.5,
9.1 (Mixture of two tautomers); MS m/z: 308 (M+, 1), 291
(6), 277 (20), 262 (3), 248 (30), 222 (21), 206 (18), 178
(10), 163 (18), 149 (20), 135 (10), 108 (7), 93 (10), 70 (30),
44 (100).
1,1¢,3,3¢,5,5¢-Hexamethyl-1H,1¢H-spiro[furo[2,3-d]pyr-
imidine-6,5¢-pyrimidine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-penta-
one 7b
White solid, mp 210-212 °C (decomps.). FT-IR (KBr)
2982, 2955, 1689, 1646 cm-1. 1H NMR (300 MHz, DMSO-
d6, d): 1.40 (s, 6H), 3.28 (s, 3H), 3.36 (s, 6H), 3.43 (s, 3H).
13C NMR (75 MHz, DMSO-d6, d): 164.3, 160.2, 158.9,
151.0, 150.2, 93.2, 91.1, 53.9, 29.6, 29.1, 27.9, 23.3. Anal.
Calcd. for C15H18N4O6 (MW 350.33): C, 51.38; H, 5.14; N,
15.99. Found: C, 51.23; H, 5.63; N, 16.14%.
5,5-Dimethyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-6,5¢-
pyrimidine]2,2¢-dithioxo-4,4¢,6¢(3H,3¢H,5H)-trione 7c
Pale yellow crystalline solid, mp 190 °C (decomps.).
FT-IR (KBr) 3437, 2968, 1666 cm-1. 1H NMR (300 MHz,
DMSO-d6, d): 1.20 (s, 6H), 1.26 (s, 6H), 12.40 (bs, 4H),
13.32 (bs, 4H) (The mixture of two tautomers 7c[I] and
7c[II]). 13C NMR (75 MHz, DMSO-d6, d): 171.9, 167.6,
162.0, 157.8, 108.4, 87.6, 85.2, 67.8, 28.8, 14.3.
5-Ethyl-1,1¢,3,3¢,5-pentamethyl-1H,1¢H-spiro[furo[2,3-
d]pyrimidine-6,5¢-pyrimidine]2,2¢,4,4¢,6¢(3H,3¢H,5H)-
pentaone 8b
White crystalline solid, mp 197 °C (decomps.). FT-IR
(KBr) 2959, 1690, 1654 cm-1. 1H NMR (300 MHz, DMSO-
d6, d): 1.32 (s, 3H), 3.31 (s, 3H), 3.37 (s, 3H), 3.38 (s, 3H),
3.44 (s, 3H), 3.81 (q, 2H, J = 6.9 Hz). 13C NMR (75 MHz,
DMSO-d6, d): 165.8, 163.4, 161.1, 159.2, 151.1, 149.9,
88.9, 87.9, 66.0, 54.0, 47.8, 29.8, 29.5, 29.0, 28.0, 14.9;
MS m/z: 364 (M+, 1), 336 (30), 293 (10), 249 (12), 220
(30), 181 (100), 149 (35), 124 (8), 97 (5), 80 (10), 57 (15),
43 (18).
Teriethylammonium-5-bromo-2,4,6-trioxohexahydropy
rimidin-5-ide 6a
White solid (50%), mp 155-158 °C (decomps.). FT-
IR (KBr) 3130, 2985, 1658, 524 cm-1. 1H NMR (300 MHz,
DMSO-d6, d): 1.16 (t, 9H), 3.08 (q, 6H), 8.93 (bs, 1H), 9.38
(s, 2H). 13C NMR (75 MHz, DMSO-d6, d): 161.3, 152.0,

One-pot New Barbituric Acid Derivatives
J. Chin. Chem. Soc., Vol. 58, No. 3, 2011 317
5-Ethyl-5-methyl-1H,1¢H-spiro[furo[2,3-d]pyrimidine-
6,5¢-pyrimidine]2,2¢-dithioxo-4,4¢,6¢(3H,3¢H,5H)-trione
8c
ogy (IUT) from Iran for his helpful discussion and guid-
ance.
Yellow crystalline solid, mp 204 °C (decomps.).
FT-IR (KBr) 3432, 2925, 1640, 1635 cm-1. 1H NMR (300
MHz, DMSO-d6, d): 1.15 (t, 3H), 2.50 (s, 3H), 3.06 (m,
2H), 8.85 (bs, 1H), 9.71 (bs, 1H), 10.89 (bs, 1H), 12.12 (bs,
1H). 13C NMR (75 MHz, DMSO-d6, d): 178.0, 176.0,
168.2, 166.6, 165.6, 163.7, 90.3, 83.0, 46.2, 13.4, 9.1.
5,6-Dihydro-l,3-dimethyl-5,6-bis-[l¢,3¢-dimethyl-2¢,4¢,6¢-
trioxo-pyrimid(5¢,5¢)yl]furo[2,3-d]uracil 16b28
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