Preparation of 5-diaminomethylenebarbiturates by barbituric acid addition to carbodiimides

Article abstract of DOI:10.1016/S0040-4020(03)00489-7

Through NMR spectroscopic monitoring of barbituric acid addition to carbodiimide, a general synthetic procedure for the preparation of 5-diaminomethylenebarbiturates (DABA) was developed. This procedure is very simple and applicable to the preparation of large quantities of DABA derivatives. Through an X-ray structural study of one of the DABA derivatives, it was established that these compounds have an ylide-type structure with strong charge separation within the molecule.

Full text of DOI:10.1016/S0040-4020(03)00489-7

Tetrahedron 59 (2003) 3427–3432
Preparation of 5-diaminomethylenebarbiturates by barbituric
acid addition to carbodiimides
*
Branko S. Jursic, Fred Douelle and Edwin D. Stevens
Department of Chemistry, University of New Orleans, Lakefront, New Orleans, LA 70148, USA
Received 7 February 2003; revised 24 March 2003; accepted 24 March 2003
Abstract—Through NMR spectroscopic monitoring of barbituric acid addition to carbodiimide, a general synthetic procedure for the
preparation of 5-diaminomethylenebarbiturates (DABA) was developed. This procedure is very simple and applicable to the preparation of
large quantities of DABA derivatives. Through an X-ray structural study of one of the DABA derivatives, it was established that these
compounds have an ylide-type structure with strong charge separation within the molecule. q 2003 Elsevier Science Ltd. All rights reserved.
1
. Introduction
3 (Scheme 1). If thorough biological evaluation of the
structural isomers of 3 is to be successful, then reliable
synthetic procedures for the preparation of these isomers
must be developed. These procedures should ensure the
synthesis of large quantities of material of high purity, and a
common synthetic procedure should be applicable for the
preparation of a large number of structural variations of
compound 3.
It was previously determined that some simple nitro-
phenylhydrazones of aromatic ketones (compound 1,
1
Scheme 1) possess strong anticancer activity. In addition,
it was also determined that these compounds possess
2
immuno-modulating and strong molecular binding
3
capabilities. Therefore, one might speculate that the
anticancer activity of 1 could be the result of the immuno-
4
modulating capabilities of these compounds. There are also
5
Examining the structural characteristics of our target
molecule (3), it is obvious that DABA contains two major
moieties, urea and barbituric acid (Scheme 2). These readily
some literature reports on both the anticancer and immuno-
6
modulating capabilities of barbituric acid derivatives,
8
which has directed our research toward the development
of new barbituric acid derivatives as anticancer drugs that
act as immuno-modulating agents. This research has led to
the design of a new barbituric acid derivative 2 with both
available starting reagents can be condensed by virtue of
one water molecule elimination. Although condensation
reactions between carbonyl compounds and barbituric acid
are well documented, the reaction is mostly successful with
7
9
anticancer and immuno-modulating activity.
aromatic aldehydes and with some activated ketones. To be
able to perform urea–barbituric acid condensation, urea
should be activated through its transformation into a more
reactive intermediate, such as carbodiimide (Scheme 2).
Using this rationale, DABA derivatives can be prepared by
barbituric acid addition to carbodiimides. To the best of our
knowledge there is no available literature procedure for the
By close comparison of the structural properties of the
biologically active compounds that have been prepared and
tested in our laboratories, we have extended our search for
anticancer compounds to a new family of barbituric acid
derivatives that have the structural properties of compound
Scheme 1. Structures of known anticancer compounds 1 and 2 and our general synthetic target 3.
Keywords: barbituric acid; 5-diaminomethylenebarbiturates; immuno-modulating agents.
*
Corresponding author. Tel.: þ1-5042807090; fax: þ1-5042806860; e-mail: bjursic1@uno.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00489-7

3428
B. S. Jursic et al. / Tetrahedron 59 (2003) 3427–3432
Scheme 2. Transformation of barbituric acid and urea derivatives into DABA derivatives.
preparation of DABA derivatives from urea (carbo-
1
diimides) and barbituric acid.
DMSO as a reaction solvent. Although reaction conditions
0
for every reported compound in this paper were optimized
through NMR spectroscopic monitoring, only results for
barbituric acid and 1,3-dimethylbarbituric acid addition to
1,3-di(4-methylphenyl)carbodiimide will be discussed. The
addition of barbituric acid is a very slow process and with
water present in the reaction media, water addition to
carbodiimide becomes the dominant reaction. That was
demonstrated with NMR spectroscopic monitoring of
barbituric acid addition to di(4-methylphenyl)carbodiimide
at room temperature (Fig. 1). Using a tenfold barbituric acid
excess ensured that large quantities of water were added into
the reaction media. All starting material was practically
consumed after 24 h at room temperature and 1,3-di(4-
methylphenyl)urea was formed (Fig. 1). We believe that this
urea derivative immediately forms a molecular complex
with the surrounding barbituric acid, which is evident by the
appearance of the NH singlet of the barbituric acid moiety in
the complex at 10.15 ppm. Same NMR pattern is obtained
for DMSO solution of barbituric acid and 1,3-di(4-
methylphenyl)urea. There is only a small amount of the
desirable product 4. With elevated temperatures the ratio of
the product, with regards to water addition to the
carbodiimide, increases (Fig. 1). It seems that the best
reaction temperature is 1508C, at which the reaction is
completed after 15 min and more than 95% of the target
product 4 is formed.
However, there are some literature data that suggest that this
synthetic approach might be successful. It was demonstrated
that compounds with active methylene groups such as
1
1
diethyl malonate can add to carbodiimides. This conden-
sation reaction was carried out at a high temperature with
diphenyl ether as the reaction solvent. In many chemical
reactions, barbituric acid is considered to be a compound
with an active methylene group. If barbituric acid and 1,3-
dicyclohexylcarbodiimide (DCC) are mixed together in
THF in the presence of pyridine, immediately the color of
the reaction mixture changes to fluorescent purple. In fact,
DCC in combination with pyridine has been used for the
1
2
analytical detection of barbituric acid, but the products for
1
this reaction have not been isolated.
3
2
. Results and discussion
In our initial experiments, we demonstrated that in THF
barbituric acid adds to DCC, but the reaction requires a long
time (several weeks at room temperature) to be com-
1
4
pleted. Additionally, besides the major product of this
reaction, one can also obtain the 1,3-dicyclohexylurea
byproduct of water addition to DCC. If the reaction is
performed in refluxing THF, products of decomposition
were formed. Therefore, we have carefully explored
reaction conditions for the barbituric acid addition to
carbodiimides through the NMR spectroscopic monitoring.
Similar results were observed when other barbituric acid
derivatives were added to di(4-methylphenyl)carbodiimide.
That is demonstrated by the methyl portion of the NMR
spectrum in the 1,3-dimethylbarbituric acid addition to 1,3-
di(4-methylphenyl)carbodiimide (Fig. 2). The water con-
centration is substantially lower than in the previous
experiment (the bulk of the water in the reaction media is
associated with barbituric acid), and the desirable product 5
is present in a much higher ratio. The addition of the
barbituric acid is very slow at room temperature and 9 days
Experiments are performed in aprotic solvents such as
tetrahydrofuran, dioxane, benzene, toluene, dimethylforma-
mide, and dimethyl sulfoxide. The solubility of barbituric
acid in some of these solvents is very low. The most reliable
experimental data that can also be applied to large scale
(
100 g) preparations of target compound 3 are obtained in
1
Figure 1. The H NMR spectroscopic monitoring of barbituric acid (10 mM) addition to 1,3-di(4-methylphenyl)carbodiimide (1 mM) in DMSO-d
6
(1 mL).

B. S. Jursic et al. / Tetrahedron 59 (2003) 3427–3432
3429
1
Figure 2. The methyl region of the H NMR spectra for 1,3-dimethylbarbituric acid (1 mM) addition to 1,3-di(4-methylphenyl)carbodiimide (1 mM) in
DMSO-d (1 mL).
6
are required for both reactants to be consumed (Fig. 2);
mmol of each reactant in 1 mL of DMSO yielded an
almost equimolar ratio of product 5 and the molecular
complex (Fig. 2). If the reaction was performed at 1508C for
molecular sieves for a few days to eliminate water that
usually accompanies barbituric acid. Into such dried
solution corresponding carbodiimide should be added and
the reaction mixture should be kept in a closed container at
room temperature for 14 days. Solvent was evaporated and
the remaining residue was crystallized from methanol,
resulting in the pure target compounds 4–12 in 85–95%
yield. Due to low solubility of barbituric acid derivatives in
tetrahydrofuran this procedure is practical for the
preparation of small quantities of 5-diaminomethylene-
barbiturates. For large-scale preparation DMSO is much
more suitable as reaction solvent. Isolated yields and
applied methods for the preparation of 5-diaminomethyl-
enebarbiturates 4–12 are listed in Table 1.
1
15 min then the major product of the reaction (95%
conversion) is condensation product 5.
From these experiments, it is obvious that our target
compounds can be prepared at elevated temperatures
(
1508C) in a very short reaction period (15 min). Satisfac-
tory yields of the condensation products can also be
obtained if the reaction is performed in other inert solvents,
such as tetrahydrofuran at room temperature. Tetrahydro-
furan solution of barbituric acid should be dried over
Table 1. Isolated yields of 5-diaminomethylenebarbiturates 4–12
Compound
Method
R
1
R
2
R
3
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
4
5
6
7
7
8
8
9
A
B
A
C
D
C
D
C
D
E
4-CH
4-CH
4-CH
3
3
3
C
C
C
6
6
6
H
H
H
4
4
4
H
CH
H
CH
H
H
H
CH
CH
H
H
H
89
90
89
83
86
87
85
92
87
89
95
93
3
3
C
6
H
5
(CH
(CH
(CH
(CH
(CH
(CH
3
3
3
3
3
3
)
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
H
H
)
)
)
)
)
CH
CH
3
3
3
3
C
C
6
H
H
5
5
9
6
0
1
2
10
11
12
C
C
C
6
6
6
H
11
H
11
H
11
H
CH
B
B
3
CH
H
3
C
6
H
5
Figure 3. ORTEP drawing of X-ray crystallographic structure of 11 and its ylide structure.

3430
B. S. Jursic et al. / Tetrahedron 59 (2003) 3427–3432
To confirm the structural properties of the prepared target
barbituric acid derivatives, compound 11 was selected for
X-ray structural studies. Our spectroscopic data for
product 4 (,95%) and 1,3-di(4-methylphenyl)urea (,5%).
The reaction mixture was cooled to room temperature,
diluted with methanol (,100 mL), and left at room
temperature overnight for the solvent to slowly evaporate
to a volume of ,30 mL. The white precipitate was
separated by filtration, washed with cold methanol
5
-diaminomethylidenebarbiturates are in full agreement
with the X-ray determined structure of 11 (Fig. 3). It is
interesting to mention that the C(7)–C(8) bond between
urea and the barbituric acid moiety has only partial double
bond character. The compound can be better described as an
ylide with a positive charge located on the urea carbon and a
negative charge on the barbituric acid moiety. This charge
separation is perfectly demonstrated with strong vO· · ·HN
hydrogen bonding and a very high chemical shift for the
urea NH hydrogen (Fig. 3).
(3£5 mL) and dried at 1108C for 30 min to give 310 mg
1
(89%) pure product. Mp 278.78C. H NMR (DMSO-d ,
6
500 MHz) d 12.61 (2H, s, NHAr), 10.88 (2H, s, NH), 6.84
(4H, d, J¼8.0 Hz, m-H), 6.81 (4H, d, J¼8.0 Hz, o-H), and
1
3
2.10 (6H, s, CH ). C NMR (DMSO-d , 500 MHz) d 167.2,
3
6
157.9 (carbonyl carbons), 149.1, 80.3 (CvC carbonyls),
134.4, 133.7, 128.9, 122.9 (aromatic carbons, and 20.3 ppm
þ
(
methyl carbon). MS-ES (CH OH) m/z 405 (MþCH -
3
3
þ
þ
(350.14): C, 65.13; H, 5.18; N, 15.99. Found:
þ
þ
OHþNa , 100%) , 723 (2MþNa , 90%) . Anal. calcd for
3. Conclusion
C H N O
19 18 4 3
C, 65.11; H, 5.20; N, 15.95.
In conclusion it can be stated that through careful NMR
spectroscopic monitoring it was possible to develop a
general synthetic procedure for the preparation of large
quantities of 5-diaminomethylenebarbiturates from substi-
tuted carbodiimides (urea) and barbituric acid. Preparation
of a wide variety of structural isomers of these compounds is
now possible. It was also demonstrated that strong
electrostatic interactions between these two moieties (urea
and barbituric acid) exist and that these interactions are
responsible for strong charge separation throughout the
molecule that has ylide-like structural properties.
4.1.2. Typical procedure B. Preparation of 5-[di(4-
methylphenylamino)methylene]-1,3-dimethylpyrimi-
dine-2,4,6-trione (5)
A mixture of 1,3-dimethylbarbituric acid (156 mg; 1 mmol),
di(4-methylphenyl)carbodiimide (222 mg; 1 mmol) and
dimethyl sulfoxide (1 mL) was heated at 1508C for
15 min. The reaction solution was left at room temperature
for 2 h, and a white crystalline product precipitated. This
suspension was diluted with methanol (15 mL), and solid
product was separated by filtration, washed with methanol
(
3£5 mL) and dried at 1108C for 30 min resulting in 340 mg
1
4. Experimental
(90%). Mp 211.88C. H NMR (CDCl
3
, 500 MHz) d 12.85
(
2H, s, NH), 6.75 (4H, d, J¼9.0 Hz, m-H), 6.69 (4H, d,
), and 2.12 ppm (6H, s,
3
4
.1. General
J¼9.0 Hz, o-H), 3.36 (6H, s, NCH
1
3
CH ). C NMR (CDCl , 500 MHz) d 165.7, 158.8
3
3
All reagents and starting materials were purchased from
Aldrich Chemical Company and were used without further
purification. Solvents were purchased from Fisher Chemical
Company and were used without previous distillation or
drying. All NMR spectra were recorded on a 500 MHz
(carbonyl carbons), 151.0, 81.8 (CvC carbons), 135.2,
134.0, 128.1, 123.5 (aromatic carbons), 27.9 (NCH
3
þ
carbon), and 20.8 ppm (CH
carbon). MS-ES (CH
COOH)
3
3
m/z: 379 (Mþ1, 55%), 767 (2Mþ1, 25%). Anal. calcd for
C H N O
21 22 4 3
(378.42): C, 66.65; H, 5.86; N, 14.81. Found:
Unity Varian NMR instrument with DMSO-d (2.50 ppm,
6
C, 66.46; H, 5.90; N, 14.70.
for hydrogen and 39.51 ppm for carbon) and CDCl3
(
7.27 ppm for hydrogen and 77.23 ppm for carbon) as an
4.1.3. Preparation of 5-[di(4-methylphenylamino)methyl-
ene]-1-phenylpyrimidine-2,4,6-trione (6). Compound 6 was
internal reference. Electro-spray mass spectrometric
analysis was performed on a Micromass Quattro 2 Triple
Quadropole Mass spectrometer. X-Ray structure determi-
nation was performed on a Bruker SMART 1KCCD
automated diffractometer. Crystals of compound 11 were
obtained by slow crystallization from a diluted methanol
solution of 11. Melting points were determined on an
Electrothermal 9100 melting point apparatus and are not
corrected.
prepared by following procedure outlined in typical procedure
1
A. The isolated yield is 89%. H NMR (CDCl , 500 MHz) d
3
12.85 (2H, broad s, ArNH), 10.90 (1H, s, NH), 7.40 (2H, t,
J¼8.0 Hz), 7.35 (1H, t, J¼8.0 Hz), 7.18 (2H, d, J¼8.0 Hz),
6.77 (4H, d, J¼9.0 Hz), 6.65 (4H, d, J¼9.0 Hz), 2.15 ppm
(6H, s). C NMR (CDCl , 500 MHz) d 166.5, 166.3, 165.9,
3
1
3
165.7, 160.1, 151.0, 125.8, 135.2, 134.0, 129.8, 128.6, 128.1,
þ
127.9, 123.5, 80.3, and 20.6 ppm. MS-ES (CH
þ
OH) m/z: 449
27%), 875
(426.17): C,
3
þ
(
MþNa , 10%), 481 (MþCH OHþNa
3
þ
4
.1.1. Typical procedure A. Preparation of 5-[di(4-
methylphenylamino)methylene]pyrimidine-2,4,6-trione
4)
(2MþNa , 100). Anal. calcd for C25
H
N
22
4
O
3
70.41; H, 5.20; N, 13.14. Found: C, 70.29; H, 5.31; N, 13.09.
(
4.1.4. 5-(Diisopropylaminomethylene)pyrimidine-2,4,6-
trione (7). This compound was prepared by applying either
Barbituric acid (128 mg; 1 mmol), di(4-methylphenyl)car-
bodiimide (222 mg; 1 mmol) and dimethyl sulfoxide (1 mL)
were heated at 1508C for 15 min. Initially, the reaction
mixture was a suspension that first turned to a yellow
solution and then to a dark brown solution. The H NMR
test of the reaction mixtures suggests that all starting
carbodiimide was consumed and transferred into the desired
typical procedure C or D, obtaining the target product in 83
1
and 86% yields, respectively. H NMR (DMSO-d
,
6
400 MHz) d, 10.78 (2H, s, NHCHMe ), 10.43 (2H, s,
2
1
NH), 3.824 (2H, m, J¼6.0 Hz, CH), 1.21 (12H, d,
1
3
J¼6.0 Hz). C NMR (DMSO-d
, 400 MHz) d 166.8,
160.5, 151.7, 79.3, 45.4, and 23.2 ppm. ES-MS
6
þ

B. S. Jursic et al. / Tetrahedron 59 (2003) 3427–3432
3431
þ
(
CH CO H), 255 (MþH , 100%), 337 (MþCH CO Hþ
acid (12.8 g; 0.1 mol) and dicyclohexylcarbodiimide
(20.6 g; 0.1 mol) was heated at 1408C for 20 min. The
clear, deep brown reaction mixture was left at room
temperature for 4 h, and glass like plates of 1,3-dicyclo-
hexylurea (1.3 g) were separated by filtration. The dimethyl
sulfoxide filtrate was diluted with water (1 L). The resulting
suspension was stirred at room temperature for 30 min, and
a white solid was separated by filtration, washed with water
3
2
3
2
þ
C H N O (254.14): C, 51.96; H, 7.13; N, 22.03. Found:
þ
Na , 25%), 509 (2MþH , 30%). Anal. calcd for
1
1 18 4 3
C, 51.88; H, 7.23; N, 21.95.
4
.1.5. Typical procedure C. Preparation of 5-[di(1-
methylethylamino)methylene]-1,3-dimethylpyrimidine-
,4,6-trione (8)
2
(
3£50 mL) and mixed with methanol (150 mL). The
A tetrahydrofuran (50 mL) solution of 1,3-dimethylbar-
bituric acid (156 mg; 1 mmol) and diisopropylcarbodiimide
resulting methanol suspension was stirred at room tempera-
ture for 30 min; a solid residue was separated by filtration,
washed with methanol (3£30 mL) and dried at 1108C for
1 h. In this way pure product in 89% (29.7 g) yield was
obtained. If necessary, the product can be purified by
(
138 mg; 1.1 mmol) was stirred in a closed round bottle
flask for 10 days. Solvent was evaporated, the oily residue
was dissolved in absolute ethanol–benzene (1:3) solution
(
50 mL), and the solvent was evaporated. This procedure
crystallization from a large volume of methanol. Mp
1
was repeated three more times. The semi-solid residue was
mixed with methanol (100 mL) and the resulting mixture
was refluxed for 1 h, filtered and left in an open beaker
295.18C. H NMR (DMSO-d , 500 MHz) d 10.91 (2H, d,
6
J¼5.5 Hz, NH), 10.46 (2H, s, barbituric acid NH), 3.49 (2H,
m, CH), 1.87 (4H, m), 1.66 (4H, m), 1.50 (2H, m), and
1.34 ppm (10H, m). C NMR (DMSO-d , 500 MHz) d
1
3
(
150 mL) at room temperature for several days. Methanol
6
slowly evaporated at room temperature almost to dryness,
and formed large glassy-like needles of the product were
separated by filtration, washed with cold methanol
166.8, 160.2 (carbonyl carbons), 149.1, 79.3 (CC double
bond carbons) 51.8, 32.6, 24.9, 23.2 ppm (cyclohexane
þ
moiety carbons). MS-ES (CH OH) m/z: 389 (MþCH -
3
3
þ
þ
(
(
3£5 mL) and dried at 1108C for 2 h to give 245 mg
OHþNa , 60%), 581 (MþDCUþNa , 40%), 805
þ þ
Anal. calcd for C H N O (334.20): C, 61.06; H, 7.84;
1
87%) of pure product. Mp 169.38C. H NMR (DMSO-d ,
6
(Mþ2DCUþNa , 60%), 915 (2MþDMUþNa , 35%).
5
00 MHz) d 10.75 (2H, s, NH), 3.86 (2H, m, CH), 3.12 (6H,
1
1
7 26 4 3
3
s, NCH ), and 1.22 ppm (12H, d, J¼6.0 Hz, C(CH ) ). C
NMR (DMSO-d , 500 MHz) d 164.1, 160.3 (carbonyl
N, 16.75. Found: C, 61.05; H, 7.89; N, 16.69.
3
3 2
6
carbons), 150.4, 81.0 (CvC carbons), 45.5, 23.0 (isopropyl
þ
4.2.3. Preparation of 5-[di(cyclohexylamino)methylene)-
1,3-dimethylpyrimidine-2,4,6-trione (11). Compound 11
carbons), and 27.3 ppm (NCH carbon). MS-ES (CH3-
3
þ
COOH) m/z: 283 (MþH , 100%), 365 (MþCH COOHþ
was prepared by following the procedure outlined in typical
1
3
þ
Anal. calcd for C H N O (382.17): C, 55.30; H, 7.85; N,
þ
þ
Na , 18%), 565 (2MþH , 22%), 869 (3MþNa , 25%).
procedure B. The isolated yield is 85%. H NMR (CDCl ,
3
500 MHz) d 10.97 (2H, d, J¼7.5 Hz, NH), 3.29 (2H, m),
1
3 22 4 3
1
9.84. Found: C, 55.28; H, 7.90; N, 19.72.
3.14 (6H, s, CH ), 1.82 (4H, m), 1.65 (4H, m), 1.46 (2H, m),
3
1
3
1.30 (4H, m), and 1.20 ppm (6H, m). C NMR (CDCl3,
500 MHz) d 165.3, 160.9 (two carbonyl carbons), 150.8,
4
.2. Typical procedure D
81.1 (two CC double bond carbons) 53.2, 33.4, 27.4, 25.2,
and 24.2 ppm (four cyclohexane carbons). MS-ES
þ
þ
Compound 8 was also prepared by typical procedure D. The
reaction was performed with the same quantities of the
reactants as in typical procedure C, except dimethyl
sulfoxide (1 mL) was used as solvent. The reaction mixture
was heated in a closed container at 1508C for 15 min and the
solvent was evaporated at 10 mm pressure to an oily
residue. This residue was crystallized from methanol in the
same manner as described in method C. The product was
prepared in 85% yield.
(CD OD) m/z: 363 (Mþ1þ, 7%), 417 (MþCH OHþNa ,
3
3
þ
45%), 609 (MþdicyclohexylureaþNa , 55%), 747
þ
(2MþNa , 75%). Anal. calcd for C H N O (362.23):
1
9 30 4 3
C, 62.96; H, 8.34; N, 15.46. Found: C, 62.89; H, 8.31; N,
15.32.
2
3
4.2.4. Preparation of 5-[di(cyclohexylamino)methylene)-
1-phenylpyrimidine-2,4,6-trione (12). Compound 12 was
prepared by following the procedure outlined in typical
1
4.2.1. 5-(Diisopropylaminomethylene)-1-phenylpyrimi-
dine-2,4,6-trione (9). Compound 9 was prepared by
procedure B. The isolated yield is 95%. H NMR (DMSO-
d , 500) d, 10.87 (3H, broad singlet), 7.43 (2H, t, J¼7.5 Hz),
6
following either typical procedures C or D to obtain the
1
7.37 (1H, t, J¼7.5 Hz), 7.21 (2H, d, J¼7.5 Hz), 3.51 (2H,
target product in 92 and 87% yields, respectively. H NMR
(
m), 1.89 (4H, m), 1.67 (4H, m), 1.52 (2H, m), 1.35 ppm
(10H, m). C NMR (DMSO-d , 500 MHz) d 165.9, 165.7,
1
3
DMSO-d , 500 MHz) d 10.75 (2H, s, NH), 2.03 (1H, s,
6
6
NH), 7.45 (2H, t, J¼7.5 Hz), 7.34 (1H, t, J¼7.5 Hz), 7.19
160.1 (three different carbonyl carbons), 149.2, 135.8,
129.4, 128.6, 127.7, 79.8 (aromatic and CC double bond
carbons), 52.1, 32.7, 24.9, and 23.4 ppm (cyclohexane
(
2H, d, J¼7.5 Hz), 3.86 (2H, m, CH), and 1.22 ppm (12H, d,
1
3
J¼6.0 Hz, C(CH ) ). C NMR (DMSO-d , 500 MHz) d
3
2
6
þ
þ
1
4
64.2, 163.7, 160.3, 150.2, 135.7 129.2 128.3 127.5, 81.0,
5.3, and 22.7 ppm. MS-ES (CH COOH) m/z: 331
þ
1.80; H, 6.71; N, 16.96. Found: C, 61.72; H, 6.81; N, 16.83.
moiety carbons). MS-ES (CH OH) m/z: 433 (MþNa ,
3
þ
þ
þ
100%). Anal. calcd for C H N O (410.23): C, 67.29;
20%), 465 (MþCH OHþNa , 30%), 843 (2MþNa ,
3
3
(
6
MþH , 30%). Anal. calcd for C H N O (330.17): C,
1
7
22
4
3
23 30 4 3
H, 7.37; N, 13.65. Found: C, 67.12; H, 7.36; N, 13.49.
4.2.2. Typical procedure E. Preparation of 5-[di(cyclo-
hexylamino)methylene]pyrimidine-2,4,6-trione (10)
Acknowledgements
A dimethyl sulfoxide (150 mL) suspension of barbituric
Financial support for this work has been provided by the

3432
B. S. Jursic et al. / Tetrahedron 59 (2003) 3427–3432
Louisiana Board of Reagents for their financial support
LEQSF (2001-04)-RD-B-12) and Cancer Association of
Greater New Orleans (CAGNO).
available or can be readily prepared from diethyl malonate
condensation with 1- and 1,3-disubstituted ureas. For instance
see: Vogel, A. I. A Text-Book of Practical Organic Chemistry;
(
3
rd ed. Wiley: New York, 1966.
9
. For a Knoevenagel-type of condensation between aromatic
aldehydes and barbituric acid see: (a) De Belin, J.; Romero-
Martin, M.-R.; Finn, P. W.; Sayers, L. G.; Law, N. M.;
Billington, D. C.; Ryley, S.; Bhattacharya, S. Barbituric Acid
Analogs as Therapeutic Agents. International Patent WO 01/
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(
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formation of a urea–barbituric acid complex comes from our
7
8
. Morgan, L. R.; Jursic, B. S.; Hooper, C. L.; Neumann, D. M.;
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1
few H NMR studies. In depth investigation of the complex
3407.
formation that involves NMR, ES-MS and X-ray crystal-
lography is underway.
. A wide variety of barbituric acid derivatives is commercially