Simple, Efficient, High Yield Syntheses of Substituted and Unsubstituted 5-Benzoylbarbituric Acids, and Their Corresponding Schiff Base Phenylhydrazones

Article abstract of DOI:10.1002/jhet.5570410214

Preparation procedures for biologically important benzoylbarbiturates are presented. Several procedures are optimized to cover the preparations of a wide variety of substituted 5-benzoylbarbiturates. To further explore the biological importance of these c

Full text of DOI:10.1002/jhet.5570410214

Simple, Efficient, High Yield Syntheses of Substituted and Unsubstituted
5-Benzoylbarbituric Acids, and Their Corresponding Schiff Base
Phenylhydrazones
Mar-Apr 2004
233
Branko S. Jursic*, Donna M. Neumann, Katharine L. Bowdy, and Edwin D. Stevens
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
Received October 31, 2003
Preparation procedures for biologically important benzoylbarbiturates are presented. Several procedures
are optimized to cover the preparations of a wide variety of substituted 5-benzoylbarbiturates. To further
explore the biological importance of these compounds, multi- gram preparation procedures for nitrophenyl-
hydrazones of benzoylbarbiturates and their corresponding salts with organic amines are discussed. It is
demonstrated that these compounds can exist in several tautomeric forms and that the equilibrium in solution
can be changed by temperature as well as by the pH of the solution. X-ray structural analysis performed on
one of the nitrophenylhydrazones of benzoylbarbiturates fully agrees with the presented spectroscopic stud-
ies. AM1 semi-empirical studies show that the enol form is preferred in the gas phase of benzoylbarbiturates
over the keto form, which was also confirmed by NMR spectroscopic studies with chloroform as the solvent.
Furthermore, AM1 computed structural and electronic properties of the dinitrophenylhydrazone of 4-
hydroxybenzoylbarbiturate compared favorably with the X-ray determined structure.
J. Heterocyclic Chem., 41, 233 (2004).
Introduction.
for the preparation of these compounds involves several
steps. In one of the preparation procedures, Zn(CN)2 in
acetonitrile was used as a catalyst for the acylation and
benzoylation of barbituric acid with corresponding acid
chlorides. Isolated yields are ~80%. Nevertheless, this
synthetic approach is not applicable for the preparation of
a wide variety of substituents attached to both aryl and bar-
bituric moieties of 5-benzoylbarbituric acids. Therefore,
there is a need for developing new synthetic methods for
the preparation of these compounds.
One of our research targets is to develop simple and
inexpensive synthetic procedures for heterocyclic
compounds that are of interest for medical research.
Substituted 5-benzoylbarbituric acid derivatives and the
corresponding phenylhydrazones show promising results
in some biomedical research. To be successful in finding
suitable phenylhydrazone-barbiturate drug candidates in
biomedical research, it is most important to initially have
available a wide variety of substituted 5-benzoylbarbituric
acids and phenylhydrazones. Here we would like to report
our systematic study toward the preparation of these valu-
able compounds, finalized with their simple one, or at the
most two step multi-gram preparation procedures.
For the last one hundred years barbituric acids and their
simple C5-substituted derivatives have had numerous
applications in medicinal chemistry [1]. Traditionally bar-
bituric acid derivatives have typically been used as hyp-
notic, sedative or anti-epileptic treatments [2], however,
there have been recent reports that indicate that some aro-
matic substituted barbiturates, aromatic substituted barbi-
turic acid phenylhydrazones, and other Schiff bases con-
taining barbituric acid moieties may actually possess
immuno-modulating properties [3]. To thoroughly explore
the possibility of immune-modulation within aromatic
substituted barbiturate Schiff bases, a large variety of both
substituted and unsubstituted 5-benzoylbarbiturates were
necessary precursors for the synthesis of the targeted
Schiff bases. Here, we are presenting the simple and effi-
cient synthetic procedures developed to synthesize these
crucial intermediate precursors, as well as the optimal
procedures for the sequential Schiff base reactions.
There are literature reports indicating that some substi-
tuted and unsubstituted 5-benzoyl barbiturates have been
previously synthesized and are used as herbicides and
insecticides [4]. However, the typical synthetic procedure
Scheme 1
Syntheses of 5-benzoyl and 5-(methoxybenzoyl)barbiturates 1a-1g.

234
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
Results and Discussion.
All of the 5-benzoylbarbiturates are relatively strong
carbon acids due to the mobility of the hydrogen atom
attached at the C-5 position of the barbituric acid ring.
This acidity is responsible for the keto-enol equilibrium
that is present in solution. The equilibrium is relatively
slow and it is possible to follow the change in the equilib-
rium constant by 1H-NMR. Depending on the method of
purification and crystallization of the 5-benzoylbar-
biturate, one can isolate either the keto only or enol only
product. This was perfectly demonstrated on the example
of 5-(3-nitrobenzoyl)-1,3-dimethylbarbituric acid (1i,
Figure 1). The precipitated product formed by the conden-
sation reaction between 3-nitrobenzoyl chloride and barbi-
turic acid in THF and N-methylmorpholine as a base is
exclusively in the keto form. If the product is purified by
crystallization from large quantities of water, then the enol
form is present in crystalline form. It is also obvious that
the enol form is the thermally more stable species as
demonstrated by NMR following thermal distribution of
keto-enol forms in DMSO at 80 ºC (Figure 1).
The simplest way to prepare benzoyl substituted barbi-
turic acids is to condense N-substituted barbituric acids
(R1,R2=H, alkyl, or aryl, Scheme 1) with the correspond-
ing acid chloride. Many of these starting materials are
commercially available, however if the desirable starting
materials are not available they can be readily prepared
[6]. Pyridine seems to be an ideal solvent for this reac-
tion. It is not necessary to fully dissolve the reactants for
the reaction to be completed; therefore a relatively small
amount of pyridine is necessary. In many instances the
reaction is completed after 30 minutes. Isolation
involves pouring the pyridine reaction mixture into
hydrochloric acid (conc. HCl:H2O 3:1). The formed
crystalline product is of sufficient purity (~98%) that
further purification either by chromatography or by
crystallization is not necessary.
These simple preparation procedures are not applicable
for the preparation of 5-benzoylbarbiturates with strong
electron-withdrawing groups, such as nitro groups. These
compounds can also be prepared in pyridine as reaction
media, but the isolation and separation from both pyridine
and the resulting pyridinium chloride is very difficult.
Therefore, another synthetic route using N-methyl mor-
pholine as a base and dioxane or tetrahydrofuran as the
reaction solvent was developed for the preparation of these
compounds. In these cases, the desired product was
isolated in higher than 90% yield (Scheme 2).
There are couple of very interesting points that can be
concluded from the NMR following of the keto-enol equi-
librium presented in Figure 1. Presence of the enol form
of 1i is determined by the nature of the solvent as well as
the temperature. In solvents that cannot form strong
hydrogen bonding of deprotonated barbiturates, such as 1i,
the keto form is dominant or the only present tautomer. In
solvents such as DMSO and water, which can form strong
Scheme
2
General route for preparation of 5-(nitrobenzoyl)barbiturates 1h-1m.
Figure 1. The NMR following of thermal induced transformation of the keto form of 1i into the enol form in DMSO-d at 80 ºC.
6

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
235
hydrogen bonding with the enol alcohol group, the enol
tautomer is dominant. Our AM1 computational studies
agree that the enol form is thermally more stable (by 0.8
kcal/mol). Structural properties for these two tautomers
are considerably different. The carbonyl group of the p-
nitrobenzoyl moiety of the keto form of 1a is almost per-
pendicular to the barbituric ring (the O16-C10-C9-C14
dihedral is 79.4º) while in its enol form, it is almost copla-
nar with the barbituric acid ring (O16-C10-C9-C14 dihe-
dral ring is 5.7º) (Figure 2). The structural orientation of
the carbonyl group toward the p-nitrophenyl moiety is
exactly opposite (almost coplanar in its keto-form) and
perpendicular in its enol-form, Figure 2). There is also a
very short distance between H27 and O15 of the enol-form
(1.914 A), indicating strong hydrogen bonding in the gas
phase. This might not be the case with such polar solvents
as DMSO because the DMSO oxygen is a much better pro-
ton acceptor than the amide carbonyl of barbituric acid.
This is also evident by the fact that it was not possible to
observe the barbituric acid hydrogen in the NMR spectra
of the DMSO-d6 solution of 1a due to the H-D exchange.
DMSO-d6 at elevated temperature. The methyl range
should be different because at 80 ºC in DMSO, due to low
rotational barrier, the two methyl groups are equivalent
and in chloroform at room temperature they are not
(Figure 3). The strongest evidence for the enol-form of 1i
comes from the fact that at 17.8 ppm there is a broad sin-
glet with an integral of 1H, corresponding to the enol
hydrogen involved in internal hydrogen bonding interac-
tions with one of the carbonyl oxygens of the barbituric
acid moiety (Figure 3).
None of the discussed procedures applied for the prepa-
ration of methyl, methoxy, and nitrobenzoyl barbiturates
but they can be used for the preparation of hydroxybenzoyl
barbiturates. Additionally, our exhaustive literature
searches provided no evidence that there is a method of
preparation for these hydroxybenzoyl barbiturates.
Naturally, the hydroxyl group attached to the benzoyl moi-
ety must be protected during the course of the preparation
of hydroxybenzoyl barbiturates. Since we already devel-
oped the preparation procedures for methoxybenzoyl bar-
biturates, we attempted to use these compounds as starting
materials for the preparation of the corresponding hydrox-
ybenzoyl barbiturates. Unfortunately, during the course of
the methoxy group transformation into the unprotected
hydroxyl group, the barbituric acid part of the molecule
decomposed [7]. After exploring several routes for the
preparation of these compounds, we developed a simple
and high yield preparation. The preparation starts with
acetyloxybenzoyl acid, which is converted into the corre-
sponding acid chloride. Then, following the previously
described procedure for the benzoyl chloride condensation
with barbituric acid in pyridine, the hydroxyl-protected
product is produced. The final step involves hydrolysis of
the acetyl protecting group, followed by the isolation of
pure product upon acidification (Scheme 3).
Figure 2. The AM1 semi-empirical computed structures of keto and enol
forms of 1i.
NMR spectroscopic studies of 1i in chloroform should
be much closer to our AM1 gas-phase computational stud-
ies. Therefore one can assume that the enol form with
intramolecular hydrogen bonding should be present.
Furthermore, the existence of C9-C10 double bond in the
enol-form will make two of the methyl barbituric acid
groups spectroscopically nonequivalent. In other words,
the aromatic portion of the NMR spectra in chloroform at
room temperature should be similar to the NMR in
With these successful developments of synthetic proce-
dures for the preparation of aryl substituted 5-benzoylbar-
biturates, we turned our attention to the preparation of the
corresponding phenylhydrazones. As mentioned above,
the preparation of various Schiff bases between amines
and amino acids with acylbarbiturates was previously
described and some of these derivatives were used as her-
Figure 3. The NMR (500 MHz) spectra of chloroform solution of 1i at room temperature.

236
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
Scheme 3
Synthetic partway for preparation hydroxybenzoylbarbiturates 1n-1s.
bicides [4]. None of the patented work has focused on 5-
benzoylbarbituric phenylhydrazones. Our attempt to
apply their synthetic procedures for the preparation of our
phenylhydrazones of benzoylbarbiturates was not success-
ful. From these experiments it was obvious that our ben-
zoylbarbiturates are substantially less reactive toward
hydrazine condensation reactions. In some instances,
products were formed but isolation and purification from
the reaction mixture was very difficult. Furthermore, our
experiments suggested that both the reactants and the
products of the reaction were very sensitive to reaction sol-
vent and the pH of the reaction media. Therefore, we care-
fully explored reaction conditions to select the optimal
reaction conditions for the preparation of these valuable
compounds.
barbiturates, we performed several NMR reaction-follow-
1
ing experiments. A typical H-NMR reaction-following
experiment for these compounds is demonstrated by the
transformation of p-nitrophenylhydrazine and 5-(4-
methoxybenzoyl)-1,3-dimethyl pyrimidine-2,4,6-trione
(1g) into 5-{(4-Methoxyphenyl)-[N'-(4-nitrophenyl)hydra-
zino]methylene}-1, 3-dimethyl-pyrimidine-2, 4, 6-trione
(2g) (Figure 4). The reaction was followed by taking a
sample of the reaction mixture [8] (one drop), evaporating
the solvent under a nitrogen stream at room temperature
and preparing the sample in a DMSO-d6 solution. p-N i t r o-
phenylhydrazine was used in slight excess in the reaction
mixture. After the reaction mixture was refluxed for fif-
teen minutes all benzoylbarbiturate 1g was consumed. It
is obvious that there are two major products of the con-
densation reaction. When sulfuric acid is added, one of
the products is transformed into the other. Prolonged
In order to find and optimize appropriate reaction condi-
tions for the preparation of phenylhydrazones of benzoyl-
1
Figure 4. The H-NMR (DMSO-d , 500 MHz) reactions following for the condensation reaction in 1-propanol without and with sulfuric acid as catalyst.
6

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
237
refluxing of the reaction mixture does not noticeably
change the composition of the product. After cooling
down the reaction mixture, a solid precipitate containing
only one molecular species, compound 2g (Figure 4) was
isolated. Following this synthetic procedure, or by slight
modification of this procedure, the phenylhydrazones of
benzoylbarbiturates (Scheme 4) were prepared. It is
important to mention that for the preparation of these com-
pounds, precipitation of the product from the reaction mix-
ture during the reaction is crucial for obtaining both high
yield of the product, as well as high product purity. In
some cases, solvents such as methanol and ethanol can be
used, but 1-propanol seems to be applicable to almost all
reactions performed, and the yields and purities of the
products prepared in 1-propanol are high. To obtain better
isolated yields for some specific cases of the phenylhydra-
zones 2, specific reaction conditions were developed and
are mentioned in the experimental section of this paper.
solvents where the other form crystallizes from polar apro-
tic solvents. For instance, phenylhydrazone 2e crystallizes
from the 1-propanol reaction mixture as the hydrazone
with a double bond between nitrogen and carbon (2eCN).
1
In pure DMSO solution H-NMR shows that the solution
actually contains this isomer as a major isomer (Figure 5).
After the addition of trifluoroacetic acid, the nitrogen of
the C=N is protonated and equilibrium is shifted toward
the enamine form 2eCC (Figure 5). In the DMSO-d6-
CF 3CO 2H solution after one hour 2eCC is the only
detectable isomer. Similar behavior was observed with
other prepared hydrazones.
A major problem in the evaluation of biological proper-
ties for 5-benzoylbarbiturates comes from the low solubil-
ity of these compounds in aqueous media and most com-
mon organic solvents. This is even more evident for aryl
substituted derivatives. Considering that increasing the
size of the aliphatic or aromatic moieties of 5-benzoylbar-
Scheme 4
Preparation path for phenylhydrazones of benzoylbarbiturates.
As in the cases of 5-benzoylbarbiturates, phenylhydra-
biturates makes these compounds even less water soluble.
In order to evaluate their potential pesticide and herbicide
activities, it is important to make them water soluble. Both
acyl and benzoylbarbiturates have acidic hydrogens in the
5 position of the barbituric acid moiety, making prepara-
zones of 5-benzoylbarbiturates have several tautomeric
forms. In solution, equilibrium can be reached where sev-
eral tautomeric forms are present. It is often the case that
one tautomeric form can crystallize from nonpolar aprotic
1
Figure 5. H-NMR (500 MHz) isomerization following of 2eCN transformation into 2eCC in CF CO H.
3
2

238
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
tion of their ammonium salts with secondary amines
straightforward. Preparation procedures included mixing
benzoylbarbituric acid derivatives with the amine in a sol-
vent, such as tetrahydrofuran or dioxane or even propanol,
evaporating the solvent, and finally purification of the
product (Scheme 5).
show different ratios of two tautomeric forms, as is
demonstrated in Figure 5. To confirm these findings, X-
ray structural analysis of 2g obtained from a 1-propanol
solution with a few drops of sulfuric acid was performed
(Scheme 6). According to our NMR spectroscopic studies,
hydrazones 2 in acidic polar media should be in an
Scheme 5
Preparation of substituted ammonium salts of substituted benzoylbarbiturates.
Scheme 6
Preparation of piperidinium salts 4 of phenylhydrazones 2.
Similar to benzoylbarbiturates, phenylhydrazones also
enamine form (2 C C) while in neutral polar media, the
Schiff base form (2CN) should be present, as it was
demonstrated on the NMR equilibrium experiment with
hydrazone 2e. Considering this finding, even if hydrazone
2g is present in its Schiff base 2gCN form in neutral solu-
tion, in the acidic polar media the enamine isomer 2gCC
(Figure 6) should be a dominant species. This isomer
should also be present in the crystalline state if 2g is crys-
tallized from 1-propanol with sulfuric acid present.
The X-ray structure of 2g (Figure 7) fully confirms our
structural assignment based on the NMR spectroscopy.
Compound 2g is in its enamine form (double bonds are
C6C7 and C56C57) with strong hydrogen bonding
between the hydrazine hydrogen and the barbituric acid
carbonyl (N8-H----O20 and N58-H----O70). Two of the
molecular units of 2g are combined through stacking the
nitrophenyl and methoxyphenyl moieties of two
have low solubility in aqueous media. Besides possible
herbicide activity, our preliminary results suggest that
these compounds might possess anticancer activity
through immuno-modulating properties [9]. These com-
pounds are strong carbon acids due to the mobility of
hydrogen attached to C-5 of the barbituric acid moiety of
compounds 2. Preparation of the corresponding salts with
almost any amine was a straightforward process. Reaction
components were dissolved in methanol, ethanol, or 1-
propanol, stirred at room temperature for a few hours and
the resulting salt was isolated from the reaction mixture
(see experimental procedures G and H).
It is very important to emphasize again that both 5-ben-
zoylbarbiturates 1 and their phenylhydrazones 2 can exist
in several different tautomeric forms. Therefore, the NMR
spectra of the same compound in different solvents can

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
239
acidic α-hydrogen of the barbituric acid moiety is removed
with piperidene as a base. The negative charge is mostly
located on O22 and O26 of the barbituric acid moiety.
At this point it is very interesting to compare structural
features of 4 obtained from X-ray experimental data and
ones obtained by AM1 semi-empirical modeling of the
anion portion of 4b in the gas phase (Table 1). Both exper-
iment and theory agree that the barbituric acid moiety is
almost planar (the bond angles dihedral ring for O22-C1-
C6-C5 is close to 180º, Table 1). There is relatively good
agreement between experimental and computed structural
properties with the biggest discrepancy coming from esti-
mating dihedral angels and hydrogen bond distances. For
instance, from x-ray structural studies it is obvious that
there is very strong hydrogen bonding between N9H and
the nitro O17 oxygen (the O17-H9 bond distance is 1.937
Å, Table 1), while there is little bonding interaction with the
barbituric acid carbonyl O26 that bears the partial negative
c h a rge. The AM1 estimates fairly well the first hydrogen
bond distances, while substantially underestimates the lat-
ter one (Table 1). It is obvious that both experimental (X-
ray) and computational (AM1) data agree that the hydrogen
in the barbituric acid ring is more acidic than the phenolic
hydrogen, therefore it is removed by piperidene. The nega-
tive charge is localized on two oxygens (O22 and O27) and
one carbon (C6) atom of barbituric acid moiety (the AM1
computational studies estimates 1/3 of negative charge
being on each of these three atoms). Strong hydrogen
bonding between the NH hydrogen and the oxygen of the
nitro group of the dinitrophenylhydrazine moiety of 4b
keeps this portion of the molecule in one plane.
Figure 6. Schiff base 2gCN and enamine 2gCC tautomeric forms of 2g
present in solutions.
hydrazones of 2g, as well as hydrogen bonding between
two of these units N9-H-----O66 (Figure 7).
Figure 7. The ORTEP drawing x-ray determined structure of 2g.
The X-ray structure of piperidinium salt 4 b w a s
obtained from a single crystal grown from acetonitrile as a
solvent. The structure is in full agreement with our spec-
troscopic characterization of this compound. The hydro-
gen from C6, rather than from O33 of the phenol moiety, is
removed by the base to form perfect conjugation through-
out entire molecule (Figure 8). Hydrogen bonding no
longer exists between the nitrogen of the hydrazone moi-
ety and barbituric acid moiety, as in 2g due to fact that the
Table 1
The X-ray Determined and AM1 Computed
Properties for the Anionic Part of 4b Salt
X-Ray
AM1
X-Ray
AM1
Atoms
Bond distance in Å Atoms
Bond angles in (º)
C1-C6
C5-C6
C6-C7
C7-N8
1.417
1.411
1.483
1.303
1.439 C1-C6-C5
1.433 C1-C6-C7
1.448 C6-C7-N8
1.323 Atoms
121.5
119.3
123.8
121.6
118.9
128.7
Dihedral angles in (º)
N8-N9 1.373
O22-C1 1.231
O26-H9 2.740
O17-H9 1.936
1.354 O22-C1-C6-C5
1.253 C1-C6-C7-N8
2.098 C6-C7-N8-N9
-171.2
123.7
-5.7
175.6
131.0
0.0
2.116 C32-C27-C7-N8 156.2
130.4
Conclusion.
In conclusion, very efficient synthetic procedures for
the preparation of both aryl and barbituric acid substi-
tuted derivatives of 5-benzoylbarbiturates and their cor-
responding phenylhydrazones were developed [11 ] .
Through NMR reaction following experiments, it is pos-
sible to direct the reaction for almost quantitative trans-
formation of starting material into desired products.
Figure 8. The ORTEP drawing of X-ray determined structure of 4b.

240
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
13
ppm (2H, t, J=7.5 Hz); C-NMR (DMSO-d , 500 MHz): δ 186,
Due to strong C-H acid properties, several tautomeric
forms are present in the solution. Through appropriate
choice of solvent as well as temperature, one tautomer
structure can be dominant and also crystallize from the
solution. This was confirmed by X-ray analysis of one
of the compounds. To make 5-benzoylbarbiturates and
their phenylhydrazones more soluble in aqueous media
these compounds were transferred into their salts using
o rganic amines.
6
163, 145, 131, 128, 125, 123, and 91ppm.
Anal. Calcd for C H N O (232.05): C, 56.90; H, 3.47; N,
11 8 2 4
12.06. Found C, 56.81; H, 3.56; N, 11.91.
Preparation 5-Benzyl-1-phenylpyrimidine-2,4,6-trione (1b).
This compound was prepared in 83% isolated yield by follow-
1
ing General Procedure A. H-NMR (DMSO-d , 500 MHz): δ
6
12.09(1H, s), 7.59(2H, d, J=7.2 Hz), 7.51(d, 1H, J=6.9 Hz),
13
7.42(5H, m J=7.8 Hz), and 7.29 ppm (2H, d, J=9.3 Hz); C-
NMR (DMSO-d ): δ 186, 164, 161, 145, 131, 131, 127, 125, 125,
6
124, 124, 123, and 92 ppm.
EXPERIMENTAL
Anal. Calcd for C
H N O (308.08): C, 66.23; H, 3.92; N,
17 12 2 4
9.09; Found C, 66.11; H, 3.98; N, 10.98.
All starting materials, reactants, and solvents are purchased from
Aldrich and used without prior purification. All NMR spectra
were recording on 300, 400, or 500 MHz Varian NMR spectropho-
tometers. The NMR reaction-following experiments were per-
formed on a UNITY 500 Varian NMR spectrophotometer.
Preparation of 5-Benzoyl-1-methylpyrimidine-2,4,6-trione (1c).
This compound was prepared in 77% yield by following
1
General Procedure A. H-NMR (DMSO-d , 500 MHz): δ
6
11.91(1H, s), 7.56(2H, d, J=8.1 Hz), 7.44(3H, t+t), and 3.09 ppm
1
13
Chemical shifts for both H-NMR and C-NMR are referred to
chemical shifts for solvent (for DMSO-d it is 2.50 ppm for proton
13
(3H, s); C-NMR (DMSO-d ): δ 186, 163, 159, 146, 131, 127,
6
6
124, 123, 91, and 23 ppm.
Anal. Calcd for C
and 39.51 ppm carbon NMR). Electro-spray mass spectral analy-
ses were performed on a Micromass Quattro 2 Triple Quadropole
M a s s p e c t r o m e t e r. Melting points were determined on
Electrothermal 9100 melting point apparatus and they are not cor-
rected. Elemental analyses were performed by Atlantic Microlab
Inc. X-ray structure determination was performed on Bruker
SMART 1KCCD automated diffractometer. Crystals of compound
2b were obtained by crystallization from 1-propanol. Semi-empir-
ical computational studies were performed on PC IBM compatible
computer with MOPAC [12] computational package with AM1
[13] semi-empirical method for molecules in gas phase.
H N O (246.06): C, 58.54; H, 4.09; N,
12 10 2 4
11.38; Found C, 58.68; H, 4.01; N, 11.22.
Preparation of 5-(4-Methoxybenzoyl)pyrimidine-2,4,6-trione
(1f).
This compound was prepared in 87% yield by following
1
General Procedure A. H-NMR (DMSO-d , 500 MHz): δ
6
11.41(2H, s), 7.61(2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.7 Hz), and
13
3.80 ppm (3H, s); C-NMR (DMSO-d ): δ 185,162, 159, 145,
6
128, 123, 109, 90, and 51 ppm.
Anal. Calcd for C
H N O (262.06): C, 54.97; H, 3.84; N,
12 10 2 5
10.68; Found C, 54.86; H, 3.92; N, 10.55.
General Procedure A.
Preparation 5-Benzoyl-1-butylpyrimidine-2,4,6-trione (1e).
General Procedure B.
Benzoyl chloride (14.1 g; 0.1 mol) was slowly added over 10
minutes into a stirring pyridine (60 mL) solution of 1-butylbarbi-
turic acid (18.4 g; 0.1 mol). Resulting reaction mixture was
stirred at room temperature for additional two hours. Pyridine
reaction mixture was then slowly added over thirty minutes into
stirring solution of methanol (60 mL), water (50 mL) and con-
centrated hydrochloric acid (150 mL). Resulting suspension was
stirred at room temperature for additional half an hour and at 0 ºC
for an additional hour. Solid precipitate was separated by filtra-
tion, washed (3x15 mL) with diluted hydrochloric acid (one part
of concentrated hydrochloric acid and nine parts of water). Solid
Preparation 5-(4-Methoxybenzoyl)-1,3-dimethylpyrimidine-
2,4,6-trione (1g).
4-Methoxybenzoyl chloride (17g; 0.1 mol) was slowly added
to stirring pyridine (60 mL) solution of 1,3-dimethylbarbituric
acid (15.6 g; 0.1 mol). Resulting reaction suspension was
stirred at room temperatures for four hours and then added into
aqueous hydrochloric acid made from water (50 mL) and con-
centrated hydrochloric acid (150 mL). Resulting suspension
was stirred at room temperature for thirty minutes and then at
70 ºC for 30 minutes. After heating, the reaction suspension
became a clear water solution. The water solution was
extracted (4x100mL) with ethyl acetate. Combined ethyl
acetate extracts were dried over anhydrous magnesium sulfate
and evaporated to an oily residue. The oily residue was dis-
solved in ethanol (10 mL) and kept at 0 ºC to form yellow crys-
tals that were separated by filtration, washed with ice cold
product was dried at 110 ºC for half an hour to afford pure 1e in
1
28.0 g (97%). M.p. 138.9-139.7 ºC. H-NMR (DMSO-d , 500
6
MHz): δ 11.90 (1H, s), 7.55 (2H, d, J=7 Hz), 7.53 (1H, t, J=7.5
Hz), 7.43 (2H, t, J=7.5 Hz), 3.71 (2H, t, J=7.5 Hz), 1.47 (2H, m),
13
1.24 (2H, m), and 0.86 ppm (3H, t, J=7 Hz); C-NMR (DMSO-
d , 500 MHz): δ 186.9, 164.0, 161.0, 146.0, 131.7, 127.9, 125.0,
6
124.0, 91.8, 36.0, 26.1, 16.1, and 10.2 ppm. MS-ES (CH OH)
+
ethanol (3x 5 mL) and dried on the air to give 26.1 g (90%) of
1
1 g. M. p. 143.8-145.1 ºC. H-NMR (DMSO-d , 500 MHz): δ
3
+
m/z: 289 (M+1+), 311 (M+Na+), 343 (M+CH OH+Na ).
Anal. Calcd for C
6
7.61 (2H, d, J=8 Hz), 6.98 (2H, d, J=8 Hz), 3.84 (3H, s), and
3
H N O (288.30): C, 62.49; H, 5.59; N,
15 16 2 4
9.72. Found C, 62.23; H, 5.56; N, 9.88.
13
3.17 ppm (6H, s); C-NMR (DMSO-d , 500 MHz): δ 188.7,
6
162.5, 159.0, 150.1, 126.5, 112.8, 94.7, 55.4, and 27.8 ppm.
Preparation 5-Benzoylpyrimidine-2,4,6-trione (1a).
This compound was prepared in 90% isolated yield by follow-
+
+
+
M S - E S ( C H OH) m/z: 291 (M+1 ), 313 (M+Na ), 345
3
(M+CH OH+Na ).
+
3
Anal. Calcd for C
Found C, 57.83; H, 4.78.
1
ing General Procedure A. H-NMR (DMSO-d , 500 MHz): δ
H N O (290.27): C, 57.93; H, 4.86.
14 14 2 5
6
11.48(2H, s), 7.56(2H, d, J=8.7 Hz), 7.53(1H, t, J=6.3), and 7.42

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
241
Preparation of 5-Benzoyl-1,3-dimethylpyrimidine-2,4,6-trione
(1d).
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione (1j).
This compound was prepared in 93% yield by following
1
General Procedure C. H-NMR (DMSO-d , 500 MHz): δ 11.64
This compound was prepared in 84% yield by following
1
General Procedure B. H-NMR (DMSO-d , 500 MHz): δ
6
(2H, s, NH), 8.27 (2H, d, J=9.0Hz), and 7.79 ppm (2H, d,
6
7.53(3H, d+t, J=3.0 Hz), 7.44(2H, t, J=8.1 Hz), and 3.17 ppm (s,
13
J=9Hz); C-NMR (DMSO-d , 500 MHz) δ 188.2, 149.3, 148.6,
6
141.7, 129.6, 122.8, and 95.8 ppm.
13
6H); C-NMR (DMSO-d , 500 MHz): δ 185, 163, 146, 131,
6
127, 124, 124, 92, and 24 ppm.
Preparation of 5-(3,5-Dinitro-benzoyl)-pyrimidine-2,4,6-trione
(1l).
Anal. Calcd for C
H N O (260.25): C, 60.00; H, 4.65; N,
12 12 2 4
10.76. Found C, 59.91; H, 4.73; N, 10.65.
This compound was prepared in 90% yield by following
General Procedure C.
1
General Procedure C. H-NMR (DMSO-d , 500 MHz): δ 9.90
13
6
(2H, s), 8.79 (1H, s), and 8.42 ppm (2H,s); C-NMR (DMSO-
Preparation of 5-(4-Nitrobenzyl)-1,3-dimethylbarbituric Acid
(1k).
d , 500 MHz): δ 186.3, 165.4, 151.2, 147.5, 147.2, 127.5, 118.1,
6
and 93.3 ppm.
Into tetrahydrofuran solution (200 mL) of 1,3-dimethylbarbi-
turic acid (17.2 g; 0.11 mol) and 4-nitrobenzoyl chloride (18.5
g; 0.1 mol) with stirring N-methylmorpholine (15.15 g; 0.15
mol) was added. Color of the reaction mixture immediately
changes from yellow to deep red and white precipitate (N-
methylmorpholinium chloride) starts to form. Tetrahydrofuran
was distilled off under atmospheric pressure until the volume of
the reaction suspension was ~50 mL. This suspension was
poured into ice cooled aqueous hydrochloric acid (800 mL
water and 200 mL concentrated hydrochloric acid). Yellow pre-
cipitate was separated by filtration and washed with ice water
(3x20 mL). Product contains ~3% 4-nitrobenzoic acid. Crude
product was added to aqueous sodium bicarbonate (3 g
Preparation of 5-(3,5-Dinitrobenzoyl)-1-methylpyrimidine-2,4,6-
trione (1m).
This compound was prepared in 93% yield by following
1
General Procedure C. H-NMR (DMSO-d , 500 MHz): δ 8.78
13
6
(1H, s) , 8.41 (2H, s), and 3.05 ppm (6H, s); C-NMR (DMSO-
d , 500 MHz): δ 187.1, 163.2, 152.3, 148.2, 147.4, 127.3, 118.1,
6
93.4, and 27.1 ppm.
Anal. Calcd for C H N O (336.21): C, 42.87; H, 2.40; N,
12
16.66; Found C, 42.78; H, 2.51; N, 16.55.
8 3 8
General Procedure D.
NaHCO in 200 mL water) and resulting suspension was stirred
3
Preparation of 5-(3-Hydroxybenzoyl)barbituric Acid (1n).
at room temperature for one hour. Solid was separated by fil-
tration, washed with ice water and added to aqueous ammonium
chloride (4 g =NH Cl in 100 mL water). Resulting suspension
was refluxed for five minutes, cooled in ice-water. White crys-
talline product was separated by filtration, washed with ice
water (3x15 mL) and dried at 110 ºC for half an hour to aff o r d
Chloroform solution (150 mL) of 3-acetoxybenzoic acid (1.8
g; 0.01 mol) and oxalyl chloride (2.5 g 0.02 mol) was stirred at
room temperature for four hours. After evaporation of solvent
the oily residue was dissolved in carbon tetrachloride (70 mL)
and solvent was again evaporated. Chloroform (~30 mL) of
this oily residue was slowly added into stirring pyridine (30
mL) suspension of barbituric acid (1.28 g; 0.01 mol).
Resulting dark red reaction mixture was stirred at room tem-
perature for additional hour and then added slowly over 20
minutes into stirring aqueous hydrochloride (10 mL water, 20
mL concentrated hydrochloric acid, and 5 mL methanol).
Resulting suspension was stirred at room temperature for addi-
tional half an hour and kept at 0 ºC for one hour. Solid mater-
ial was separated by filtration and it contains both 5-(3-acety-
loxybenzoyl)barbituric acid and 5-(3-hydroxybenzoyl)barbi-
turic acid (1 n). To complete the ester hydrolysis solid material
was mixed with aqueous sodium hydroxide (0.6 g; 0.015 mol
of NaOH in 30 mL water) and heated at 70 ºC for half an hour.
Resulting reaction mixture was acidified to pH=2 at ice-water
bath temperature. Formed white solid precipitate was sepa-
rated by filtration, washed with ice-cooled water (3x5 mL) and
dried at 110 ºC for 30 minutes. Isolated yield of 5-(3-hydroxy-
4
27.8 g (91%) pure product. Product decomposes at tempera-
1
tures above 190 ºC. H-NMR (DMSO-d , 500 MHz): δ 8.21
6
(2H, d, J=8 Hz), 7.64 (2H, d, J=8 Hz), and 3.12 ppm (6H, s);
13
C-NMR (DMSO-d , 500 MHz) δ 189.1, 163.9, 151.1, 147.7,
+
6
128.6, 122.8, 95.2, and 27.4 ppm. MS-ES (CH OH) m/z: 360
3
+
(M+CH OH+Na ), 382 (NaM+CH OH+Na ).
+
3
Anal. Calcd for C H N O (305.24): C, 51.15; H, 3.63; N,
3
13 11 3 6
13.77; Found C, 51.08; H, 3.71; N, 13.72.
Preparation of 5-(4-Nitro-benzoyl)-pyrimidine-2,4,6-trione (1h).
This compound was prepared in 93% isolated yield by follow-
1
ing General Procedure C. H-NMR (DMSO-d , 500 MHz): δ
6
8,61 (1H, s), 8.46 (1H, d, J=11Hz), 8.34 (1H, d, J=13Hz), and
13
7.81 (1H, t, J=13 Hz) ppm (6H, s); C-NMR (DMSO-d , 500
6
MHz) δ 188.2, 161.4, 154.0, 143.8, 131.3, 128.4, 126.5, 119.6,
and 95.5 ppm.
Preparation of 1,3-Dimethyl-5-(4-nitrobenzoyl)pyrimidine-2,4,6-
trione (1i).
benzoyl)barbituric acid (1 n) is 91% (2.26 g). Product decom-
1
poses at temperatures above 270 ºC. H-NMR (DMSO-d , 500
6
MHz): δ, 11.43 (2H, s), 9.65 (1H, s), 7.22 (1H, t, J=8 Hz), 6.97
(1H, d, J=8 Hz), 6.95 (1H, s), and 6.93 ppm (1H, d, J=8 Hz);
13
C-NMR (DMSO-d , 500 MHz): δ 190.3, 156.6, 149.4, 136.4,
This compound was prepared in 95% yield by following
1
General Procedure C. H-NMR (DMSO-d , 500 MHz): δ 8.34
6
(1H, d, J=12Hz), 8.33 (1H, s), 7.95 (1H, d, J=11Hz), 7.73 (1H, t,
6
+
13
128.8, 119.3, 118.6, 115.3, and 95.1 ppm. MS-ES (CH OH)
+
J=13 Hz), and 3.15 ppm (6H, s);
C-NMR (DMSO-d , 500
6
3
m/z: 249 (M+1 ), 271 (M+Na ), 313 (M+2CH OH+1 ), 519
+
+
MHz): δ 187.3, 164.8, 150.7, 147.3, 137.9, 134.8, 129.8, 125.7,
123.3, 96.2, and 28.0 ppm.
Anal. Calcd for C H N O (305.24): C, 51.15; H, 3.63; N,
3
+
(2M+Na ).
Anal. Calcd for C H N O (248.19): C, 53.23; H, 3.25; N,
11
11.29; Found C, 53.42; H, 3.34; N, 11.19.
8 2 5
13 11
3 6
13.77. Found C, 51.05; H, 3.76; N, 13.65.

242
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
Preparation of 1-Butyl-5-(4-hydroxybenzoyl)pyrimidine-2,4,6-
trione (1o).
δ 7.72(2H, d, J=8.5 Hz), 7.03(1H, t, J=7.8 Hz), 6.96(2H, t, J=7. 0
13
Hz), 6.81(2H, d, J=8.0 Hz), and 6.38 ppm (2H, d, J=9.5 Hz); C-
NMR (CF CO H-DMSO-d , 500 MHz): δ 177, 166, 152, 151,
3
2
6
141, 131, 129, 129, 126, 126, 112, and 89 ppm.
This compound was prepared in 77% isolated yield by follow-
1
ing General Procedure D. H-NMR (DMSO-d , 500 MHz): δ,
6
11.67(1H, s), 7.51(2H, d, J=8.5 Hz), 6.80(2H, d, J=8.5 Hz), 3.70
(2H, t, J=7.2 Hz), 1.47 (2H, m), 1.25 (2H, m), and 0.86 ppm (3H,
Preparation of 4-{N'-[Phenyl-(2, 4, 6-trioxo-1-phenylhexahy-
dropyrimidin-5-yl)methylene]-hydrazino}benzoic Acid (2b).
13
t, J=7.0 Hz); C-NMR (DMSO-d , 500 MHz) δ 186, 163, 161,
6
158, 145, 128, 121, 110, 90, 36, 26, 16, 10 ppm.
1-Propanol (20 mL) mixture of 5-benzoyl-1-phenylpyrimi-
dine-2,4,6-trione (1b) (1.0 g; 3.25 mmol) and 4-hydrazino-ben-
zoic acid (0.494 g; 3.25 mmol) were added. To the resulting reac-
tion mixture 1 drop of sulfuric acid was carefully added. The
reaction was stirred while refluxing and became a clear solution
after 10 minutes. The reaction mixture was allowed to reflux for
4 hours. The resulting reaction mixture was then cooled to room
temperature, and a solid yellow precipitate formed. The solid
was removed by filtration and washed with ether (3 x 15 mL).
The resulting solid was oven dried at 110 ºC for 2 hours. Isolated
Preparation of 5-(4-Hydroxybenzoyl)-1,3-dimethylpyrimidine-
2,4,6-trione (1p).
This compound was prepared in 85% isolated yield by follow-
1
ing General Procedure D. H-NMR (DMSO-d , 500 MHz): δ
6
7.51(2H, d, J=6.3 Hz), 6.80 (2H, d, J=6.9 Hz), and 3.17 ppm (6H,
13
s); C-NMR (DMSO-d , 500 MHz): δ 185, 161, 158, 146, 128,
6
121, 110, 90, and 24 ppm.
Anal. Calcd for C
H N O (276.24): C, 56.52; H, 4.38; N,
13 12 2 5
10.14; Found C, 56.45; H, 4.42; N, 10.09.
yield of pure product is 1.1 g (79 %). Product decomposes at
1
temperatures above 200 ºC. H-NMR(CF CO H-DMSO-d , 500
3
MHz): δ 7.57(d, 2H, J=4.5, Ar), 7.06(d of t, 3H, J=3.0, Ar),
2
6
Preparation of 5-(4-Hydroxybenzoyl)pyrimidine-2,4,6-trione (1 r).
This compound was prepared in 80% isolated yield by follow-
7.01(t, 1H, J=7.0, Ar), 6.93(t, 2H, J=7.0, Ar), 6.86(d of t, 4H,
13
1
ing General Procedure D. H-NMR (DMSO-d , 500 MHz): δ
J=3.5, Ar), 6.37(d, 2H, J=4.5, Ar): C-NMR(CF CO H-
3 2
DMSO-d , 500 MHz): δ 176, 173, 166, (162, 161, 161, 160 quar-
6
11.33 (2H, s), 7.52 (2H, d, J=8.0 Hz), and 6.82 ppm (2H, d, J=8.5
6
tet belonging to CF CO H), 152, 150, 132, 132, 131, 130, 130,
13
Hz);
128, 121, 110, 90 ppm.
C-NMR (DMSO-d , 500 MHz): δ 186, 162, 158, 145,
6
3
130, 129, 128, 126, 121, (120, 116, 113, 109 quartet belonging to
2
+
CF CO H), 113, 90 ppm. MS-ES (MeOH) m/z 195(75%),
3
2
360(100%), 408(60%), 465 (M + 23). MW=442.42 g/mol + 0.3
Preparation of 5-(4-Hydroxybenzoyl)-1-phenylpyrimidine-2,4,6-
trione (1s).
molecules H O.
2
A n a l. Calcd for C
This compound was prepared in 83% isolated yield by follow-
1
ing General Procedure D. H-NMR (DMSO-d , 500 MHz): δ
H N O : C, 64.36; H, 4.19; N, 12.51.
24 18 4 5
Found C, 64.36; H, 4.21; N, 12.53.
6
11.91 (1H, s), 7.55 (2H, d, J=8.5 Hz), 7.44 (2H, t, J=7.5 Hz), 7.38
(1H, t, J=7.0 Hz), 7.28 (2H, d, J=8.0 Hz), and 6.78 ppm (2H, d,
Preparation of 5-{[N'-(2,4-Dinitrophenyl)hydrazino]phenylmeth-
ylene}-1,3-dimethylpyrimidine-2,4,6-trione (2c).
13
J=8.5 Hz); C-NMR (DMSO-d , 500 MHz): δ 186, 164, 161,
6
158, 145, 131, 128, 125, 125, 124, 121, and 110, 90 ppm.
This compound was prepared in 83% isolated yield by follow-
1
ing General Procedure E. H-NMR (CF CO H-DMSO-d , 500
3
MHz): δ 9.42(1H, s), 8.55(1H, s), 8.01(1H, d, J=9.5 Hz),
2
6
General Procedure E.
Preparation of 5-[[2,4-Dinitrophenyl)hydrozono]-(4-methoxy-
phenyl)methyl]-1,3-dimethylpyrimidine-2,4,6-trione (2h).
7.00(1H, d, J=6.5 Hz), 6.9(3H, m), 6.86 (2H, t, J=8.0 Hz), and
13
2.96 ppm (6H, s); C-NMR (CF CO H-DMSO-d , 500 MHz) δ
3
2
6
175, 165, 152, 146, 139, 131, 130, 130, 130, 129, 125, 123, 116,
91, and 28 ppm.
To a 1-propanol (20 mL) suspension of 5-(4-methoxybenzoyl)-
1,3-dimethylpyrimidine-2,4,6-trione (1 g) (1.0 g; 3.4 mmol) and
2,4-dinitrophenylhydrazine (0.683 g; 3.4 mmol) one drop of sul-
furic acid was added. The reaction mixture was stirred while
refluxing and became a clear solution after 30 minutes. The reac-
tion mixture was refluxed for additional four hours and left at 0 ºC
for one hour. Resulting orange precipitate was separated by filtra-
tion, washed with 1-propanol (3x5 mL), ether (3x10 mL) and
Preparation of 5-{[N'-(2,4-Dinitrophenyl)hydrazino]phenylmeth-
ylene}-1-phenylpyrimidine-2,4,6-trione (2d).
This compound was prepared in 88% yield by following
1
General Procedure E. H-NMR (DMSO-d , 500 MHz): δ 11.51
6
(1H, s), 10.69 (1H, s), 8.88 (1H, d, J=2.4 Hz), 8.37 (1H, d,
J =12.6 Hz, J =2.7 Hz), 8.10 (1H, d, J=9.6 Hz),7.83 (2H, d,
J=9.0 Hz), 7.39 (5H, m), 7.30 (1H, t, J=7.2 Hz), and 7.21 ppm
dried at 50 ºC for twenty minutes. The isolated yield of pure 2h is
1
1.30 g (81%). Mp: 98-99.2 ºC. H-NMR(CF CO H-DMSO-d ,
1
2
3
2
6
13
(2H, d, J=7.8 Hz); C-NMR (DMSO-d , 500 MHz): δ 157, 157,
6
500 MHz): δ 9.51(1H, s), 8.62(1H, d, J=2.5 Hz), 8.01 (1H, d, J= 9
Hz), 6.94 (1H, d, J=9 Hz), 6.83 (2H, d, J=7 Hz), 6.56 (2H, d,
150, 147, 140, 134, 133, 132, 126, 125, 125, 125, 124, 124, 124,
123, 119, 113, and 77 ppm.
13
J=7Hz), 3.44 (3H, s), 2.97(6H, s); C-NMR (CF CO H-DMSO-
3
d , 500 MHz): δ 176.2, 165.5, 163.2, 153.1, 146.5, 139.5, 131.2,
2
A n a l. Calcd for C
H N O : C, 56.56; H, 3.30; N, 17.21.
23 16 6 7
Found C, 56.48; H, 3.41; N, 17.09.
6
128.6, 123.8, 123.4, 114.9, 109.3, 92.1, 55.4, and 28.4 ppm. MS-
+
ES (MeOH) m/z 413 (75%), 423 (55%), 493 (M + 23).
Preparation of 5-{[N'-(2,4-Dinitrophenyl)hydrazino]phenylmeth-
ylene}-pyrimidine-2,4,6-trione (2e).
Anal. Calcd for C
H N O (470.39): C, 51.07; H, 3.86; N,
20 18 6 8
17.87; Found C, 51.01; H, 3.92; N, 17.82.
This compounds was prepared in 84% isolated yield by fol-
1
lowing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
Preparation of 5-{[N'-(4-Nitrophenyl)hydrazino]phenylmethyl-
ene}pyrimidine-2,4,6-trione (2a).
6
11.41 (1H, s), 10.74 (2H, s), 8.87 (1H, d, J=2.7 Hz), 8.39 (1H, d,
J =12.3 Hz, J =2.4 Hz), 8.12 (1H, d, J=9.9 Hz), 7.79 (2H, t,
13
This compound was prepared in 73% isolated yield by following
1
General Procedure E. H-NMR(CF CO H-DMSO-d , 500 MHz):
1
2
J=9.9 Hz), and 7.39 (3H, J=3.2 Hz); C-NMR (DMSO-d , 500
6
3
2
6

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
243
13
(2H, d, J=4.5 Hz), and 3.03 ppm (3H, s); C-NMR (DMSO-d ,
MHz): δ 158, 148, 147, 140, 133, 133, 126, 125, 125, 124, 123,
119, 113, and 78 ppm.
6
500 MHz): δ 158, 157, 155, 153, 149, 140, 132, 126, 126, 125,
124, 120, 113, 111, 77, and 22 ppm.
Preparation of 4-{N'-[(1,3-Dimethyl-2,4,6-trioxotetrahydropy-
rimidin-5-ylidene)phenylmethyl]hydrazino}-benzoic Acid (2f).
Preparation of 1-Butyl-5-[[N'-(2,4-dinitrophenyl)hydrazino]-(4-
hydroxyphenyl)-methylene]pyrimidine-2,4,6-trione (2l).
This compound was prepared in 79% isolated yield by follow-
1
ing General Procedure E. H-NMR (CF CO H-DMSO-d , 500
This compound was prepared in 80% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
3
2
MHz): δ 7.55 (2H, d, J=8.5 Hz), 7.01 (1H, t, J=7.5 Hz), 6.95 (2H,
6
6
t, J=7.5 Hz), 6.81 (2H, d, J=7.5 Hz), 6.36 (2H, d, J=8.5 Hz), and
13
2.95 ppm (6H, s); C-NMR (CF CO H-DMSO-d , 500 MHz):
11.34 (1H, s), 10.98 (1H, s), 8.86 (1H, d, J=2.5 Hz), 8.36 (1H, d,
J=12.0 Hz), 8.05 (1H, d, J=9.5 Hz), 7.63 (2H, d, J=8.5 Hz), 6.79
(2H, d, J=8.5 Hz), 3.72 (2H, t, J=7.5 Hz), 1.50 (2H, m), 1.26 (2H,
3
2
6
δ 175, 173, 165, 153, 151, 132, 131, 130, 129, 126, 120, 112, 90,
13
and 28 ppm.
m), and 0.86 ppm (3H, t, J=7.5 Hz); C-NMR (DMSO-d , 500
6
MHz): δ 157, 156, 155, 149, 147, 140, 133, 126, 125, 125, 124,
119, 113, 111, 78, 26, 26, 16, and 10 ppm.
Preparation of 5-{(4-Methoxyphenyl)-[N'-(4-nitrophenyl)-
hydrazino]methylene}-1,3-dimethylpyrimidine-2,4,6-trione (2g).
Preparation of 5-[[N'-(2,4-Dinitrophenyl)-hydrazino]-(4-hydroxy-
phenyl)methylene]-pyrimidine-2,4,6-trione (2m).
This compound was prepared in 82% isolated yield by follow-
1
ing General Procedure E. H-NMR (CF CO H-DMSO-d , 500
3
MHz): δ 9.51 (1H, s), 8.03 (2H, d, J=9.0 Hz), 7.16 (2H, d, J=9.0
2
6
This compound was prepared in 91% isolated yield by following
1
General Procedure E. H-NMR (DMSO-d , 500 MHz): δ 11.36
Hz), 6.86 (2H, d, J=9.0 Hz), 6.75 (2H, d, J=9.0 Hz), 3.73 (3H, s),
13
6
(1H, s), 10.79 (2H, s), 8.85 (1H, d, J=2.1 Hz), 8.36 (1H, d, J=10.5
Hz), 8.04 (1H, d, J=9.9 Hz), 7.63 (2H, d, J=8.7 Hz), and 6.78 ppm
and 3.11 ppm (3H, s); C-NMR (CF CO H-DMSO-d , 500
MHz): δ 162.8, 158.0, 150.5, 151.6, 149.8, 137.3, 132.6, 128.3,
3 2 6
13
(2H, d, J=9.0 Hz); C-NMR (DMSO-d , 500 MHz): δ 158, 156,
126.1, 113.1, 110.4, 81.2, 53.4, and 26.5 ppm.
A n a l. Calcd for C
6
147, 147, 140, 133, 126, 126, 125, 123, 118, 113, 111, and 78 ppm.
H
N O : C, 56.47; H, 4.50; N, 16.46.
2o 19 5 6
Found C, 56.33; H, 4.58; N, 16.38.
A n a l. Calcd for C
H N O : C, 47.67; H, 2.82; N, 19.62.
17 12 6 8
Found C, 47.55; H, 2.93; N, 19.54.
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-methoxy-
phenyl)methylene]-1,3-dimethyl-pyrimidine-2,4,6-trione (2h) .
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-hydroxy-
phenyl)methylene]-1-phenylpyrimidine-2,4,6-trione (2n).
This compound was prepared in 81% isolated yield by following
1
General Procedure E. H-NMR (CF CO H-DMSO-d , 500
This compound was prepared in 83% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
3
MHz): δ 9.51(1H, s), 8.62(1H, d, J=2.5 Hz), 8.01 (1H, d, J=9 Hz),
2
6
6
6.94 (1H, d, J=9 Hz), 6.83 (2H, d, J=7 Hz), 6.56 (2H, d, J=7Hz),
13
3.44 (3H, s), and 2.97 ppm (6H, s): C-NMR (CF CO H-DMSO-
11.52 (1H, s), 10.37 (1H, s), 8.87 (1H, d, J=2.7 Hz), 8.33 (1H, d,
J=12.0 Hz), 8.03 (1H, d, J=9.9 Hz), 7.67 (2H, d, J=9.0 Hz), 7.38
(2H, t, J=7.4 Hz), 7.28 (1H, t, J=7.5 Hz), 7.19 (2H, d, J=8.4 Hz),
and 6.76 ppm (2H, d, J=8.4 Hz); C-NMR (DMSO-d , 500
6
MHz): δ 158, 157, 156, 149, 147, 140, 133, 132, 126, 126, 125,
3
d , 500 MHz): δ 176.2, 165.5, 163.2, 153.1, 146.5, 139.5, 131.2,
2
6
128.6, 123.8, 123.4, 114.9, 109.3, 92.1, 55.4, and 28.4 ppm.
13
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-methoxy-
phenyl)methylene]-1-methylpyrimidine-2,4,6-trione (2 i).
125, 125, 124, 124, 119, 113, 111, and 79 ppm.
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-hydroxy-
phenyl)methylene]-1-methylpyrimidine-2,4,6-trione (2o).
This compound was prepared in 81% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz) δ
6
11.32 (1H, s), 11.01 (2H, s), 8.83 (1H, d, J=2.7 Hz), 8.33 (1H, d,
J=6.0 Hz), 8.05 (1H, d, J=9.6 Hz), 7.73 (2H, d, J=8.7 Hz), 6.93
This compound was prepared in 84% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
6
11.40 (1H, s), 10.34(1H, s), 8.85 (1H, d J=3.0 Hz), 8.33 (1H, d,
13
(2H, d, J=9.0 Hz), and 3.76 ppm (3H, s). C-NMR (DMSO-d ,
6
500 MHz) δ 163, 158, 157, 147, 140, 133, 126, 125, 125, 119,
113, 110, 109, 78, and 51 ppm.
J =12.5 Hz, J =3.0 Hz), 7.99 (1H, d, J=9.5 Hz), 7.61 (2H, d,
1 2
13
J=8.5 Hz), and 6.75 ppm (2H, d, J=8.5 Hz); C-NMR (DMSO-
d , 500 MHz): δ 158, 157, 155, 153, 149, 140, 132, 126, 126,
6
125, 124, 119, 112, 111, and 78, 24 ppm.
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(3-hydroxy-
phenyl)methylene]-1-methylpyrimidine-2,4,6-trione (2j).
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-hydroxy-
phenyl)methylene]-1,3-dimethylpyrimidine-2,4,6-trione (2p).
This compound was prepared in 88% isolated yield by following
1
General Procedure E. H-NMR (DMSO-d , 500 MHz): δ 11.37
6
(1H, s), 10.76 (2H, s), 8.87 (1H, d, J=2.1 Hz), 8.41 (1H, d, J=12.0
This compound was prepared in 91% isolated yield by following
1
General Procedure E. H-NMR (DMSO-d , 500 MHz): δ 11.40
Hz), 8.06 (1H, d, J=9.5 Hz), 7.24 (1H, t, J=7.5 Hz), 7.17 (2H, d),
13
6
and 6.79 ppm (1H, d, J=10.0 Hz): C-NMR (DMSO-d , 500
MHz): δ 158, 153, 148, 147, 140, 135, 133, 126, 125, 125, 119,
(1H, s), 10.35 (1H, s), 8.34 (1H, d of d, J =16 Hz, J =4 Hz), 8.00
1 2
6
(1H, d, J=16 Hz), 7.61(2H, d of d, J =11 Hz, J =4 Hz), and 6.70
1 2
13
114, 113, 112, 110, and 78 ppm.
ppm (2H, d of d, J =11 Hz, J =3 Hz); C-NMR (DMSO-d , 500
1 2 6
MHz): δ 157.1, 155.6, 153.7, 149.1, 140.4, 132.5, 126.3, 126.2,
Preparation of 5-[[N'-(2,4-Dinitrophenyl)hydrazino]-(4-hydrox-
yphenyl)methylene]-1-methylpyrimidine-2,4,6-trione (2k).
125.2, 124.9, 120.0, 113.0, 111.4, 78.2, and 23.8 ppm.
Preparation of 5-[[(2,4-Dinitrophenyl)hydrazono]-(4-nitro-
phenyl)methyl]pyrimidine-2,4,6-trione (2r).
This compound was prepared in 88% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
6
11.44 (1H, s), 10.34 (1H, s), 8.86 (1H, d, J=1.5 Hz), 8.33 (1H, d,
J=6.0 Hz), 8.04 (1H, d, J=4.5 Hz), 7.60 (2H, d, J=4.0 Hz), 6.75
To a 250 mL round bottom flask charged with 20 mL propanol,
5(4-nitro-benzoyl)-pyrimidine-2,4,6-trione (1 b) (0.277 g; 1.00

244
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
mmol), 2,4-dinitrophenylhydrazine (0.198 g; 1.00 mmol), and
drop of sulfuric acid was stirred with refluxing for six hours.
After cooling to room temperature orange solid product was sep-
arated by filtration, washed with 1-propanol (1 x10 mL), ether
(3x15 mL) and dried at 110ºC for two hours. The yield of pure
Preparation of 5-(4-Methoxybenzoyl)pyrimidine-2,4,6-trione
Piperidinium Salt (3c).
This compound was prepared in 88% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
9.70 (2H, s,), 8.58 (2H, s), 7.51 (2H, d, J=8.7 Hz), 6.83 (2H, d,
J=8.7 Hz), 3.76 (3H, s), 2.98 (4H, t, J=5.4 Hz), 1.61 (4H, m), and
product was 0.409 g (89%). Product decomposes at temperatures
1
above 275 ºC. H-NMR(DMSO-d , 500 MHz): δ 11.51 (1H, s,
6
13
1.51 ppm (2H, m); C-NMR (DMSO-d , 500 MHz): δ 188, 161,
6
157, 147, 131, 127, 108, 89, 51, 40, 18, and 18 ppm.
NH), 10.59 (2H, s, NH), 8.87 (1H, d, J=1.0 Hz), 8.40 (1H, d,
J=5.5 Hz), 8.20 (2H, d, J=4.5 Hz), 8.14 (1H, d, J=5.0 Hz), 8.00
13
(2H, d, J=4.5 Hz); C-NMR (DMSO-d , 500 MHz): δ 159, 147,
Preparation of 5-(4-Methoxybenzoyl)-1,3-dimethylpyrimidine-
2,4,6-trione Piperidinium Salt (3d).
6
146, 143, 140, 140, 133, 126, 126, 125, 119, 119, 113, 78 ppm.
+
MS-ES (MeOH) m/z 408(100%).
A n a l. Calcd for C H N O : C, 44.65; H, 2.42; N, 21.44.
17 11 7 9
Found C, 44.65; H, 2.54; N, 21.20.
This compound was prepared in 93% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
8.40 (2H, s), 7.52 (2H, d J=8.7 Hz), 6.85 (2H, d, J=8.7 Hz), 3.77
(3H, s), 3.07 (6H, s), 3.00 (4H, t, J=5.4 Hz), 1.63 (4H, m), and
Preparation of 5-[[N'-(2, 4-Dinitrophenyl)hydrazino]-(4-nitro-
phenyl)methylene]pyrimidine-2,4,6-trione (2s).
13
1.54 ppm (2H, m); C-NMR (DMSO-d , 500 MHz): δ 188, 159,
6
157, 148, 130, 127, 109, 89, 51, 40, 23, 18, and 18 ppm.
This compound was prepared in 91% isolated yield by follow-
1
ing General Procedure E. H-NMR (DMSO-d , 500 MHz): δ
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione
Piperidinium Salt (3e).
6
11.51 (1H, s), 10.59 (2H, s), 8.87 (1H, d, J=2.5 Hz), 8.40 (1H, d,
J=11.5 Hz), 8.20 (2H, d, J=8.5 Hz), 8.14 (1H, d, J=10.0 Hz), and
This compound was prepared in 95% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
13
8.00 ppm (2H, d, J=9.0 Hz); C-NMR (DMSO-d , 500 MHz): δ
6
6
9.65 (2H, s), 8.50 (2H, s), 8.12 (2H, d, J=8 Hz), 7.51 (2H, d, J=8
159, 147, 146, 143, 140, 140, 133, 126, 126, 125, 119, 119, 113,
and 78 ppm.
13
Hz), 3.00 (4H, m), 1.61 (4H, m), and 1.52 ppm (2H, m); C-
NMR (DMSO-d , 500 MHz): δ 190.5, 165.3, 151.5, 151.3,
General Procedure F.
6
147.1, 128.3, 122.8, 93.6, 44.1, 22.3, and 21.8 ppm.
Preparation of 5-(4-Nitrobenzoyl)-1,3-dimethylpyrimidine-2,4,6-
trione Morpholinium Salt (3k).
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione
Morpholinium Salt (3f).
Tetrahydrofuran (200 mL) solution of 5-(4-nitrobenzoyl)-1,3-
dimethylpyrimidine-2,4,6-trione (1k) (610 mg; 2 mmol) and
morpholine (191 mg; 2.2 mmol) was stirred at room temperature
for half an hour. The solvent was evaporated and the solid
residue was mixed with ether (100 mL), and resulting suspension
was stirred at room temperature for ten minutes. Solid product
was separated by filtration, washed with ether (3x15 mL) and
dried at 110 ºC for half an hour. The yield of product is 740 mg
This compound was prepared in 90% isolated yield by following
1
General Procedure F. H-NMR (DMSO-d , 500 MHz): δ 9.75(2H,
6
s), 8.11(2H, d, J=8.0 Hz), 7.52 (d, 2H, J=8.0), 3.74 (4H, m), and
13
3.09 ppm (4H, m); C-NMR (DMSO-d , 500 MHz): δ 190.9,
6
165.6, 151.5, 151.2, 147.2, 128.4, 122.9, 93.9, 63.5, and 43.3 ppm.
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione N-
Methylmorpholinium Salt (3g).
1
(94%). Product decomposes at temperatures above 220 ºC. H-
NMR (DMSO-d , 500 MHz): δ 8.12 (2H, d, J=8.5 Hz), 7.52 (2H,
This compound was prepared in 91% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
d, J=8.5 Hz), 3.77 (4H, m) , 3.13 (4H, m), and 3.06 ppm (6H, s);
13
C-NMR (DMSO-d , 500 MHz): δ 191.0, 163.0, 152.2, 151.4,
6
9.68 (2H, s), 8.12 (2H, d, J=8 Hz), 7.52 (2H, d, J=8 Hz), 3.80
6
146.9, 127.9, 122.6, 93.7, 63.4, 43.1, and 26.9 ppm.
13
(4H, m), 3.20 (4H, m), and 2.79 ppm (3H, s); C-NMR
(DMSO-d , 500 MHz): δ 190.5, 165.3, 151.4, 151.0, 147.2,
Anal. Calcd for C H N O (392.36) C, 52.04; H, 5.14; N,
17 20 4 7
14.28. Found C, 51.96; H, 5.12; N, 14.15.
6
128.4, 122.8, 93.7, 63.6, 53.0, and 40.0 ppm.
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione
Ethanolammonium Salt (3h).
Preparation of 5-Benzoylpyrimidine-2,4,6-trione Piperidinium
Aalt (3a).
This compound was prepared in 98% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
This compound was prepared in 80% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
9.62 (2H, s), 8.12 (2H, d, J=8 Hz), 7.79 (3H, s), 7.52 (2H, d, J=8
6
7.47 (2H, d, J=7.0 Hz), 7.36 (1H, t, J=7.5 Hz), 7.30 (2H, t, J=7.5
13
Hz), 3.67 (2H, m), and 2.85 ppm (2H, m); C-NMR (DMSO-d ,
Hz), 2.97 (4H, t, J=5.5 Hz), 1.61 (4H, m), and 1.51 ppm (2H, m);
13
C-NMR (DMSO-d , 500 MHz): δ 190, 162, 148, 139, 126,
6
500 MHz): δ 190.3, 165.2, 151.5, 151.0, 147.2, 128.4, 122.8,
93.5, 57.6, and 41.5 ppm.
6
125, 124, 90, 41, 19, and 18 ppm.
Preparation of 5-Benzoyl-1-methylpyrimidine-2,4,6-trione
Piperidinium Aalt (3b).
Preparation of 5-(4-Nitrobenzoyl)pyrimidine-2,4,6-trione 4-
Dimethylaminopyridinium Salt (3i).
This compound was prepared in 95% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
This compound was prepared in 97% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
9.69 (1H, s), 8.52(2H, s), 7.45 (2H, d, J=9.9 Hz), 7.28 (3H, m)
3.01 (4H, t, J=6.0 Hz), 2.99 (3H, s), 1.64 (4H m), and 1.54 ppm
6
9.50 (2H, s), 8.17 (2H, d, J=7 Hz), 8.11 (2H, d, J=8 Hz), 7.51
13
(2H, d, J=8 Hz), 6.95 (2H, d, J=7Hz), and 3.16 ppm (6H, s); C-
NMR (DMSO-d , 500 MHz): δ 190.1, 165.0, 157.1, 151.5,
13
(2H, m); C-NMR (DMSO-d , 500 MHz): δ 189, 160, 159, 148,
6
140, 125, 124, 123, 89, 40, 22, 18, and 18 ppm.
6
151.3, 147.1, 139.3, 128.4, 122.8, 107.1 93.3, and 39.8 ppm.

Mar-Apr 2004
Substituted and Unsubstituted 5-Benzoylbarbituric Acids
245
Preparation of 5-(4-Nitrobenzoyl)1,3-dimethylpyrimidine-2,4,6-
trione Piperidinium Salt (3j).
This compound was prepared in 93% isolated yield by follow-
1
ing General Procedure G. H-NMR (DMSO-d , 500 MHz): δ
6
11.48(1H, s), 10.31 (2H, s), 8.87 (1H, d, J=2.7 Hz), 8.37 (1H, d,
J=12.3 Hz), 8.05 (1H, d, J=9.6 Hz), 7.24 (1H, t, J=7.8 Hz), 7.16
(2H, m. J=7.8), 6.76(1H, d, J=10.2 Hz), 2.91(4H, t, J=5.1 Hz),
This compound was prepared in 92% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
8.13 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5 Hz), 3.07 (6H, s), 3.03
13
1.57(4H, m), and 1.48 ppm (2H, m); C-NMR (DMSO-d , 500
6
13
(4H, m), 1.65 (4H, m), and 1.54 ppm (2H, m); C-NMR
(DMSO-d , 500 MHz): δ 191.0, 163.0, 152.2, 151.5, 146.9,
MHz) δ 159.2, 153.7, 150.6, 148.2, 140.6, 135.9, 133.0, 126.5,
125.5, 125.2, 119.9, 115.0, 113.1, 112.9, 111.1, 78.0, 40.4, 18.7,
and 18.2 ppm.
6
127.9, 122.6, 93.7, 44.0, 26.3, 22.3, and 21.8 ppm.
Preparation of 5-(4-Nitrobenzoyl)1,3-dimethylpyrimidine-2,4,6-
trione N-Methylmorpholinium salt (3l).
Preparation of Piperidinium Salt of 5-[[2,4-Dinitrophenyl)hydra-
zono]-(4-hydroxyphenyl)methyl]-1-phenylpyrimidine-2,4,6-tri-
one (4c).
This compound was prepared in 89% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
8.13 (2H, d, J=8.5 Hz), 7.54 (2H, d, J=8.5 Hz), 3.81 (4H, m),
This compound was prepared in 81% isolated yield by follow-
1
ing General Procedure G. H-NMR (DMSO-d , 500 MHz): δ
13
6
3.22 (4H, m), 3.08 (6H, s), and 2.80 ppm (3H, s); C-NMR
(DMSO-d , 500 MHz): δ 191.2, 163.1, 152.1, 151.4, 146.9,
8.89 (1H, d, J=2.7 Hz), 8.31(1H, d, J=12.3 Hz), 8.04 (1H, d,
J=10.2 Hz), 7.65 (2H, d, J=8.7 Hz), 7.37 (2H, t, J=7.5 Hz), 7.27
(1H, t, J=7.5 Hz), 7.19 (2H, d, J=8.1 Hz), 6.75 (2H, d, J=8.4 Hz),
6
127.9, 122.6, 93.8, 63.5, 52.9, 43.1, and 26.9 ppm.
13
Preparation of 5-(4-Nitrobenzoyl)1,3-dimethylpyrimidine-2,4,6-
trione N-Ethanolammonium Salt (3m).
2.91 (4H, t, J=5.2 Hz), 1.56 (4H, m), and 1.50 ppm (2H, m); C-
NMR (DMSO-d , 500 MHz): δ 158.4, 158.2, 155.1, 153.3,
6
148.6, 140.4, 133.8, 132.2, 126.3, 126.1, 126.0, 125.9, 124.6,
124.5, 123.3, 120.0, 113.1, 111.2, 77.1, 40.4, 18.8, and 18.2 ppm.
This compound was prepared in 92% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
8.31 (2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz), 3.48 (2H, m), .3.06
Preparation of Methyl L-Lysine Salt of 5-{(4-Methoxyphenyl)[2-
(4-nitrophenyl)hydrazino]methylene}pyrimidine-2, 4, 6-trione
(4d).
13
(6H, s), and 2.98 ppm (2H, m);
MHz): δ 170.1, 150.9, 147.4, 141.3, 128.0, 123.6, 89.3, 59.2,
C-NMR (DMSO-d , 500
6
47.3, and 27.3 ppm.
Methanol (500 mL) suspension of 5-{(4-methoxyphenyl)[2-
(4-nitrophenyl)hydrazino]methylene}pyrimidine-2, 4, 6-trione
(397 mg; 1 mmol) and L-lysine (146 mg; 1 mmol) was stirred at
50 ºC for ten minutes until reaction mixture becomes solution.
Solvent was evaporated to solid residue. Solid residue was
mixed with ether (50 mL). Solid was separated by filtration from
resulting suspension, washed with ether (3x20 mL) and dried at
110 ºC for ten minutes to give 525 mg (97%) of 4d. Product
Preparation of 5-(4-Nitrobenzoyl)1,3-dimethylpyrimidine-2,4,6-
trione N-4-Diemethylaminopyridinium Salt (3n).
This compound was prepared in 93% isolated yield by follow-
1
ing General Procedure F. H-NMR (DMSO-d , 500 MHz): δ
6
8.22 (2H, d, J=8 Hz), 8.11 (2H, d, J=8.5 Hz), 7.52 (2H, d, J=8.5
Hz), 6.97 (2H, d, J=8.0 Hz), 3.18 (6H, s), and 3.04 ppm (6H, s);
13
C-NMR (DMSO-d , 500 MHz): δ 190.4, 162.5, 156.9, 152.4,
151.4, 146.9, 139.2, 128.1, 122.6, 106.9, 93.1, and 26.8 ppm.
6
1
decomposes at temperatures above 200 ºC. H-NMR (DMSO-
d , 500 MHz): δ 10.09 (1H, s), 9.44 (2H, s), 8.06 (2H, d, J=9.5
6
General Procedure G.
Hz), 7.56 (2H, d, J=9 Hz), 7.14 (2H, d, J=7.5 Hz), 6.84 (2H, d,
J=7.0 Hz), 3.76 (3H, s), 3.26 (1H, t, J=6 Hz), 2.74 (2H, d, J=7
Preparation of Piperidinium Salt of 5-[[2,4-Dinitrophenyl)hydra-
zono]-(4-hydroxyphenyl)methyl]-1, 3-dimethyl-pyrimidine-
2,4,6-trione (4b).
13
Hz), 1.65 (2H, m), 1.51 (2H, m), and 1.37 ppm (2H m); C-
NMR (DMSO-d , 500 MHz): δ 171.4, 163.6, 159.1, 152.4,
6
151.6, 149.6, 137.1, 132.6, 128.3, 126.0, 113.0, 111.5, 81.7, 55.1,
1-Propanol (20 mL) suspension of 5-[[2,4-dinitrophenyl)-
hydrazono]-(4-hydroxyphenyl)methyl]-1, 3-dimethyl-pyrimi -
dine-2,4,6-trione (2p) (0.50 g; 1.09 mmol) and piperidine (1.3
mL; 0.111 g; 1.30 mmol) was stirred at room temperature for 2
hours. Reaction suspension was diluted with ether (50 mL) and
solid precipitate was separated by filtration, washed with ether (3
x 15 mL), and dried at 110 ºC for 2 hours to give 0.535 g (98%)
+
53.5, 38.5, 30.1, 26.6, and 21.7 ppm. MS-ES (CH OH), m/z:
3
381 (M-H O-Lysine, 100%), 632 (MNa +Na ), 654 (MNa +
+
2
Na ), 676 (MNa + Na ), 708 (MNa + CH OH + Na ), 984
3
4
+
+
+
5
5
3
(2MNa-Lysine).
Anal. Calcd for C
17.97; Found C, 52.82; H, 5.07; N, 17.97.
H
N O (545.22): C, 52.84; H, 5.73; N,
7 8
24 31
of pure product. Product decomposes at temperatures above 250
1
ºC. H-NMR(DMSO-d , 500 MHz): δ 11.48 (1H, NH), 8.85
(1H, d, J=3.5 Hz), 8.31 (1H, d, J=11.0 Hz), 8.03 (1H, d, J=16
Hz), 7.56 (2H, d, J=14 Hz), 6.72 (2H, d, J=14 Hz), 3.10 (6H, s),
Acknowledgement.
6
We would like to thank the Louisiana Board of Regents
(LEQSF(2001-04)-RD-B-12) and Cancer Association of Greater
New Orleans (CAGNO) for their financial support.
13
2.98 (4H, t, J=9 Hz), 1.61 (4H, m), and 1.54 ppm (2H, m); C-
NMR (DMSO-d , 500 MHz): δ 157.1, 155.0, 153.8, 149.5,
6
140.4, 132.1, 126.3, 126.1, 125.9, 124.5, 120.0, 113.0, 111.2,
REFERENCES AND NOTES
+
77.2, 40.3, 23.5, 18.7, and 18.1 ppm. MS-ES (CH COOH) m/z
3
360 (100%).
Anal. Calcd for C
17.93. Found C, 52.82; H, 5.07; N, 17.97.
[1] For instance see: [a] B. G. Katzung, "Basic & Clinical
Pharmacology" eighth edition, McGrawHill, New York, 2001; [b] J. Y.
De Belin, M.-R. Romero-Martin, P. W. Fin, L. G. Sayers, N. M. Law, D.
Billington, S. Ryley and S. Bhattacharya, "Barbituric Acid Analogs as
Therapeutic Agents" International Patent WO 01/93841A2; Chem. Abstr.,
31669, 136 (2001) and references therein.
H N O •0.3 H O: C, 52.71; H, 5.09; N,
24 27 7 8 2
Preparation of Piperidinium Salt of 5-[[2,4-Dinitrophenyl)hydra-
zono]-(3-hydroxyphenyl)methyl]pyrimidine-2,4,6-trione (4a).

246
B. S. Jursic, D. M. Neumann, K. L. Bowdy, and E. D. Stevens
Vol. 41
[2a] I. Watanabe, T. Andoh, R. Furuya, T. Sasaki, Y. Kamiya and
(2002); [f] B. S. Jursic, J. Heterocyclic Chem. in press; [g] Jursic, B. S.;
Stevens, E. D. in press.
H. Itoh, Anesthesia & Analgesia (Baltimore) 88, 1406 (1999); [b] J. M. J.
Gonzales, N e u ro c h e m., 6 4, 2559 (1995); [c] K. Hirota, M. Kudo, T.
Kudo, M. Kitayama, T. Kushikata, D. G. Lambert and A. Matsuki,
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[3a] T. R. Bailey and D. C. Young, "Methods for treating or pre-
venting viral infections and associated diseases using barbituric acid and
thiobarbituric acid derivatives" International Patent WO 13708(2000);
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denebis[barbituric acids] and 5,5'-arylidenebis[2-thiobarbituric acids]
having antibacterial, antichlamydial, antiviral and immuno-modulating
activity" International Patent WO 25699 (1999); Chem. Abstr., 5267, 131
(1999); [c] L. R. Morgan, B. S. Jursic, C. L. Hooper, D. M. Neumann, K.
Thangaraj and B. LeBlanc, Bioorg. Med. Chem. Lett., 12, 3407 (2002).
[4a] D. L Lee and C. G. Carter, "Herbicidal Method and
Composition Utilizing Certain 5-(2-Substituted Benzoyl)-Barbituric
Acids" United States Patent 4,797,147 (1989); Chem. Abstr., 148889, 111
(1989); [b] I. T. Kay, F. C. Peacock and W. S. Waring, "5-Acyl Barbituric
Acid Derivatives" United State Patent 3,828,043 (1974); Chem. Abstr., ,
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[6] For preparation of barbituric acid derivatives by simple con-
densation of malonic esters with substituted urea see: (a) Vogel "Text-
Book of Preparative Organic Chemistry", Third Edition, John Wiley,
New York, 1966 (a) Buzz, Recreational Drugs, Loompanics Unlimited,
1989.
[7] For methods oftransformation of methyl aryl ethers into phe-
nole derivatives (deprotetion of phenol OH group) see: T. W. Greene and
P. G. M. Wuts, Protective Groups in Organic Synthesis 3rd Ed., John
Wiley & Sons, Inc., New York, 1999.
[8] Reaction was carried under conditions described in General
Procedure E.
[9] L. R. Morgan, B. S. Jursic, C. L. Hooper, D. M. Neumann, K.
Thangaraj and B. LeBlanc, Bioorg. Med. Chem. Lett., 12, 3407 (2002).
[10] In X-ray study of these compounds it was determined that in about
5% there was a presence of a cocrystal between a new derivative of 2g as
well as 2g by itself. The derivative was formed by elimination of methyl
from the methoxy group and by substitution of a hydrazone hydrogen
with 1-propyloxy group. It is our speculation that this product was
formed by crystallization of 2g from propanol with traces of sulfuric acid.
In this unique reaction alcohol is added to the NN double bond of the
hydrazone moiety and in this way a very exciting new compound with
NOR moiety was formed. This reaction mechanism and outcome
requires further studies and results will be published elsewhere.
[11] Patent application in preparation.
[5] For instance see: [a] B. S. Jursic and D. M. Neumann,
Tetrahedron Lett., 42, 4103 (2001); [b] B. S. Jursic and D. M. Neumann,
Tetrahedron Lett., 42, 8435 (2001); [c] D. M. Neumann, B. S. Jursic and
K. L. Martin, Tetrahedron Lett., 43, 1603 (2002); [d] B. S. Jursic, F.
Douelle, K. Bowdy and E. D. Stevens, Tetrahedron Lett., 4 3, 2002
(2002); [e] B. S. Jursic and E. D. Stevens, Tetrahedron Lett., 43, 5681
[12] All calculations were carried out with MOPAC version 6.0.
Quantum Chemistry Program Exchange (QCPE), Program Number 455.
[13] M. J. S. Dewar, E. G. Zoebisch, E. F. Healy and J. J. P. Stevart, J. Am.
Chem. Soc., 107, 3902 (1985); M. J. S. Dewar and E. G. Zoebisch, J. Mol.
Struct. (Theochem), 180, 1 (1988).