Preparation of 5,5′-pyrilidene and 5,5′-quinolidene bis-barbituric acid derivatives

Article abstract of DOI:10.1002/jhet.5570400310

NMR reaction following experiments were used to find optimal conditions for the barbituric acid double addition to aromatic and heteroaromatic carboxaldehydes. It was established that aromatic aldehydes with electron-donating substituents such as hydroxy, methoxy, and dimethylamino produce only the single addition barbituric acid adduct (barbituric acid benzylidenes). If these electron-donating substituents are transformed into electron-withdrawing substituents by virtue of protonation (NMe₂ to NHMe₂⁺) then the double barbituric acid adduct becomes the sole product of the reaction. This is also true regardless of the reaction media if strong electron-withdrawing substituents (such as a nitro group) are present. Considering that the reactive species for nitrogen containing aromatic heterocycles are actually the conjugated acids (electron deficient molecule) only the double barbituric acid adducts are isolated. All synthetic procedures presented are applicable to multi-gram scale preparations of double barbituric acid adducts.

Full text of DOI:10.1002/jhet.5570400310

465
Preparation of 5,5'-Pyrilidene and 5,5'-Quinolidene
Bis-barbituric Acid Derivatives
May-Jun 2003
Branko S. Jursic* and Donna M. Neumann
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148
Received March 4, 2002
NMR reaction following experiments were used to find optimal conditions for the barbituric acid double
addition to aromatic and heteroaromatic carboxaldehydes. It was established that aromatic aldehydes with
electron-donating substituents such as hydroxy, methoxy, and dimethylamino produce only the single addi-
tion barbituric acid adduct (barbituric acid benzylidenes). If these electron-donating substituents are trans-
+
formed into electron-withdrawing substituents by virtue of protonation (NMe to NHMe ) then the double
2
2
barbituric acid adduct becomes the sole product of the reaction. This is also true regardless of the reaction
media if strong electron-withdrawing substituents (such as a nitro group) are present. Considering that the
reactive species for nitrogen containing aromatic heterocycles are actually the conjugated acids (electron
deficient molecule) only the double barbituric acid adducts are isolated. All synthetic procedures presented
are applicable to multi-gram scale preparations of double barbituric acid adducts.
J. Heterocyclic Chem., 40, 465 (2003).
Introduction.
be aromatic and heteroaromatic aldehydes and nitrogen
substituted barbituric acids (Scheme 1).
There are some molecular systems that are capable of
modulating human immune responses, thus effectively
opening an avenue for new and innovative treatments that
combat terrible diseases such as AIDS and cancer [1].
Until recently barbituric acid derivatives were mostly used
as sedative and anesthetic drugs [2]. However, more non-
traditional uses for barbiturates may become predominant
in medicinal chemistry due to the fact that recent results
suggest that some aromatic-dibarbiturates may possess
anticancer activity by modulating human immune
responses [3]. A major problem associated with these com-
pounds is the evaluation of the biological properties of aro-
matic-dibarbiturates, namely because there are not many
derivatives available for testing, and those that are avail-
able do not have sufficient solubility in aqueous media.
One can postulate that both of these problems can be elim-
inated if the aromatic moieties of the dibarbiturates are
substituted with either a pyridine or quinoline moiety.
These aromatic heterocycles are more water soluble than
the corresponding benzene or naphthalene derivatives.
Unfortunately, procedures for the preparation of aromatic
and heterocyclic dibarbiturates are not available. From the
point of synthetic simplicity and availability, ideal starting
materials for the preparation of these compounds should
In general, barbituric acids condense with aromatic alde-
hydes to form Knoevenagel condensation products [4].
The outcomes of these condensations are not always the
simple arylidenebarbiturate, but also some very interesting
condensation products can be formed. The nature of these
condensation products is determined by the nature of the
applied arylcarboxaldehyde. For instance, when 1,3-
dimethylbarbituric acid is condensed with 2-pyridinecar-
boxaldehyde, regardless of the reaction solvent used
(DMSO, methanol, acetic acid, etc.) the final product is the
unique dipyridine-dibarbituric acid ylide 2 (Scheme 2) [5].
When barbituric acid is used instead of 1,3-dimethylbarbi-
turic acid the reaction outcome is different. Thus, in triflu-
oroacetic acid the condensation product between
2-pyridinecarboxaldehyde and barbituric acid is
2-pyridinemethylenedibarbiturate 1 rather than the corre-
sponding dipyridine-dibarbituric acid ylide 2 (Scheme 2).
This is not true for all reaction conditions. Even with bar-
bituric acid as a starting material (R=H) the reaction condi-
tions can be optimized in such way that ylide 2 (R=H)
becomes the major product of the condensation [6]. This
finding suggests that through careful exploration of the
reaction conditions, a variety of aromatic-dibarbiturates
Scheme 1
Possible precursors for one-pot preparation of aromatic and heteroaromatic-dibarbiturates.

466
B. S. Jursic and D. M. Neumann
Vol. 40
Scheme 2
Two different products of barbituric acid (R=H) and 1,3-dimethylbarbituric acid (R=CH ) condensation with 2-pyridinecarbaldehyde.
3
∆, 30 days
can be prepared from the same starting materials. Here we
would like to present a systematic study of aromatic and
heteroaromatic aldehydes in condensation with barbituric
acids with the target being to prepare both aromatic and
heteroaromatic-dibarbiturates.
Now we will demonstrate the influence of both the sol-
vent and the nature of the substituents attached to benzalde-
hyde on the outcome of the condensation reaction. In our
previous studies we demonstrated that a benzaldehyde with
electron donating substituents, such as the dimethylamino
group, form the Knoevenagel condensation product easily
[4]. This reaction is practically completed after several min-
utes in refluxing methanol. The same product is detected if
the condensation reaction is performed in dimethyl sulfox-
ide as a reaction media (dimethyl sulfoxide is selected as the
reaction media for NMR following reactions because the
reaction mixture is a solution, while with methanol as a
reaction media the condensation product 4 precipitates from
the reaction mixture). Even in dimethyl sulfoxide the
Knoevenagel condensation reaction is completed after four-
teen hours at room temperature (Figure 2). In this NMR fol-
lowing reaction, we were not able to detect traces of the
double barbituric acid addition product 5. One can argue
that this is due to the fact that the addition of the second bar-
bituric acid to the condensation product 4 is a slow process.
The second addition of barbituric acid in many ways resem-
bles the Michael-type of nucleophilic addition to α,β-unsat-
urated carbonyl compounds [7]. In order to perform this
reaction a strong nucleophile should be used. The second
addition of barbituric acid can only be accomplished with
the enol form of barbituric acid. Therefore, strong acidic
media are required for this reaction.
Results and Discussion.
The fact that the major product of the Knoevenagel con-
densation between aromatic aldehydes and barbituric acid
is the 5-arylidenebarbituric acid is perfectly demonstrated
in our NMR following experiment for the condensation
between 1-naphthaldehyde and barbituric acid (Figure 1).
Regardless of the nature of the reaction media (neutral,
acidic, or basic) only one product of the reaction is
detected and isolated, 5-naphthalen-1-ylmethylenebarbi-
turic acid. This reaction can be completed in many differ-
ent solvents (methanol, dioxane, tetrahydrofuran, and
dimethyl sulfoxide to name some of them) in a period of
20-40 hours at room temperature. In acidic solvents such
as trifluoroacetic acid, the reaction is practically over in
two hours at room temperature. We were not able to obtain
the double barbituric acid addition product with 1-naph-
thaldehyde even when the reaction was conducted using a
ten-fold molar excess of barbituric acid and at higher tem-
peratures (~70-120 ºC) overnight. The same reaction out-
come was obtained when the reaction was carried out with
benzaldehyde instead of naphthaldehyde.
1
Figure 1. H-NMR (500 MHz) reaction following for 1-naphthaldehyde (1 mM) condensation with barbituric acid (5 mM) in CF COOH.
3

May-Jun 2003
Preparation of 5,5'-Pyrilidene and 5,5'-Quinolidene Bis-barbituric Acid Derivatives
467
Figure 2. The NMR (500 MHz) reaction following of 4-dimethylaminobenzaldehyde condensation with barbituric acid in DMSO (a, b, and c) and
CF COOH (d, e, and f).
3
1
Through our NMR following experiments in many acidic
The HNMR barbituric acid condensation with both
media (D O-HCl, CH CO H, H SO , CF CO H,
4-methoxy and 4-hydroxybenzaldehyde (Figure 3) in trifluo-
roacetic acid fully confirm this assumption. Aromatic alde-
hydes with strong electron-donating groups such as hydroxy
and methoxy react selectively with barbituric acid deriva-
tives to produce only the Knoevenagel condensation product
in quantitative yield regardless of the applied reaction media
2
3
2
2
4
3
2
CF SO H, and H SO ) the best results for the formation of
3
3
2
4
the double addition products are obtained with trifluo-
roacetic acid. The reaction is practically over in one hour.
Formation of the Knoevenagel condensation product 4 was
observed (Figure 2e). This intermediate is a very good α,β-
unsaturated carbonyl compound that facilitates the second
barbituric acid addition in trifluoroacetic acid, which results
in the dibarbituric acid adduct 5 (Figure 2e and 2f). In this
way we were able to fully convert 4-dimethylaminoben-
zaldehyde into the double barbituric acid adduct 5. At this
(methanol, H O-HCl, H SO , CH CO H, CF CO H) [8].
2
2
4
3
2
3
2
That is clearly demonstrated on the NMR reaction following
for the 4-hydroxybenzaldehyde condensation with barbituric
acid in trifluoroacetic acid. Only the condensation product 6
was detected in the NMR solution (Figure 3).
1
Figure 3. H-NMR reaction following of 4-hydroxybenzaldehyde condensation with barbituric acid in CF CO H.
3
2
point one can argue that for the double barbituric acid addi-
tion to aromatic aldehydes, a strong electron-withdrawing
group attached to the aldehyde's aromatic ring is required. In
If it is true that strong electron-withdrawing substituents
on the aromatic ring facilitate the second barbituric acid
addition to benzaldehyde, then the preparation of aro-
matic-dibarbiturates from nitrobenzaldehyde should occur
in protic as well as aprotic solvents. This is perfectly
demonstrated with the NMR reaction following experi-
ments for the barbituric acid addition to benzaldehyde in
both dimethyl sulfoxide and trifluoroacetic acid as
solvents (Figure 4). The same double addition product 7
DMSO-d as a reaction media the electron-donating
6
(CH ) N group attached to the aromatic ring was not proto-
3 2
nated, therefore only the Knoevenagel condensation product
4 was detected and isolated. In trifluoroacetic acid media
(pK =0.0) the dimethylamino group is protonated,
a
+
(CH ) HN , and therefore electron-withdrawing [8].
3 2

468
B. S. Jursic and D. M. Neumann
Vol. 40
was obtained regardless of the nature of the solvent, the
difference being only the time required for the reaction
completion. For instance, the reaction is completed in 40
minutes in trifluoroacetic acid media and in 24 hours in
dimethyl sulfoxide media, both at room temperature.
A similar parallel can be drawn between the reactivity of
nitronaphthaldehydes and quinolinecarboxaldehydes. If
this assumption is true then the addition of barbituric acid
to quinolinecarboxaldehyde in any solvent should afford
the double addition product and the required reaction time
1
Figure 4. H-NMR reaction following in DMSO-d and CF COOH with electron-deficient aromatic aldehydes.
6
3
In many reactivity aspects nitrogen heterocycles are
similar to the corresponding nitroaromates [9].
Heterocyclic compounds similar to substituted benzenes
have preferences for nucleophilic and electrophilic reac-
tions. For pyridine [9] it is not the free base that is involved
in the electrophilic reaction but it is its conjugate acid. This
is also true if a neutral nucleophile such as barbituric acid,
malonic ester, phenylacetonitrile, etc. is added to the
heterocyclic carboxaldehyde N-oxide.
should be relatively short. This is perfectly demonstrated
in the NMR reaction following for the barbituric acid addi-
tion to 4-quinolinecarboxaldehyde (Figure 5). The reaction
is practically completed after one hour at room tempera-
ture. It appears that the second addition of barbituric acid
to the Knoevenagel intermediate is a faster reaction than
the first addition of barbituric acid to 4-quinolinecarbox-
aldehyde, because not even a trace of the condensation
intermediate was detected in our NMR experiment.
1
Figure 5. The H-NMR (DMSO-d , 500 MHz) reaction following for 4-quinolinecarboxaldehyde condensation with barbituric acid.
6

May-Jun 2003
Preparation of 5,5'-Pyrilidene and 5,5'-Quinolidene Bis-barbituric Acid Derivatives
469
Scheme 3
Reactive intermediates that were detected in our NMR following experiments of the barbituric acid addition to 2,2’-dipyridine-4,4’-dicarboxaldehyde.
BA = barbituric acid
BDPDA = 2,2'-dipyridine-4,4'-carboxaldehyde
1
Figure 6. H-NMR (500 MHz) following of barbituric acid (10 mM) condensation with 2,2’-bipyridine-4,4’-carboxaldehyde (2.5 mM) in TFA-DMSO
(3:1) at room temperature.
It is now logical to assume that larger barbituric acid
adducts can be formed if two or more heterocyclic carbox-
aldehydes are covalently bound together. There is consid-
erable interest to prepare these compounds as immuno-
modulating agents, as well as to determine whether dou-
bles of the structural moieties necessary for molecular
activity would have additive effects on the biological
activity. Synthetically, this is not always a simple task.
Increasing the size and the number of the heterocycles
makes the new target molecule hard to handle in regards to
the formation of various reaction intermediates, their
solubility in the course of the reaction, as well as the
solubility of the final compound. This is perfectly

470
B. S. Jursic and D. M. Neumann
Vol. 40

May-Jun 2003
Preparation of 5,5'-Pyrilidene and 5,5'-Quinolidene Bis-barbituric Acid Derivatives
471
demonstrated on the example for the tetra barbituric acid
addition to the dipyridinedicarboxaldehyde (Figure 6).
Although the reaction occurs in any given solvent that can
dissolve both barbituric acid and dipyridinedicarboxalde-
hyde, the solubility of various reaction intermediates as
well as tetra-adduct 9 limits us to dimethyl sulfoxide as a
solvent and the reaction concentration must not be higher
than 0.1 mM. In the course of the NMR reaction, signals
for every intermediate of the barbituric acid adducts can be
detected (the first Knoevenagel adduct, the second
Knoevenagel adduct, the first Michael-type of adduct and
the second Michael-type of adduct (compound 9, Scheme
3). There are many more intermediates involved in the
barbituric acid tetra-addition to dipyridinedialdehyde
DPDA. With close evaluation of the NMR spectra five
minutes after the reagents are mixed (Figure 6) two new
aldehyde hydrogen signals around 9.9 ppm and a signal for
α-CHOH at 6.7 ppm (besides the signals for the starting
aldehyde DPDA) indicate the formation of i1. Signals at
10.15 ppm and 8.2 ppm are assigned to the aldehyde and
the vinyl hydrogen of intermediate i2, respectively. A
small singlet at 8.25 ppm belongs to intermediate i4, and
Finally, we carefully explored the double addition
reaction through NMR experiments in various organic
solvents, as well as various acid-base conditions, and
simple and very efficient reaction conditions were
developed for the preparation of these valuable
compounds. Isolated yields are almost quantitative and in
many cases isolation and purification of the product
simply involve filtration and washing the precipitate with
solvent.
In conclusion, it can be stated that through careful NMR
experiments with aromatic and heteroaromatic carboxalde-
hydes in both protic and aprotic solvents, optimal reaction
conditions for the preparation of double barbituric acid
addition adducts to aromatic aldehydes were developed.
The preparation procedures are applicable to multi-gram
as well as multi kilogram scales. Considering the
simplicity of the preparation and isolation of these
compounds, the presented procedures are directly
applicable to the industrial scale preparation. All reactive
intermediates involved in the condensation reactions were
also spectroscopically identified.
the singlet at 6.08 ppm belongs to the α-CH(Ba) of
intermediate i5, while the singlet at 6.15 ppm belongs to
2
EXPERIMENTAL
the same hydrogen (α-CH(Ba) ) of the tetra-adduct 9
2
All NMR reaction following experiments were performed on
(Scheme 3 and Figure 6). This analysis is performed with
the assumption that the barbituric acid addition to the C=O
is faster than the addition to the C=C double bond, and that
elimination of water is faster from intermediates i1 and i3
than both the barbituric acid additions. Further
spectroscopic study of the mechanism of the tetra-addition
of barbituric acid is currently underway [10].
500 MHz UNITY500 Varian NMR instrument with DMSO-d
6
(2.50 ppm, for hydrogen and 39.51 ppm for carbon) as an internal
reference. All reaction solutions for NMR monitoring reactions
were 1 mM for aromatic aldehydes and 5 mM for barbituric acid,
except for the study of barbituric acid tetra-addition to 2,2'-dipyri-
dine-4,4'-dicarboxaldehyde for which the concentration was 0.1
mM. All DMSO-d samples were clear solutions. The CF COOH
6
3

472
B. S. Jursic and D. M. Neumann
Vol. 40
samples contained a few drops of DMSO-d as an internal refer-
left at room temperature and the solvent was slowly evaporated at
room temperature almost to dryness (eight days). The white crys-
talline product that formed was separated by filtration and washed
with trifluoroacetic acid. The yield of the product is 0.37 g (95%).
This compound is very sensitive to elevated temperature and other
solvents that are not strong acids, such as alcohol. It immediately
decomposes to barbituric acid and the benzylidene product. It is
stable in crystalline form and in strong acid at room temperature.
The trifluoromethanesulfonic acid solution was stable for several
months at 0 ºC. The NMR spectra were recorded in CF SO H
6
ence and part of barbituric acid was not in the solution. Electro-
spray mass spectral analysis was performed on a Micromass
Quattro 2 Triple Quadropole Masspectrometer. Melting points
were determined on Electrothermal 9100 melting point apparatus
and are not corrected. Preparation procedures for compounds 1
and 2 have been reported previously. There are literature reports
for the preparation of compounds 3, 4, and 6 but our procedures
are superior, and the isolated yields are higher and for some of
them there are no spectroscopic characterizations reported in the
literature. Therefore, for these compounds our preparation proce-
dures and our spectroscopic characterization data are reported.
3
3
with three drops of DMSO-d as an internal standard and source
6
of the deuterium lock signal. Product decomposition occurs at
1
temperatures above 285 ºC. H-NMR (CF SO H-DMSO-d , 300
3
3
6
Preparation of 5-Naphthalen-1-ylmethylenepyrimidine-2,4,6-
trione (3).
MHz): δ 7.57 (1H, broad singlet), 6.94 (2H, d, J=8.7 Hz), 6.87
13
(2H, d, J=8.4 Hz), 5.48 (1H, s), and 2.71 (6H, d, J=5.1 Hz); C-
NMR(CF SO H-DMSO-d , 300 MHz): δ 167.6, and 152.8 (two
Acetic acid (400 mL) solution of 1-naphthalenecarboxalde-
hyde (3.12 g; 0.02 mol) was added at once into a stirring
hydrochloric acid (100 mL) solution of barbituric acid (2.56 g;
0.02 mol). The brown emulsion was heated at 80 ºC for thirty
minutes. After a few minutes a yellow precipitate was formed
and the suspension became very hard to stir. The reaction
suspension was cooled to room temperature, and product was
separated by filtration, washed with water (3x20 mL), methanol
(3x30mL) and dried at 110 ºC for six hours to afford 5.13 g (96%)
3
3
6
carbonyl carbons), 143.9, 138.0, 131.7, and 122.7 (four aromatic
carbons), 95.5 (benzyl carbon), 49.8 (two dimethylamino car-
bons), and 34.2 ppm (barbituric acid C-5 carbon).
Preparation of 5-(4-Hydroxybenzylidene)pyrimidine-2,4,6-trione
(6).
This compound was previously prepared by several groups.
Concentrated hydrochloric (100 mL) solution of barbituric
acid (1.28 g; 0.01 mol) and 4-hydroxybenzaldehyde (1.22 g;
0.01 mol) was stirred at room temperature for 20 hours. Both
of the reagents are soluble in concentrated hydrochloric acid
and the reaction mixture is a solution at the beginning of the
reaction. The color of the reaction changes to yellow and a
yellow precipitate starts to form after approximately fifteen
minutes stirring at room temperature. After twenty hours stir-
ring at room temperature the reaction suspension was filtered
and yellow solid product, thus collected, was washed with
cold water (3x10 mL), slurred in methanol (30 mL) again col-
lected by filtration and dried at110 ºC for five hours. The yield
of 6 is 2.15 g (93%). Product decomposition occurs at temper-
of product 3. Product decomposition occurs at temperatures
1
exceeding 270 ºC. H-NMR (DMSO-d , 500 MHz): δ 11.51
6
(1H, s, NH), 11.22 (1H, s, NH), 8.29 (1H, s, vinyl H), 8.02 (1H, d,
J=8.0 Hz), 7.99 (1H, m), 7.81 (1H, m), 7.84 (1H, d, J=7.0 Hz),
13
and 7.57 ppm (3H, m). C-NMR (DMSO-d , 500 MHz instru-
6
ment): δ 163.0, 161.0 (two carbonyl carbons), 152.4, 150.4 (two
vinyl carbons), 132.7, 131.0, 130.7, 128.7, 128.4, 127.1, 126.3,
124.9, 124.3 and 121.9 ppm (ten aromatic carbons).
Anal. Calcd. for C
H N O : C, 67.67; H, 3,79; N, 10.52.
15 10 2 3
Found: C, 67.58; H, 3.85; N, 10.37.
Preparation of 5-(4-Dimethylaminobenzylidene)pyrimidine-
2,4,6-trione (4).
1
atures greater than 300 ºC. H-NMR (DMSO-d , 500 MHz): δ
6
11.23 (1H, s, NH), 11.09 (1H, s, NH), 10.78 (1H, s, OH), 8.30
Methanol solution (300 mL) of 4-dimethylaminobenzaldehyde
(3 g; 0.02 mol), barbituric acid (2.56 g; 0.02 mol), and a few drops
of sulfuric acid was refluxed in an open beaker with stirring.
(2H, d, J=9.0Hz, o-H), 8.20 (1H, s, vinyl H), and 6.86 ppm
13
(2H, d, J=9.0Hz, m-H). C-NMR (DMSO-d6, 500 MHz
instrument): δ 164.20, 163.11, 162.37 (three different
carbonyl carbons), 155.7, 150.3 (two carbons of vinyl double
bond), 138.4 123.9, 115.6, and 114.2 (four different aromatic
carbons).
Resulting deep red suspension was concentrated to volume of
1
about / of its original volume by evaporation of methanol at
4
atmospheric pressure, cooled in ice-water bath and the solid prod-
uct was separated by filtration, washed with methanol (3x30 mL)
and dried at 110 ºC for five hours to afford pure product in 95%
(4.95g) yield. Product decomposition occurs at temperatures
Preparation of 5,5'-(4-Nitrobenzylidene)dibarbituric Acid (7a).
Into a clear trifluoroacetic acid solution (30 mL) of barbi-
turic acid (0.270 mg; 0.0021mol), p-nitrobenzaldehyde (151
mg; 1 mmol) was added. The clear reaction mixture was left at
room temperature for solvent to slowly evaporate. A hard
white precipitate was formed. Solid was separated by fitration,
washed with cold trifluoroacetic acid (3x3 mL), with
methanol (3x10 mL), and dried in vacuum at 60 ºC for three
hours to afford pure white product in 87% yield (340 mg).
Compound decomposes in neutral solvents such as DMSO. In
this solvent an equilibrium is established between dibarbitu-
rate 7 and its decomposition products, free barbituric acid and
5-(4-nitrobenzylidene)pyrimidine-2,4,6-trione. The amount of
5-(4-nitrobenzylidene)pyrimidine-2,4,6-trione can be dimin-
ished if the concentration of barbituric acid is increased in the
solution. On the other hand, the acetic acid solution is suffi-
1
exceeding 285 ºC. H-NMR (DMSO-d , 500 MHz): δ 11.0 (2H,
6
broad singlet, NH), 8.41 (2H, d, J=9 Hz, o-hydrogens), 8.14 (1H, s,
vinyl hydrogen), 6.78 (2H, d, J=9 Hz, m-hydrogens), and 3.11 (6H,
13
s, methyl hydrogens). C-NMR (DMSO-d , 500 MHz instru-
6
ment): δ 164.7, 162.7, 155.5 (three carbonyl carbons), 154.1, 150.3
(two vinyl carbons), 139.0, 120.0, 111.1, 109.5 (four aromatic car-
bons), and 39.7 ppm (one aliphatic carbon).
Anal. Calcd for C
H N O : C, 60.22; H, 5.05; N, 16.21.
13 13 3 3
Found: C, 60.07; H, 5.13; N, 16.11.
Preparation of 5,5'-(4-Dimethylaminobenzylidene)dibarbituric
Acid (5).
Into a clear trifluoroacetic acid solution (30 mL) of barbituric
acid (0.270 mg; 0.0021 mol), 4-dimethylaminobenzaldehyde
(0.149 g; 0.001 mol) was added. The clear reaction mixture was
1
ciently stable that H-NMR spectra can be recorded. Product

May-Jun 2003
Preparation of 5,5'-Pyrilidene and 5,5'-Quinolidene Bis-barbituric Acid Derivatives
473
1
Preparation of 2,2'-Di[4,4'-di(2,4,6-trioxa-3,5-diazacyclo-
decomposes at temperatures above 200 ºC. H-NMR
(CF SO H-DMSO-d , 300 MHz): δ 7.67 (2H, d, J=7.5Hz,
hexyl)methyl]pyridine (9).
3
3
6
3H-benzene hydrogens), 6.88 (2H, d, J=7.5 Hz, benzene 2H
hydrogens), and 5.49 ppm (1H, benzyl hydrogen). C-NMR
Into a clear trifluoroacetic acid solution (30 mL) of barbituric
acid (0.320 g; 0.0025 mol) the trifluoroacetic acid solution (5
mL) of 2,2'-bipyridine-4,4'-carboxaldehyde (0.106 mg; 0.0005
mol) was kept at room temperature for three days. Formed
white precipitate was separated by filtration, washed with triflu-
oroacetic acid (3x1 mL), methanol (3x5 mL) and dried in
vacuum at 90 ºC for one hour to afford 0.330 g (97%) of pure
13
(CF SO H-DMSO-d , 300 MHz): δ 167.7 and 152.5 (two dif-
3
3
6
ferent barbituric acid carbonyls), 148.6, 144.8, 130.6, and
127.1 (four aromatic carbons), 127.0, 122.8, 118.6, 114.5
(quartet from solvent – CF SO H), 94.9 (benzyl carbon, and
3
3
34.8 ppm (barbituric C-5 carbon).
Preparation of 5,5'-(4-Nitrobenzylidene)di(1,3-dimethylbarbi-
turic Acid) (7b).
product. Product decomposition occurs at temperatures exceed-
1
ing 290 ºC. H-NMR (DMSO-d , 300 MHz): δ 10.32 (8H, s,
6
NH), 8.60 (2H, d, J=5.4Hz, 6H of pyridine ring), 8.03 (2H, s,
A trifluoroacetic acid solution (30 mL) of 1,3-dimethylbarbi-
turic acid (328 mg; 2.1 mmol) and 4-nitrobenzaldehyde (151 mg;
1 mmol) was left at room temperature for solvent to slowly evap-
orate for four days. In this period the volume of the solvent was
reduced to approximately 10 mL and a hard white solid was
formed. Solid was separated by filtration, washed with ice-cold
trifluoroacetic acid (3x 2mL), ice-cold methanol (3x3 mL) and
dried in open air to afford 365 mg (82%) pure product. This com-
pound has very low solubility in DMSO, and it is temperature
sensitive. The NMR sample was prepared in ice-cold trifluo-
romethanesulfonic acid by keeping a suspension of 70 mg/0.7
3H of pyridine ring) 7.47 (2H, d, J=5.4Hz, 5H of pyridine ring),
13
and 6.06 (2H, s, benzyl hydrogen). C-NMR(DMSO-d , 300
6
MHz): δ 161.4 and 158.6 (two barbituric acid carbonyls), 147.3,
144.4, 142.4, 121.8, and 118.4 (five pyridine carbonyls), 84.5
+
and 29.1 ppm (two aliphatic carbons). MS-ES (CH COOH)
3
m/z 115 (100%), 277 (50%), 387 (45%), 483 (83%), 505 (43%),
and 689 (M+1, 70%).
Anal. Calcd. for C
H N O : C, 48.84; H, 2.93; N, 20.34.
28 20 10 12
Found: C, 48.74; H, 2.98; N, 20.22.
Preparation of 2,2'-Di[4,4'-di(2,4,6-trioxa-3,5-diaza-3,5-
dimethylcyclohexyl)methyl]pyridine (10).
mL of CF SO H at room temperature for approximately one
3
3
hour. Two drops of DMSO-d were added as both internal refer-
6
A trifluoroacetic acid (50 mL) solution of 2,2'-bipyridine-4,4'-
carboxaldehyde (0.106 g; 0.0005 mmol) and 1,3-dimethylbarbi-
turic acid (0.343 g; 0.0022 mol) was kept at room temperature for
three days. Solvent was evaporated to dryness. Solid material was
crystallized from large amount of methanol to produce pure prod-
uct 10 in 92% (0.370 mg) yield. If necessary, further purification
can be obtained by crystallization from a small amount of acetic
ence signal as well as solvent for the NMR signal lock. Product
1
melting point is 179.2-181.1 ºC. H-NMR (CF SO H-DMSO-d ,
3
3
6
300 MHz): δ 7.67 (2H, d, J=8.4 Hz, 3H aromatic hydrogens),
6.85 (2H, d, J=8.4Hz, 2H aromatic hydrogens), 5.50 (1H, s, ben-
13
zyl hydrogen), 3.05 ppm (12H, s, methyl hydrogens); C-NMR
(CF SO H-DMSO-d , 300 MHz): δ 166.2, 153.8 (two different
3
3
6
carbonyls), 148.8, 144.0, 130.5, 127.4 (four aromatic carbons),
127.0, 122.8, 118.6, and 144.4 (quartet from CF SO H), 96.2
acid. Product decomposition occurs at temperatures exceeding
3
3
1
167 ºC. H-NMR (DMSO-d , 300 MHz): δ 8.60 (2H, d, J=5.4Hz,
6
(benzyl carbon), 37.3 (barbituric C-5 carbon), and 34.0 ppm
(methyl carbons).
6H of pyridine ring), 8.02 (2H, s, 3H of pyridine ring) 7.56 (2H, d,
J=5.4Hz, 5H of pyridine ring), 6.37 (2H, s, benzyl hydrogen), and
Anal. Calcd. for C
H N O : C, 51.24; H, 4.30; N, 15.72.
19 19 5 8
13
3.14 ppm (24H, s, methyl hydrogens). C-NMR(DMSO-d , 300
6
Found: C, 51.15; H, 4.43; N, 15.61.
MHz): δ 159.2 and 159.0 (two different carbonyls of the barbituric
acid moiety), 147.8, 143.5, 141.9, 122.0, 118.3 (five carbons of
the pyridine moiety), 85.1 (benzyl carbon), 31.7 (C-5 of the barbi-
Preparation of 5,5'-(4-Quinolidinylmethylene)dibarbituric Acid
(8).
+
turic acid moiety), and 24.5 ppm (methyl carbon). MS-ES
4-Quinolinecarboxaldehyde (0.160 g; 0.001 mol) was added
into refluxing methanol (400 mL) solution of barbituric acid
(0.256 mg; 0.002 mol). Reaction mixture was refluxed for three
hours and the volume was reduced to 1/5 by evaporation of
methanol at atmospheric pressure. Solid product was separated
by filtration, washed with ice-cold methanol (3x30 mL) and
dried at 110 ºC for three hours to give 0.36 g (91%) product 8.
(CH COOH) m/z 143 (35%), 277 (50%), 415 (44%), 539 (83%),
3
661 (33%), 677 (22%), 801 (M+1, 42%).
Anal. Calcd. for C
H N O : C, 54.00; H, 4.53; N, 17.49.
36 36 10 12
Found: C, 53.88; H, 4.61; N, 17.36.
General Procedures for Preparation of Heterocyclic-
Dibarbiturates.
Product decomposes at temperatures exceeding 280 ºC.
Procedure A. Preparation of 1-Methyl-5-[(1-methyl-2,4,6-trioxo-
hexahydropyrimidin-5-yl)(pyridin-2-yl)methyl]pyrimidine-
2,4,6(1H,3H,5H)-trione (11).
1
H-NMR(DMSO-d , 300 MHz): δ 10.324 (4H, s, NH), 9.096
6
(1H, d, J=0.020, quinoline 2-H), 8.483 (1H, d, J=0.030, quino-
line 8-H), 8.155 (1H, d, J=0.029, quinoline 5-H), 8.031 (1H, t,
J=0.024, quinoline 7-H), 8.401(1H, t, J=0.021, quinoline 6-H),
7.830 (1H, d, J=0.019, quinoline 3-H), and 6.761 ppm (1H, s,
After 1-methylbarbituric acid (0.71 g; 0.005 mol) was dis-
solved in refluxing methanol (100 mL) 2-pyridinecarboxalde-
hyde (0.27 g; 0.005 mol) was added. After a few minutes a white
precipitate starts to form. The resulting methanol suspension was
refluxed for an additional twenty minutes and the reaction sus-
pension was reduced to a volume of about 30 mL by evaporating
methanol at atmospheric pressure. Suspension was cooled to
room temperature. Solid product was separated by filtration,
washed with methanol (3x20 mL), ether (3x50 mL) and dried at
13
benzyl H); C-NMR (DMSO-d , 300 MHz): δ 161.139 and
6
161.016 (two different carbonyl carbons), 146.879, 139.916,
133.806, 130.040, 125.415, 123.624, 121.919, 117.936, 117.622
(nine quinoline carbons), 86.450 (benzyl carbon), and 27.479
ppm (barbituric C-5).
Anal. Calcd. for C
H N O : C, 58.53; H, 4.69; N, 15.51.
22 21 5 6
Found: C, 58.35; H, 4.81; N, 15.42.

474
B. S. Jursic and D. M. Neumann
Vol. 40
Kruse, Cancer Treat. Rev., 27, 375 (2001); [c] F. Lori, AIDS
(London), 13, 1433 (1999); [d] H. Baba, T. Kunimoto, K. Nitta, K.
Sato, S. Hashimoto, M. Kohno, Y. Kita and H. Ogawa, Int.
J. Immunopharmacol., 8, 569 (1986).
[2a] I. Watanabe, T. Andoh, R. Furuya, T. Sasaki, Y. Kamiya
and H. Itoh, Anesthesia & Analgesia (Baltimore), 88, 1406 (1999);
[b] J. M. Gonzales, J. Neurochem., 64, 2559 (1995); [c] K. Hirota,
M. Kudo, T. Kudo, M. Kitayama, T. Kushikata, D. G. Lambert and
A. Matsuki, Neuroscience Lett., 291, 175 (2000); [d] P. R. Andrews,
G. P. Jones and D. B. Poulton, Eur. J. Pharmacol., 79, 61 (1982);
[e] G. B. Young, W. T. Blume, C. F. Bolton and K. G. Warren, Can.
J. Neurological Sciences, 7, 291 (1980).
[3a] T. R. Bailey and D. C Young, International Patent WO
13708 (2000); Chem. Abstr., 132, 203127 (2000); [b] R. I.
Ashkinazi, International Patent WO 25699 (1999); Chem. Abstr.,
131, 5267 (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).
[4] For instance see B. S. Jursic, J. Heterocyclic Chem., 38,
655 (2001), and references therein.
[5] B. S. Jursic, D. M. Neumann, Z. Moore and E. D. Stevens,
J. Org. Chem., 67, 2372 (2002).
[6] B. S. Jursic, J. Heterocyclic Chem., 00, 0000 (2003).
[7] For reviews of Michael reactions see: [a] E. D. Bergmann,
D. Ginsburg and R. Pappo, Org. React., 10, 179 (1959); [b] L. A.
Yanovskaya, G. V. Kryshtal and V. V. Kulganek, Russ. Chem. Rev.,
53, 744 (1984).
110 ºC for 30 minutes. The isolated yield of 11 is 80.0 % (0.75g).
Product decomposition occurs at temperatures above 200 ºC.
Procedure B. Preparation of 1-Butyl-5-[(1-butyl-2,4,6-trioxo-
hexahydropyrimidin-5-yl)(pyridin-2-yl)methyl]pyrimidine-
2,4,6(1H,3H,5H)-trione (12).
Acetic acid solution (300 mL) of 1-butylbarbituric acid (920
mg; 5 mmol) and 2-pyridinecarbaldehyde (255 mg; 2.5 mmol)
was refluxed for four hours. Almost immediately, a dark solution
was formed. Solvent was evaporated to gummy residue. This
residue was dissolved in refluxing methanol (200 mL). The
methanol solution was left at room temperature in a paraffin foil
covered beaker with a small opening for solvent evaporation.
After seven days at room temperature, the volume of the mixture
was reduced to 50 mL and an orange precipitate was formed.
From the ice-cooled suspension the solid was separated by filtra-
tion, washed with cold methanol (3x30 mL) and dried at 80º C
under reduced pressure for five hours. The yield of the product is
750 mg (66%) of product. Product decomposition occurs at 200
ºC. (See Table 1 NMR data).
Procedure C. Preparation of 5-[(2,4,6-Trioxohexahydropyri-
midin-5-yl)(pyridin-3-yl)methyl]pyrimidine-2,4,6(1H,3H,5H)-
trione (14).
Into a hot (110 ºC) acetic acid (200 mL) solution of barbituric
acid (1.28 g; 10 mmol) 3-pyridinecarbaldehyde (0.55 g;
0.005 mol) was added. After a few minutes a pink precipitate
starts to form. Resulting suspension was heated at 110 °C for
30 minutes and the formed precipitate was separated by filtration,
washed with acetic acid (3x20 mL), acetone (3x20 mL) and dried
at 80 °C under reduced pressure for several hours. Product
[8] The pK of protonated anilines 10-12 is considerably
a
higher than the pK of trifluoroacetic acid. Therefore anilines should
a
be protonated in trifluoroacetic acid. On the other hand the pK for
a
protonated phenols and anisoles is between -6 to -8. In trifluoroacetic
acid they are practically in Ar-OH and Ar-OCH forms. For more
3
+
decomposition occurs at temperatures above 250 ºC. MS-ES (in
information see: T. H. Lowry and K. S. Richardson “Mechanism and
Theory in Organic Chemistry” Third Edition, Harper & Row,
Publishers, New York, N.Y. 1987 and references therein
acetic acid) 140 (38%), 209 (43%), 223 (100%), 251 (84%), 283
(26%), and 346 (M+1, 10%). (See Table 1 NMR data).
[9] For instance see: [a] A. R. Katritzky, “Handbook of
Heterocyclic Chemistry” Pergamon Press, New York, N. Y. 1985;
[b] D. L. Comins,) and S. Connor, Adv. Heterocycl. Chem., 44, 199
(1988); [c] G. A. Olah, J. A. Olah and N. A.Overchuk, J. Org. Chem.,
30, 3373 (1965).
[10] Positive electro-spray studies in diluted acetic acid and
diluted methanol are underway to fully characterize mechanism and
intermediates in diaromaticdialdehydes with substituted barbituric
acid. These experiments in conjunction with NMR spectroscopic
studies will provide close insight into the nature of tetra-barbituric
acid adducts of potential immuno-modulating agents.
Acknowledgement.
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.
REFERENCES AND NOTES
[1a] T. F Kresina, Editor “Immune-Modulating Agents” Deker,
New York, N. Y. (1998); [b] G. G. Gomez, R. B. Hutchison and C. A.