Mono C-alkylation and mono C-benzylation of barbituric acids through zinc/acid reduction of acyl, benzylidene, and alkylidene barbiturate intermediates

Article abstract of DOI:10.1016/S0040-4039(03)00111-4

Through systematic exploration of reaction conditions, very efficient preparative procedures for obtaining large quantities of substituted 5-alkyl and 5-benzylbarbituric acids were developed. The procedure involves a two step preparation in which the second step is zinc dust/acid reduction. For preparation of 5-alkylbarbiturates, the first step is the preparation of either 5-acyl or 5-alkylidenebarbiturate. If 5-benzylbarbiturate is the target product, then the first step includes the preparation of 5-benzylidene. Regardless of the nature of the first step, all reactions presented synthetic yields around 90% and isolation and purification involves only crystallization.

Full text of DOI:10.1016/S0040-4039(03)00111-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2203–2210
Mono C-alkylation and mono C-benzylation of barbituric acids
through zinc/acid reduction of acyl, benzylidene, and
alkylidene barbiturate intermediates
Branko S. Jursic* and Edwin D. Stevens
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 11 November 2002; revised 27 December 2002; accepted 7 January 2003
Abstract—Through systematic exploration of reaction conditions, very efficient preparative procedures for obtaining large
quantities of substituted 5-alkyl and 5-benzylbarbituric acids were developed. The procedure involves a two step preparation in
which the second step is zinc dust/acid reduction. For preparation of 5-alkylbarbiturates, the first step is the preparation of either
5-acyl or 5-alkylidenebarbiturate. If 5-benzylbarbiturate is the target product, then the first step includes the preparation of
5-benzylidene. Regardless of the nature of the first step, all reactions presented synthetic yields around 90% and isolation and
purification involves only crystallization. © 2003 Elsevier Science Ltd. All rights reserved.
5-Alkylated and benzylated barbituric acid derivatives
are proven to be valuable pharmaceuticals or important
intermediates in the preparation of other pharmaceuti-
cals.1 Subsequently, there are many available synthetic
procedures for their preparations.2 One of the main
targets of preparative organic chemistry is to develop
simple, safe, environmentally friendly, and inexpensive
procedures for synthesis of valuable organic com-
pounds. Our major research is to utilize barbituric acid
and 1,3-disubstituted barbituric acid to obtain new
structurally diverse heterocycles with the barbituric acid
moieties incorporated. Unsubstituted barbituric acid
(pyrimidine-2,4,6-trione) are ideal starting materials for
the preparation of a diverse number of heterocyclic
compounds. They are inexpensive and readily available,
or if necessary are quite easily prepared.
tion). In the past, we have successfully developed proce-
dures for N-alkylation of 5,5-disubstituted barbituric
acid3 and reductive C-alkylation4 of barbituric acid
analogs by catalytic (palladium or platinum) hydro-
genation of barbituric acid benzylidenes. Now we are
reporting a much more simplified procedure for the
reductive 5-benzylation and 5-alkylation of barbituric
acid derivatives with zinc in acetic acid.
The source of alkylation on C5 of barbituric acid
should be aliphatic aldehydes or ketones, as reported in
the cases of Pt/C catalytic alkylation of barbituric
acids. To explore the Zn/AcOH approach for the 5-
alkylation of barbituric acid we used the catalytic H2/
Pt-C conversion of 1,3-dimethylbarbituric acid and
acetone into 5-isopropyl-1,3-dimethylbarbituric acid
(3)5 as a standard reaction for comparison. Our
attempts to perform the two step preparation of 3, first
by generating 5-isopropylidene-1,3-dimethylbarbituric
acid (2) followed by its Zn/AcOH reduction as demon-
strated in Scheme 1, was not successful. Reduction of
An ideal synthetic approach in the preparation of any
derivative of barbituric acid is by substitution of one or
all of its four protons (two on nitrogen in 1 and
3-positions, and two on the carbon atom in the 5-posi-
Scheme 1. An example of two step reductive alkylation of barbituric acid.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00111-4

2204
B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
the CC double bond by Zn/AcOH was not accom-
plished. During the course of the realization of the
synthetic path in Scheme 1, several procedures for the
preparation of 2 in acid conditions were investigated.6
To the best of our knowledge, there are no reported
literature procedures for the preparation of isopropyl-
idene 2.
ric acid is well documented in literature.8 Our attempts
to reduce 5-acetyl-1,3-dimethylbarbituric acid with zinc
dust in acetic acid, in acetic acid with concentrated
hydrochloric acid and in acetic acid with sulfuric acid
was not successful. Therefore, we have performed the
NMR reaction following for the 5-acetyl-1,3-dimethyl-
barbituric acid reduction. Many different solvents and
reduction conditions were explored, and the best results
were obtained by zinc dust reduction in D2O-concen-
trated hydrochloric acid (Fig. 1).9 Due to the proton
exchange with D+ of the media, two singlets (one for
NCH3 and one for COCH3) of 4d were observed. The
reaction is exceptionally fast and is practically over
after 10 minutes, producing only one product. In the
course of the reduction in the D2O-H2O reaction media,
deuterium is partially incorporated into the ethyl moi-
ety of 5d. The results are that the methyl group is
actually a doublet and methylene group is a low inten-
sity triplet. Nevertheless, the course of the reaction is
clearly demonstrated by the shifting NCH3 singlet of 4d
from 3.27 to 3.24 ppm of 5d (Fig. 1). Almost identical
reaction conditions were used for the preparation of
5-alkylbarbituric acid 5 by zinc dust- hydrochloric acid
reduction of acylbarbiturate 4.10 It is interesting to
mention that under the same reaction conditions (zinc
dust in concentrated hydrochloric acid at room temper-
ature) we were not able to reduce the keto group of
1-benzoylbarbituric acid. Instead, the unchanged start-
ing material was isolated from reaction mixture. It
seems that under these conditions, aromatic barbituric
acid ketones are more resistant to reduction (Table 1).
By monitoring the H2/Pt-C reaction by NMR spec-
troscopy, it was determined that both isopropanol and
diisopropylether are byproducts of the hydrogenation.
Due to their physical properties, they can easily be
separated from the target product 3 therefore, the
preparation procedure was not complicated. This
finding suggested that isopropanol in the presence of a
strong acid, such as sulfuric acid, might be an alkylat-
ing reagent for barbituric acid derivatives. Unfortu-
nately, our attempts to C-alkylate barbituric acid and
1,3-dimethyl barbituric acid with isopropanol in the
presence of sulfuric acid, trifluoromethanesulfuric acid,
and polyphosphoric acid were not successful. Instead, a
small amount of O-alkylation product (ꢀ30%) was
isolated in sulfuric acid. The same results were obtained
with zinc dust used as a catalyst.
It is reasonable to use 5-acylbarbiturates, as precursors
for the preparation of 5-alkylbarbiturates pending that
5-acylbarbiturates are readily available. Previously, we
developed procedures for inexpensive large quantity
preparations of both 5-formyl and 5-acetylbarbituric
acid derivatives.7 Therefore, through the reduction of
these compounds, one should be able to obtain the
corresponding 5-alkylbarbituric acid. Under 5%Pd/C
catalytic hydrogenation in an acetic acid-sulfuric acid
media we were not able to detect any of the product of
reduction. About 5% of the reduction product was
detected after 24 hours if the reduction was performed
with hydrogen and 5%Pt/C in same reaction media.
Even when the reaction time (three days) was pro-
longed, there was not a substantial increase in the
percentage of the product of reduction. If 5-
acylbarbituric acid derivatives were to be precursors for
the preparation of 5-alkylbarbituric acid, then other
simple reducing reagents must be explored.
In some of our previous synthetic applications of barbi-
turic acid derivatives, we have demonstrated that con-
densation of barbituric acid derivatives with aromatic
aldehydes is a simple and straightforward synthetic
procedure.11 In the majority of cases the corresponding
benzylidenes are obtained. If it is possible to use simple
zinc dust in combination with a modest acid to reduce
the benzylidene double bond, then these compounds
might become viable starting materials for the prepara-
tion 5-benzylbarbituric acid derivatives. Many reaction
conditions (zinc dust in combination with hydrochloric
acid, trifluoroacetic acid, acetic acid, acetic acid/sulfuric
acid, acetic acid/hydrochloric acid) were explored
through NMR reaction following. The optimized reac-
tion conditions are shown in Figure 2 for benzylidene
Clemmensen reduction of carbonyl groups of ketones
to methylene groups with zinc amalgam and hydrochlo-
Figure 1. NMR reaction following of 4d reduction with zinc dust in aqueous hydrochloric acid.

B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
Table 1. Isolated yields of 5-acetylbarbituric acid 5
2205
Entry
R1
R2
5-Acylbarbiturate
5-Acetylbarbiturate
Yield (%)
1
2
3
4
5
6
H
CH3
H
CH3
H
CH3
H
H
CH3
CH3
-(CH2)8CH3
-(CH2)8CH3
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
87
91
88
96
93
97
Figure 2. The NMR (CD3CO2D, 500 MHz) reduction monitoring of 6h with Zn-CD3CO2D at room temperature.12
6h NMR reaction following. It appears that room
temperature zinc-acetic acid reduction over a period
longer than one hour is optimal for the preparation of
benzylbarbiturates. After approximately 10 minutes,
reduction is 50% completed and after approximately
one hour the reaction is practically completed.
aldehydes have too low reactivity in the condensations
with barbituric acids. This is not true for a,b-unsatu-
rated aldehydes. Once the condensation product with
two conjugated double bonds 8 is formed, its zinc-ace-
tic acid reduction should provide 5-alkylated barbituric
acid. To establish this synthetic approach, the conden-
sation reaction between cinnamaldehyde and barbituric
acid, followed by the zinc-acetic acid reduction was
followed by NMR spectroscopy. The reaction was per-
formed in acetic acid and few drops of this reaction
mixture was used for NMR reaction following.16 The
NMR reaction following for this condensation is pre-
sented in Figure 3. After twelve hours at room temper-
ature trans-cinnamaldehyde is fully converted into
alkylidene barbituric acid 9d. Reduction with zinc dust
in acetic acid is practically over after three hours.
The first step in the preparation of 5-benzylbarbituric
acid derivatives 7 involves the preparation of barbituric
acid benzylidene 6.13 The formed benzylidene is then
subjected to zinc dust reduction in acetic acid.14 It is
not necessary to isolate the intermediate barbituric acid
benzylidene 6 from the reaction mixture (acetic acid
solution for R=CH3 or acetic acid suspension for
R=H, Table 2). After the condensation is accom-
plished, zinc dust is added into the acetic acid mixture
for completion of the one pot synthesis.15 Regardless of
the way the reduction is performed, the isolation of the
product includes a simple filtration, evaporation of the
reaction solvent, and crystallization of the solid residue
from either methanol or ether. Isolated yields are
almost quantitative (Table 2).
The isolated yields some of the 5-alkylbarbituric acid 9
prepared by zinc dust-acetic acid reduction are pre-
sented in Table 3. All of the synthetic procedures
combined two step reactions with isolation of the inter-
mediate conjugated alkylidene 8 in 80–95% yield.17 The
isolated yields for the second step in the reaction for the
preparation of 9 are between 83 and 94% (Table 3).18
As mentioned above, we were not able to utilize neither
aliphatic aldehydes nor aliphatic ketones for the 5-alkyl-
ation of barbituric acids due to difficulties in the trans-
formation into the alkylidene of barbituric acid. We
believed that once the barbituric acid alkylidene was
formed, then zinc dust-acetic acid reduction should
yield to 5-alkylbarbituric acid. Obviously, aliphatic
Finally, we decided to test our synthetic approach on
barbituric acid derivatives with the two separated dou-
ble bonds of barbituric acid dibenzylidenes 10 (Table
4). The starting double benzylidenes 10 were prepared
from 1,v-benzenedicarbaldehydes and the correspond-

2206
B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
Table 2. Isolated yields of 5-benzylbarbituricacid derivatives 7
Entry
R
Y
Benzylidine 6
Benzyl 7
Yield (%)a
Yield (%)b
1
1
2
3
4
5
6
7
8
9
10
11
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
H
H
4-OH
4-OH
4-OCH3
4-OCH3
4-N(CH3)2
4-N(CH3)2
2,4-Di-OCH3
2,4-Di-OCH3
3,4,5-Tri-OCH3
3,4,5-Tri-OCH3
6a
6b
6c
6d
6e
6f
6g
6h
6i
7ac
7ac
7cc
7dc
7ec
7fd
7ge
7he
7id
7je
92
94
88
86
88
90
95
97
98
96
95
94
88
84
81
82
84
84
86
88
84
92
86
89
6j
6k
6l
7kd
7le
CH3
a Starting with benzylidene 6.
b Starting with substituted benzaldehyde.
c Purified by refluxing and washing with hot methanol.
d Purified by crystallization from methanol.
e Purified by crystallization from ether.
Figure 3. Step by step NMR reaction following of formation and zinc-acetic acid reduction of 8d.
Table 3. Preparation of 5-alkylbarbituric acid 9 by reducing conjugated alkylidenes 8
Entry
R
Y
Alkylidene 8
Product 9
Yield (%)
1
2
3
4
5
6
7
8
H
CH3
H
CH3
H
CH3
H
CH3
CH3
C6H5
C6H5
4-(CH3)2NC6H4
4-(CH3)2NC6H4
2-CH3OC6H4
2-CH3OC6H4
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
9e
9f
83
88
91
94
90
93
91
94
8g
8h
9g
9h
CH3

B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
Table 4. Isolated yields for 10 and 11
2207
Entry
R
Position
Alkylidene 10
Yield (%) of 10
Alkyl 11
Yield (%) of 11
1
2
3
4
H
CH3
H
1,3
1,3
1,4
1,4
10a
10b
10c
10d
92
94
93
95
11a
11b
11c
11d
87
92
91
90
CH3
ing barbituric acids in acetic acid-sulfuric acid as the
reactive media. Due to the low solubility of the conden-
sation product in the reaction media, isolation yields
are higher than 90%.19 Low solubility of both 10 and 11
in acetic acid is also the reason why the reaction was
performed with 10 not fully soluble in acetic acid
(suspension), accounting for why the reaction mixture
was refluxed.20
efficient synthetic procedure for the preparation of
large quantities of 5-substituted barbituric acid deriva-
tives. Regardless of the nature of the reaction interme-
diate, 5-acyl, 5-benzylidene, or 5-alkylidenebarbituric
acid, the second step in the two step preparation
involves high yield and high purity zinc dust acid
reduction. Considering that starting materials (barbi-
turic acid, acid chlorides, and aldehydes) are inexpen-
sive and readily available and that purification of the
product is accomplished by crystallization, the pre-
sented synthetic procedures are applicable to large scale
(industrial) preparations of this compounds.22
To fully characterize the prepared compounds by zinc
dust reduction we have selected the largest molecule,
product 11d for X-ray structural analysis.21 The single
crystal for the X-ray analysis was grown by slow crys-
tallization from methanol. The obtained structure fully
agrees with our determined structure by NMR and
elemental analysis. This structure has several very inter-
esting characteristics. The molecule seems to be
‘squeezed’ into a ball conformation to occupy as little
space as possible. This is perfectly demonstrated in that
both barbituric acid rings are not planar. They have a
slight boat conformation to bring both -NCON- (urea)
moieties closer to the middle of 1,4-phenylene ring (Fig.
4), indicating weak nonbonding interactions between
barbituric acid and phenyl moieties of 11d.
Acknowledgements
We would like to thank Louisiana Board of Reagents
for their financial support (LEQSF (2001-04)-RD-B-12)
and Cancer Association of Greater New Orleans
(CAGNO) for financial support of this work
References
It can be concluded that during the systematic explo-
ration of the reaction conditions by the NMR reaction
following experiments, it was possible to develop a very
1. Barbituric acid derivatives (barbiturates) are a family of
drugs that depress nerve activity in the brain producing
changes in mental activity ranging from mild sedation
and sleep, to deep coma. Commonly they are used to
treat anxiety, insomnia, seizure disorders, migraine
headaches, and use is surgery as general anesthetics. For
general information see: Olin, B. R., Ed.; Central Ner-
vous System Drugs, Sedatives and Hypnotics, Barbitu-
rates. In Facts and Comparisons Drug Information. St.
Louis, MO: Facts and Comparisons, 1993; pp. 1398–413.
2. For simple methods of preparation the most common
barbituric acid drugs see: Buzz, Recreational Drugs,
Loompanics Unlimited, 1989.
3. Jursic, B. S. Tetrahedron Lett. 2000, 41, 5325.
4. Jursic, B. S.; Neumann, D. M. Tetrahedron Lett. 2001,
42, 4103.
5. Preparation of 5-isopropyl-1,3-dimethybarbituric acid (3).
Although we have previously mentioned this product in
Table 1 of Ref. 2, the exact procedure, isolation and
characterization of this compound was not mentioned.
Figure 4. X-ray determined structure of 11d.

2208
B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
Therefore, here we are presenting detailed synthetic pro-
J2=7.5 Hz, CH2), and 0.867 ppm (3H, t, J=7.5 Hz,
CH3); 13C NMR (CDCl3, 500 MHz) l 168.71, 151.76
(two different carbonyls), 50.08, 28.52, 24.86 and 10.41
ppm (four different sp3 carbons). Anal. calcd. For
C8H12N2O3 (184.19): C, 52.17; H, 6.57; N, 15.21. Found:
C, 52.05; H 6.83, N 15.12.
cedure and characterization of 5-isopropyl-1,3-dimethyl-
barbituric acid. 1,3-Dimethylbarbituric acid 1.56 g (0.01
mol) was dissolved in acetone (200 ml) and 5%Pt/C with
50% water was added (0.3 g). Into the black suspension
concentrated sulfuric acid was added and the reaction
suspension was shaken at 75 psi hydrogen pressure for 48
hours. Catalyst was separated by filtration and washed
with acetone (3×20 ml). Combined acetone filtrates were
evaporated to dryness and solid product was crystallized
from methanol (50 ml). Formed white crystals were sepa-
11. Jursic, B. S. J. Heterocyclic Chem. 2001, 38, 655.
12. The NMR sample is prepared by mixing 2.5 mg (0.01
mmol) of 6h in 1 ml CD3CO2D. This solution was used
for recording reference spectra (0 time in Fig. 1). In this
solution zinc (6.5 mg; 0.1 mmol) was added and the zinc
addition time was used as 0 time for monitoring the
reaction.
1
rated by filtration giving 1.82 g (92%) product. H NMR
(DMSO-d6, 500 MHz) l 3.414 (1H, d, J=4 Hz, CH),
3.132 (6H, s, NCH3), 2,418 (1H, m, CH(CH3)2) and 0.966
ppm (6H, d, J=7.5 Hz, C(CH3)2); 13C NMR (DMSO-d6,
500 MHz) l 168.4 and 151.8 (two different CO), 54.5,
32.6, 27.8, and 19.3 ppm (four different aliphatic car-
bons). Anal. calcd. For C9H14N2O3 (MW 198.22): C,
54.53; H, 7.12; N, 14.13. Found: C, 54.32; H 7.25, N
14.06.
13. Typical procedure for preparation of barbituric acid ben-
zylidenes 6. Preparation of 5-(4-methoxybenzylidene)-1,3-
dimethylpyrimidine-2,4,6-trione (6f). Acetic acid (150 ml)
solution of 4-methoxybenzaldehyde (2.72 g; 0.02 mol)
and 1,3-dimethylbarbituric acid (3.12 g; 0.02 mol) was
refluxed for two hours. Yellow reaction mixture was
concentrated to ꢀ30 mL and the resulting yellow suspen-
sion left at room temperature overnight. Solid was sepa-
rated by filtration, washed with ice-cold methanol (3×10
ml) and dried at 110°C for one hour. The yield of the
product is 4.8 g (93%). 1H NMR (CDCl3, 500 MHz) l
8.449 (1H, s, CH), 8.291 (2H, d, J=9 Hz, o-CH), 6.941
(2H, d, J=9.0 Hz, m-CH), 3.875 (3H, s, OCH3), 3.368
(3H, s, NCH3), and 3.350 ppm (3H, s, NCH3). 13C NMR
(CDCl3, 500 MHz) l 164.39, 163.17, 161.05, 158.79,
151.49, 138.06, 125.65, 114.43, 114.06, 55.72, 29.12, and
ppm 28.45 (twelve different carbon atoms). Anal. calcd.
For C14H14N2O4 (274.27): C, 61.31; H, 5.14; N, 10.21.
Found: C, 61.12; H 5.22, N 10.08.
6. Acetone was used as a solvent (large excess) for isopropyl-
idene formation with acid in 10 fold excess such as acetic
acid, trifluoroacetic acid, sulfuric acid, trifluoromethane-
sulfonic acid, and in polyphosphoric acid. Even strongly
acidic DOWEX 50W-X8 was used as a catalyst after it
was dried by continuos benzene evaporation. In the last
case through NMR study of the reaction mixture, we
were able to detect traces of isopropylidene barbituric
acid.
7. Jursic, B. S.; Neumann, D. M. Tetrahedron Lett. 2001,
42, 8435.
8. (a) Clemmensen Ber. 1913, 46, 1837; (b) Martin, E. L.
Org. React. 1942, 1, 155.
9. 5-Acetyl-1,3-dimethylbarbituric acid 4d is soluble in con-
centrated hydrochloric acid. 2 mg (0.01 mmol) of acetyl-
barbituric acid 4d was dissolved in 1 ml of concentrated
hydrochloric acid. This solution was diluted with 2 ml of
D2O and used to record NMR spectra on 500 MH
Varian UNITY as a starting point in NMR following
experiment through water suppression signal. Proton in
5-postion of barbituric acid ring is exchanged by deu-
terium from the reaction media therefore two singlets
were observed. Chemical shift for higher intensity singlet
(NCH3) were placed to 3.27 ppm to correspond it to
chemical shift in pure CDCl3. Reaction mixture was
poured over zinc dust (100 mg) with the immediate
formation of hydrogen bubbles noted. Clear solution
over zinc dust occured after 2 minutes and after 10
minutes was pipetted for NMR reaction following.
10. General procedure for reduction of 5-acylbarbiturates.
Preparation of 5-ethyl-1,3-dimethylbarbituric acid (5d).
Concentrated hydrochloric acid (50 ml) solution of 5-ace-
tyl-1,3-dimethylbarbituric acid (1.98 g; 0.01 mol) was
slowly added into water (50 ml) suspension of zinc dust
(2 g). Reaction suspension was vigorously stirred at room
temperature for thirty minutes and extracted with chloro-
form (4×50 ml). Combined chloroform extracts were
dried over anhydrous sodium carbonate and evaporated.
Oily residue was crystallized from methanol (20 ml) to
allow methanol to slowly evaporate at room temperature
and atmospheric pressure. The yield of 5d is 1.77 g (96%).
1H NMR (CDCl3, 500 MHz) l 3.419 (t, 1H, J=5 Hz,
CH), 3.243 (6H, s, N-CH3), 2.123 (2H, d-t, J1=5 Hz,
14. Typical procedure for zinc dust-acetic acid reduction of
barbituric acid benzylidenes. Preparation 5-(4-methoxy-
benzyl)-1,3-dimethylpyrimidine-2,4,6-trione (7f). Acetic
acid (150 ml) suspension of benzylidene 6f (2.74 g, 0.01
mol) and zinc dust (6.4 g; 0.1 mol) was stirred at room
temperature for three hours. Acetic acid solution was
separated by filtration. Gray solid was washed with acetic
acid (3×20 ml). Combined filtrates were evaporated and
solid residue was crystallized from methanol. The yield of
1
7f is 2.47 g (90%). H NMR (CDCl3, 500 MHz) l 6.931
(2H, d, J=8 Hz, o-CH), 6.738 (2H, D, J=8 Hz, m-CH),
3.742 (3H, s, OCH3), 3.717 (1H, t, J=5 Hz, CH), 3.393
(2H, d, J=5 Hz), and 3.118 ppm (6H, s, NCH3). 13C
NMR (CDCl3, 500 MHz) l 159.22, 151.15 (two different
carbonyl carbons), 139.50, 130.09, 127.15, 114.05 (four
aromatic carbons), 55.28 (methoxy carbon), 50.97 (5-C of
barbituric acid ring), 37.21 (methylene carbon), and 28.29
ppm (NCH3 carbon). Anal. calcd. For C14H16N2O4
(276.29): C, 60.86; H, 5.84; N, 10.14. Found: C, 60.64; H,
5.96; N, 10.02.
15. Typical one pot preparation procedure of 7. Preparation
of 5-(4-methoxybenzyl)pyrimidine-2,4,6-trione (7e). Acetic
acid (200 ml) solution of barbituric acid (1.28 g; 0.01
mol) and 4-methoxybenzaldehyde (1.36 g; 0.01 mol) was
refluxed for three hours. Reaction mixture was allowed to
cool to room temperature. Benzylidene 6e product par-
tially precipitates from the reaction mixture. Into this
reaction suspension zinc dust was added (6.4 g;0.1 mol)
and resulting suspension was stirred at room tempera-
ture. Solution over gray (zinc) sediment is colorless.
Liquid was separated by filtration and solid was washed

B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
2209
with acetic acid. Combined filtrates were evaporated
under reduced pressure. Solid residue was refluxed with
methanol (30 ml). Insoluble solid was separated by filtra-
tion, washed with methanol (3×20 ml) and dried at 110°C
for one hour to afford 2.08 g (84% yield) pure product.
1H NMR (DMSO-d6, four drops of H2SO4, 400 MHz) l
11.08 (2H, NH), 6.89 (2H, d, J=8.0 Hz), 6.72 (2H, d,
J=8.0 Hz), 3.72 (1H, t, J=4.0 Hz), 3.59 (3H, s, OCH3),
and 3.10 ppm (2H, d, J=4.0 Hz, CH2). 13C NMR
(DMSO-d6, four drops of H2SO4, 400 MHz) l 167.41,
155.36 (two different carbonyls), 147.89, 127.35, 126.08,
111.04 (four different aromatic carbons), 52.30, 46.79 and
30.28 ppm (three different aliphatic carbons).
19. Preparation of alkylidenes 10 is very simple but due to
their low solubility in most common organic solvents, the
NMR spectroscopic determination of their purity is car-
ried out in concentrated sulfuric acid with three drops of
DMSO-d6. When a drop of DMSO was added, immedi-
ately orange precipitate was formed. Typical procedure
for preparation of 10, preparation of 5,5%-[1,4-phenylenedi-
(methylylidene)]bis(1,3 - dimethylpyrimidine - 2,4,6 - trione
(10d). Acetic acid (400 ml) solution of 1,4-benzenedicarb-
aldehyde (0.67 g; 5 mmol), 1,3-dimethylbarbituric acid
(1.56 g; 10 mmol), and sulfuric acid (0.3 ml) was refluxed
for one hour. Immediately color of the reaction mixture
changes to orange and an orange precipitate starts to
form. Reaction suspension was reduced to 14 of its original
volume and solid was separated from hot reaction sus-
pension by filtration. Solid yellow product was washed
hot acetic acid (3×20 ml), hot methanol (3×20 ml) and
16. Acetic acid (100 ml) solution of cinnamaldehyde (26.4
mg; 0.1 mmol) and 1,3-dimethylbarbituric acid (15.6 mg)
was stirred at room temperature. Every hour two drops
of the reaction mixture were dissolved in 0.6 ml of
DMSO-d6. To make this prepared NMR sample a clear
solution, a few drops of CF3SO3H were added. After all
starting aldehyde is transferred into condensation
product 8d zinc dust (640 mg; 10 mmol) was added into
reaction mixture and reaction progress is again moni-
tored by NMR spectroscopy in DMSO-d6–CF3SO3H.
17. All barbituric acid alkylidenes 8 are prepared from corre-
sponding a,b-unsaturated aldehyde and barbituric acid
following typical procedures for preparation of 8d. Prepa-
ration of 1,3-Dimethyl-5-(3-phenylallylidene)pyrimidine-
2,4,6-trione (8d). Acetic acid (200 ml) solution of
cinnamaldehyde (2.64g; 0.02 mol) and 1,3-dimethylbarbi-
turic acid (3.12 g; 0.02 mol) was refluxed for one hour.
Formed yellow suspension was concentrated to volume of
about 30 ml and cooled to room temperature. Solid was
separated by filtration, washed with ice-cold methanol
(3×15 ml) and dried at 110°C for one hour to afford 4.9
g (91%) of pure product. 1H NMR (CDCl3, 500Mz) l
8.456 (1H, d+d, J1=12.5 Hz, J2=11.5), 8.060 (1H, d,
J=11.5), 7.542 (2H, m), 7.29 (4H, m), and 3.249 (3H, s,
NCH3), 3.247 ppm (3H, s, NCH3). 13C NMR (CDCl3,
500 MHz) l 162.33, 161.75, 157.32, 154.29, 151.52,
135.44, 131.60, 129.22, 127.82, 125.20, 114.68, 28.80, and
28.17 ppm (twelve different carbon atoms). Anal. calcd.
For C15H14N2O3 (270.28): C, 66.66; H, 5.22; N, 10.36.
Found: C, 66.41; H, 5.38; N, 10.24.
18. Typical procedure for zinc-acetic acid reduction of barbi-
turic acid alkylidenes 8. Preparation 1,3-dimethyl-5-(3-
phenylpropyl)pyrimidine-2,4,6-trione (9d). Acetic acid
suspension (200 ml) of alkylidene 8d (2.7 g 0.01 mol) and
zinc dust (6.4 g; 0.1 mol) was stirred at room temperature
overnight. Liquid over gray sediment of the reaction
suspension is colorless. Solid was separated by filtration
and washed with acetic acid (3x50 ml). Combined filtrates
were evaporated to solid residue. Solid residue was crys-
tallized from methanol to afford 2.58 g (94%) pure
product. 1H NMR(CDCl3, 500 MHz) l 7.234 (2H, t,
J=7.0 Hz, m-H), 7.052 (1H, t, J=7.5 Hz, p-H), 6.987
(2H, t, J=6.5 Hz, o-H), 3.258 (1H, t, J=5 Hz, CH),
2.457 (2H, t, J=7.5 Hz, CH2Ph), 1.783 (2H, d+t, J1=7.5,
J2=5 Hz, CHCH2), and 1.544 ppm (2H, m, CH2). 13C
NMR (CDCl3, 500 MHz) l 170.79, 150.83, 140.83,
128.50, 128.33, 126.19, 76.37, 41.38, 35.07, 29.03, and
24.40 ppm (eleven different carbon atoms). Anal. calcd.
For C15H18N2O3 (274.32): C, 65.68; H, 6.61; N, 10.21.
Found: C, 65.52; H, 6.72; N, 10.11.
1
dried at 110°C for two hours to afford 1.95 g (95%). H
NMR (H2SO4, three drops of DMSO-d6, 500 MHz) l
8.262 (2H, s, vinyl CH), 7.316 (4H, s, aromatic H), 2.913
(6H, s, NCH3), and 2.810 ppm (6H, s, NCH3); 13C NMR
(H2SO4, three drops of DMSO-d6, 500 MHz) l 166.04,
165.90, 165.82 (three different carbonyls), 162.36, 151.50
137.13, 132.51, 116.80 (five different CC double bond
carbons), 30.86 and 30.04 ppm (two different NCH3
carbons). Anal. calcd. For C20H18N4O6 (410.38): C,
58.53; H, 4.42; N, 13.65 Found: C, 58.36; H, 4.57; N,
13.41.
20. Typical procedure for reduction of dimethylidenes 10.
Preparation
5,5%-[1,4-phenylenedi(methylene)]bis(1,3-
dimethylpyrimidine-2,4,6(1H,3H,5H)-trione) (11b). Acetic
acid (500 ml) suspension of 5,5%-[1,4-phenylenedi(methyl-
ylidene)]bis(1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-tri-
one) (10d) (1.025 g; 0.0025 mol) and zinc (3.2g; 0.05 mol)
was refluxed for three hours. From still refluxing suspen-
sion solid residue was separated by filtration and washed
with hot acetic acid (3×50 ml). Combined acetic acid
filtrates were evaporated to solid residue. White solid
product was crystallized from methanol to afford 0.93 g
1
(90%) pure product. H NMR (DMSO-d6, four drops of
H2SO4, 400 MHz) l 6.81 (4H, s), 3.91 (2H, t, J=4.4 Hz),
3.15 (4H, d, J=4.4 Hz), and 2.90 ppm (12H, s, NCH3).
13C NMR (DMSO-d6, four drops of H2SO4, 400 MHz) d
165.43 and 148.20 (two different carbonyl carbons),
132.40 and 125.86 (two different aromatic carbons), 47.24
32.21, and 24.92 ppm (three different aliphatic carbons).
Anal. calcd. For C20H22N4O6 (414.41): C, 57.97; H, 5.35;
N, 13.52. Found: C, 57.87; H, 5.45; N, 13.43.
21. X-Ray structure determination was performed on Bruker
SMART 1KCCD automated diffractometer. Crystals of
compound 11d were obtained by crystallization from
methanol by allowing slow solvent evaporation. All
reagents and solvents were purchased from Aldrich and
used without prior purification. X-Ray Single Crystal
Structure Determination of Compound 11d at 150(2) K
,
Crystal Data: C20 H22 N4 O6 0.71073 A [CH3OH], Mr=
,
297.08, monoclinic, space group P21/n, a=7.9926(4) A,
,
,
b=18.5230(9) A, c=13.6506(7) A, i=93.399(1)°, V=
2017.37(18) A , Z=4, zcalcd 1.364 Mgm−3, F000=872,
3
,
,
Wavelength (u)=0.71073 A, Absorption coefficient (m)=
0.103 mm−1
.
Data collection and reduction: Crystal size: 0.15×0.15×
0.30 mm, Theta range: 2.20–26.43°, Index ranges: −95
h510,−23,5k523,−1751517, Reflections collected:

2210
B. S. Jursic, E. D. Ste6ens / Tetrahedron Letters 44 (2003) 2203–2210
22381, Independent reflections: 4130 [Rint=0.0588],
Refinement method: Full-matrix least-squares on F2,
Data/restraints/parameters: 4130/110/372. Final R indices
[I>2|(I)]: R1=0.0423, wR2=0.1074, Goodness-of-fit on
gram(s) used to refine structure: SHELX97 (Sheldrick,
1997); molecular graphics: SHELXTL97 (Sheldrick,
1997); software used to prepare material for publication:
SHELXTL97. (a) Bruker. SMART (Version 5.060) and
SMART-Plus (Version 6.02); Bruker AXS Inc., Madison,
WI, USA, 2000; (b) Sheldick, G. M. SHELXTL DOS/
Windows/NT; Version 5.1. Bruker AXS Inc., Madison,
WI, USA, 1997; (c) Sheldrick, G. M. SHELXL-97, Uni-
versity of Go¨ttingen, Go¨ttingen, Germany, 1997.
F2: 0.953. R indices (all data) R1=0.0808, wR2=0.1074,
−3
,
Largest diff. peak and hole: 0.189 and −0.222 eA
.
Measurement, Computing and Graphics: SMART 1K
CDD (Bruker, 2000); cell refinement: SMART; data
reduction SAINT-Plus (Bruker, 2000); programs(s) used
to solve structure: SHELXS97 (Sheldrick, 1997); pro-
22. Patent application in preparation.