5,5′-bipyridyl-2,4,6,2′,4′,6′-hexaone derivatives (hydurilic acids): Syntheses, mechanism of C-C-Bond formation and properties of the dimeric barbituric acid derivatives

Article abstract of DOI:10.3987/COM-08-S(D)37

A series of hydurilic acid derivatives (5,5′-bipyrimidinyl-2,4,6,2′,4′,6′-hexaones) including several new derivatives was synthesized from 5,6-diaminouracils. Mechanisms for their formation are proposed and discussed. Furthermore, a new method for the preparation of pyrimidine-2,4,5,6-tetraone-5-oxime derivatives (violuric acids) was found starting from 5-amino-6-nitrosouracils.

Full text of DOI:10.3987/COM-08-S(D)37

HETEROCYCLES, Vol. 79, 2009
703
HETEROCYCLES, Vol. 79, 2009, pp. 703 - 720. © The Japan Institute of Heterocyclic Chemistry
Received, 27th September, 2008, Accepted, 21st November, 2008, Published online, 25th November, 2008.
DOI: 10.3987/COM-08-S(D)37
5,5’-BIPYRIDYL-2,4,6,2’,4’,6’-HEXAONE DERIVATIVES (HYDURILIC
ACIDS): SYNTHESES, MECHANISM OF C-C-BOND FORMATION AND
PROPERTIES OF THE DIMERIC BARBITURIC ACID DERIVATIVES¶
Christa E. Müller,* Carolin Roegler, and Jörg Hockemeyer
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An
der Immenburg 4, D-53121 Bonn, Germany; christa.mueller@uni-bonn.de
¶Dedicated to the memory of Dr. John William Daly, a brilliant and unique
scientist, a great teacher, and an admirable person
Abstract
–
A
series
of
hydurilic
acid
derivatives
(5,5’-bipyrimidinyl-2,4,6,2’,4’,6’-hexaones) including several new derivatives
was synthesized from 5,6-diaminouracils. Mechanisms for their formation are
proposed and discussed. Furthermore, a new method for the preparation of
pyrimidine-2,4,5,6-tetraone-5-oxime derivatives (violuric acids) was found
starting from 5-amino-6-nitrosouracils.
INTRODUCTION
In the course of our efforts to synthesize novel xanthine derivatives as adenosine receptor antagonists1 we
had developed a general synthesis of 1-monosubstituted xanthines.2 The conversion of 3-substituted
6-aminouracils3 to the corresponding 5,6-diaminouracil derivatives (1) and subsequent condensation with
formic acid for 20 to 40 h generally provided 1-monosubstituted xanthines (2) in high yields2 (Scheme 1).
One striking exception had been observed: the reaction of 5,6-diamino-3-(2-phenylethyl)uracil 3 with
formic acid under reflux conditions did not lead to the corresponding 1-substituted xanthine derivative 4,
but gave an unknown compound (5) in high yield. The desired 1-(2-phenylethyl)xanthine 4 could
meanwhile be synthesized from 3 in a yield of 92 % using triethylorthoformate after a reaction time of
only 4 h under reflux conditions.2 The present study was aimed at elucidating the structure of the new
product 5, the synthesis and characterization of analogs, and the mechanism of their formation.

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HETEROCYCLES, Vol. 79, 2009
O
O
H
R
O
NH2
NH2
R
R = alkyl
N
N
HCO2H
∆ / 20-40 h
N
N
H
1
N
O
N
H
2
R' = CH2CH2Ph
O
O
R'
H
O
O
R'
H
R'
R'
NH2
NH2
N
N
N
N
N
N
HC(OEt)3
∆ / 4 h
N
HCO2H
O
O
∆ / 20-40 h
N
O
N
H
4
O
N
O
H
O
H
5
3
Scheme 1. Formation of 1-substituted xanthine derivatives from 5,6-diamino-3-alkyluracils and
unexpected formation of 1,1’-bis-(2-phenylethyl)-[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone (5) from
5,6-diamino-3-(2-phenylethyl)uracil (3).
RESULTS AND DISCUSSION
The structure of product 5 was elucidated by a combination of analytical methods including
chromatography, spectroscopy, and elemental analysis. All observations taken together proved the
formation
of
a
symmetrical
1,1’-bis-(2-phenylethyl)-substituted
[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone 5 (Scheme 1). Presumably a mixture of stereoisomers was
formed which could not be isolated. The fact that the CH-acidic isomers can easily be converted either
into the corresponding enantiomer or into the meso-form could be a possible explanation for the difficulty
in separating the stereoisomers.
The related, N-unsubstituted compound 12 (Scheme 2) with the trivial name hydurilic acid was first
prepared and characterized by Bayer as early as 1863.4 The 5,5’-connected dimer of barbituric acid had
been obtained from 5-hydroxypyrimidine-2,4,6-trione (5-hydroxybarbituric acid, 6) by heating in glycerol
at 150 °C in a yield of 50 %,4 or in the absence of solvent at 190-200 °C in a lower yield of 34 %.5
Alternatively, 5-amino-1,3-dimethylpyrimidine-2,4,6-trione (5-amino-1,3-dimethylbarbituric acid, 7) has
been used as starting material. In the presence of two equivalents of methyl isocyanate as ammonia
scavenger a 54 % yield of tetramethyl hydurilic acid (13) was obtained after a reaction time of 16 h at
100 °C in a sealed tube.6 Based upon these findings a plausible pathway, involving three starting
molecules, can be postulated to describe the aforementioned reactions (Scheme 2). Condensation
reactions, including the formation of a carbon-carbon bond, are followed by elimination of
pyrimidine-2,4,5,6-tetraone (alloxane, 10) or 5-imino-1,3-dimethylpyrimidine-2,4,6-trione (11),
respectively.

HETEROCYCLES, Vol. 79, 2009
705
R
R
O
O
R
R
O
O
O
O
R
R
- XH2
N
N
N
N
N
N
XH
H
XH
8 R = H, X = O
2 x
O
O
O
9 R = Me, X = NH
H
6 R = H, X = O
R
O
O
7 R = Me, X = NH
N
N
XH
O
H
R
R
O
R
R
O
O
O
O
R
R
O
O
R
R
R
O
- XH2
N
N
N
N
N
N
N
12 R = H
H
O
O
O
O
13 R = Me
H
N
R
R
O
O
O
N
X
N
10 R = H, X = O
11 R = Me, X = NH
Scheme 2. Proposed pathway for the formation of hydurilic acid (12) from 5-hydroxybarbituric acid (6)
and its tetramethyl derivative (13) from 5-amino-1,3-dimethylbarbituric acid (7).
In this context it is noteworthy that the by-product of the described reactions, alloxane (10), was reported
to provide hydurilic acid itself at 170 °C in a sealed tube. The presence of a large excess of water as well
as the absence of water was shown to prevent the formation of 12.7 Due to the observed water-sensitivity
alloxane hydrate 14 (see scheme 3) could be postulated as the initial molecule for the formation of 12
from 10. Several different reaction steps have to be considered involving nucleophilic attacks, elimination
of water or other molecules, and disproportionation reactions.
H
O
O
O
H
O
H
H
H
O
N
N
N
N
N
N
N
N
OH
OH
H2O
O
O
O
O
O
H
O
O
H
H
O
14
12
10
Scheme 3. Formation of unsubstituted hydurilic acid (12) from alloxane (10).
The formation of tetramethyl hydurilic acid 13 (Scheme 4) by refluxing of
5,6-diamino-1,3-dimethyluracil 15 in aqueous solution containing various concentrations of mineralic
acid was first described by Bredereck using sulfuric acid;8 he obtained 13 in 19 % yield. Independently,
Blicke and Godt obtained a maximal yield of 54 % of 13 by using an aqueous solution of two equivalents
of hydrochloric acid in water.9 From the reaction mixtures both groups isolated the colorless pyrazine

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HETEROCYCLES, Vol. 79, 2009
derivative 1,3,7,9-tetramethyl-(1H,3H,7H,9H)-pyrimido[5,4-g]pteridine-2,4,6,8-tetrone (16)10 in yields of
31 %,9 and 23 %, respectively8 in addition to hydurilic acid derivative 13. A careful reinvestigation of this
reaction
showed
that
the
yellow
isomer
1,3,6,8-tetramethyl(1H,3H,6H,8H)pyrimido[4,5-g]pteridine-2,4,7,9-tetrone (17)11 was formed as well.
Due to its physicochemical properties 17 remained in the mother liquor, when the reaction mixture was
worked up as described by the authors (Scheme 4). It was found by Blicke and Godt9 that the formation
of 13 became predominant when the concentration of hydrochloric acid was increased. Our
reinvestigation showed that the formation of pyrazine derivatives could not completely be suppressed,
even in the presence of a large excess of hydrochloric acid.
O
O
O
H
O O
NH2
NH
H2O/excess HCl
reflux
N
N
N
N
N
N
N
N
2x
N
O
O
+
+
O
N
O
N
O
O
N
O O
16 (colorless)
13
O
N
N
N
O
NH2
NH2
N
N
N
O
N
O
N
O
17
(yellow)
15
Scheme 4. Formation of hydurilic acid and pyrazine derivatives from 5,6-diamino-1,3-dimethyluracil
(15).
In contrast to Blicke and Godt9 Bredereck presented a proposal for a detailed reaction mechanism
correlating the formation of the reduced hydurilic acid derivative with the oxidized pyrazine ring system.8
Since the nature of the redox reactions proposed by Bredereck8 still remained unclear, additional
experiments were performed to obtain more information about this reaction. Assuming that under
vigorous aqueous acidic conditions at least a partial hydrolysis of the diaminouracil 15 would take place
prior to any C-C-bond formation, a hydrolysis product of 15 should also lead to the hydurilic acid
derivative 13 under the same reaction conditions.
5-Amino-1,3-dimethylbarbituric acid (7, Scheme 2) was selected to investigate its potential conversion to
1,1’,3,3’-tetramethylhydurilic acid (13) under reflux conditions in the presence of an excess of aqueous
hydrochloric acid. Starting compound 7 could easily be prepared by reduction of the appropriate
pyrimidine-2,4,5,6-tetraone-5-oxime (violuric acid) derivative 2212 using sodium dithionite in aqueous
ammonia solution (Scheme 5).

HETEROCYCLES, Vol. 79, 2009
707
aq. NH3
Na2S2O4
60 °C, 5 min
O
O
O
2 M HCl,
10 min reflux
R
O
N
O
R
O
N
R
O
NH2
O
OH
N
O
N
N
N
N
NH2
N
R'
R'
R'
7 R = R' = Me
26 R = R' = Bu
18 R = R' = Me
19 R = R' = Bu
20 R = Me, R' = H
22 R = R' = Me
23 R = R' = Bu
24 R = Me, R' = H
25 R =
21 R =
R' = H
R' = H
O
O
O
N
N
N
N
DMSO
+
x NH4
O
7
27
C
O
O
N
O
O
excess H5C6COCl
reflux, 2 h
R
N
NH2
O
R
O
N
N
28 R = Me
29 R = Bu
O
O
N
R
N
R
7 resp. 26
Scheme 5. Synthesis of violuric acids and 5-aminobarbituric acids and reactions of
5-amino-1,3-dimethylbarbituric acid (7).
The formation of 22 was achieved by hydrolysis of the corresponding 6-amino-5-nitrosouracil 18 in
diluted aqueous hydrochloric acid under reflux conditions. To prove the general applicability of this
method, a range of mono- and disubstituted violuric acid derivatives (22-25) was prepared. In all cases
highly pure products were obtained with yields of around 80 % for the di-substituted and ca. 40 % for the
mono-substituted derivatives. We observed that the cleavage of the derivatives 22-25 by diluted
hydrochloric acid proceeded very slowly even under reflux conditions. To the best of our knowledge this
route has not yet been described for the preparation of violuric acid derivatives.
The reduction of the purple solutions of violuric acid derivatives 22 and 23 at 60 °C provided the
colorless 5-aminobarbituric acids 7 and 26 after short reaction times of less than 5 min. Although the
1
13
colorless solids are extremely sensitive to oxidation, derivative 7 could be characterized by H and C
NMR spectroscopy. The solution of 7 in d6-DMSO had to be measured immediately since it soon turned
to deep purple due to the oxidation of 7 by the solvent yielding the oxidation product murexoin 27
(confirmed by TLC analysis).13 Further characterization of 7 and 26 was achieved by derivatization with
an excess of benzoyl chloride under reflux conditions yielding the corresponding
4,6-dialkyl-2-phenyl-4H,6H-oxazolo[5,4-d]pyrimidine-5,7-diones 28 and 29.14,15

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HETEROCYCLES, Vol. 79, 2009
Aqueous solutions of freshly prepared 7 containing an excess of hydrochloric acid were refluxed, varying
the reaction times from 1 h up to 18 h (scheme 6). After cooling to rt the aqueous colorless reaction
mixtures were extracted with dichloromethane. Due to complex separation problems of water-soluble
reaction products, the aqueous phases were not investigated in detail, but were considered to contain
mainly decomposition products, such as methylammonium chloride. In all cases evaporation of the
organic solvent led to a solid residue consisting of a mixture of colorless products, none of which could
be identified as tetramethylhydurilic acid 13 or a pyrazine derivative. One main product could easily be
1
crystallized from diethyl ether. An H NMR spectrum showing only two singlets at 3.08 (3H) and 4.68
ppm (2H), a 13C NMR spectrum with four peaks at 25.9, 68.0, 156.0 and 170.4 ppm and a molecular mass
of 155 pointed to a small molecule. Together with the melting point of 133 °C (Lit.: 133-134 °C)16 all
data indicated the formation of 3-methyloxazolidine-2,4-dione 3516 (Scheme 6). After a reaction time of 1
h compound 35 was obtained in a yield of 17 %, and after a reaction time of 3 h the yield was increased to
35 %. After 18 h a significant decrease in the yield was observed, and hydroxyacetic acid (37) was
detected in the crude dichloromethane extract. Besides compound 35 another small heterocyclic
compound was observed in the crude extract. Comparison with literature NMR data confirmed the
formation of 3-methylimidazolidine-2,4-dione (3-methylhydantoine, 36).17 Compound 36 was obtained in
a yield of about 5 % after a reaction time of 3 h. Longer reaction times did not significantly alter the yield
of 36, but the enrichment of 36 in comparison with 35 in the crude organic extract indicated that the
hydantoin derivative was more stable than the oxazolidine derivative under vigorous aqueous acidic
conditions. Without providing any experimental details, Techow12 had reported on the crystallization of
5,5’-dihydroxy-1,3,1’,3’-tetramethyl[5,5’]bipyrimidyl-2,4,6,2’,4’,6’-hexaone (38, Scheme 6) from the
neutralized reaction mixture after refluxing a solution of 7 in aqueous hydrochloric acid. This observation,
which would involve a C-C-bond formation, could not be confirmed by our own experiments.
The formation of oxazolidine-2,4-diones (e.g. 35) by a ring-contraction reaction from 5-hydroxybarbituric
acid derivatives (e.g. 30) is well known18 but has typically been performed in alkaline solution or under
virtually neutral conditions.19 Several plausible mechanisms have been discussed19 and led to an
understanding of the observed reaction (Scheme 6). Presuming the hydrolysis of 7 to the
5-hydroxybarbituric acid derivative 30, the following ring contraction leads to the intermediate 31. A
competing process is the intramolecular reaction of the starting compound 7 yielding the intermediate 32.
Hydrolysis of the resulting amide derivatives (31 and 32) followed by decarboxylation of the
intermediates 33 and 34 would complete the formation of 35 and 36 (Scheme 6).

HETEROCYCLES, Vol. 79, 2009
709
O
O
H
H
NH2
O
OH
O
N
N
∆
H2O/HCl/
- NH4Cl
O
N
O
N
30
7
O
O
H
O
O
H
H2O/HCl
- MeNH3Cl
N
N
H
OH
N
?
X
X
O
O
31
32
X = O
X= NH
33
34
X = O
X= NH
O
O
O
N
OH
HO
38
N
N
∆
O
- CO2
O
N
O
O
O
O
N
N
HO
O
N
H2O/HCl
- MeNH3Cl
- CO2
OH
37
O
O
H
35
36
Scheme 6. Reaction of 5-amino-1,3-dimethylbarbituric acid (7) with an excess of hydrochloric acid
under reflux.
In consideration of the above mentioned results, the mechanism proposed by Bredereck8 concerning the
formation of hydurilic acids from 5,6-diaminouracils upon catalysis by mineralic acids in water under
reflux conditions has to be revised. Apparently the complete hydrolysis to a 5-hydroxybarbituric acid
derivative could not be the first step since this would be followed by ring contraction.
In order to obtain more information about the actual intermediates, the reaction of
5,6-diamino-1,3-dimethyluracil (15) was investigated in more detail (Scheme 7). As shown above,
conversion of the vinylic amino group of 5-amino-1,3-dimethyl-6-nitrosouracil (18) into a carbonyl group
yielding violuric acid derivative 22 was completed within less than 10 min already (Scheme 5). We
therefore stopped the reaction of 15 in refluxing hydrochloric acid after 0.5 h already: the formation of 13
as well as that of pyrazine derivatives 16 and 17 (see Scheme 4) was observed to be already at an
advanced stage after that short reaction time. TLC analysis of the crude reaction mixtures showed that
further products had been formed besides 13, 16 and 17. Two further products were isolated by extraction
of
the
crude
reaction
mixture
and
subsequent
column
chromatography:

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HETEROCYCLES, Vol. 79, 2009
1,3-dimethylimidazolidine-2,4,5-trione (dimethylparabanic acid, 45)20 and 1,3-dimethylbarbituric acid
(42).21 Compound 45 as a final product might be explained through decomposition of the alloxane
derivative 44 similar to the formation of the 5-membered ring systems described in Scheme 6. The
formation of 42 is more surprising since this derivative was neither observed nor expected before in this
context. However, the formation of 42 could be explained by oxidation of the pyrazine precursor 39 (resp.
40) by the starting compound 15 forming the final pyrazine derivative 16 (resp. 17) as well as the
intermediate 41, which is subsequently hydrolyzed to 42 (Scheme 7).
O
H
NH2
N
15
O
N
NH
2x
- 2 NH3
2x
- 2 NH3
2x
- NH3
O
O
N
O
N
H
H
O
N
N
O
N
N
N
N
O
HN
N
N
O
N
O
O
N
N
O
N
N
NH2
H
H
40
H
N
39
O
15
O
NH
9
O
N
- NH3
- NH3
N
41
O
NH
15
O
N
O
N
O
N
H2O/- NH3
O
O
N
N
N
N
O
N
N
N
N
O
2 H2O/
- 3 NH3
O
N
O
N
42
16
17
O
N
O
O
N
N
HN
O
O
O
N
O
O
O
O
2 H2O
- 2 NH3
NH
43
N
N
N
N
N
N
O
O
O
O
N
O
O
O
13
44
45
Scheme 7. Reaction of 5,6-diamino-1,3-dimethyluracil (15) with an excess of hydrochloric acid under
reflux.

HETEROCYCLES, Vol. 79, 2009
711
Another possibility for the formation of compound 45 has to be considered. The pyrazine derivatives 16
(resp. 17) may be reduced by the 5,6-diaminouracil 15 leading to 39 (resp. 40). The resulting intermediate
43 would lead to the stable dimethylparabanic acid (45) as described above (Scheme 8).
O
H
NH2
N
15
O
N
NH
O
N
O
N
H
N
N
N
N
N
39 or 40
O
O
N
H
O
N
NH
NH
16 or 17
N
O
O
N
N
43
45
O
O
Scheme 8. Reduction of pyrazine derivatives (16 or 17) by 5,6-diamino-1,3-dimethyluracil (15).
During the course of the above mentioned reaction a purple coloration was observed after ca. 10 min.
Within the following 10 min the reaction mixture turned yellow. These changes of color could be
associated with the formation of the well-known deep violet purpuric acid derivatives (compound 27,
Scheme 5). They consist of two pyrimidyl ring systems linked by a nitrogen atom forming a large
delocalized π-electron system. Structurally similar pyrazine precursors can be postulated for the reaction
investigated and could provide a plausible explanation for the purple color. Subsequent oxidation to the
final pyrazine derivatives would explain a further change of color from purple to yellow. The remaining
color can be assigned to the yellow pyrazine isomer 17. These observations indicate that the formation of
pyrazines should be completed after a reaction time of only 25 min.
Since the 5-unsubstituted barbituric acid (42) could still be detected after a reaction time of 12 h, the
compound obviously does not participate in the formation process of hydurilic acid derivative 13. This
observation is well in agreement with the finding by Biltz that 42 itself does not lead to 13 under strongly
acidic conditions in the presence of an oxidizing agent.5 However, not even traces of the oxazolidine
derivative 35 could be extracted from the reaction mixture. The absence of 35 is a further proof that a
complete hydrolysis of the 5,6-diaminouracil 15 to the 5-hydroxybarbituric acid 30 cannot be the initial
step in the reaction investigated. Both amino groups of the starting compound 15 appear to be essential

712
HETEROCYCLES, Vol. 79, 2009
not only for the formation of pyrazines but also for the C-C-bond formation of two uracil ring systems
finally resulting in the C5-C5’-bond of derivative 13 (Scheme 4).
In order to gain more information about the properties of hydurilic acid derivatives a series of derivatives
were prepared. Tetramethylhydurilic acid (13) was best prepared as previously described by Blicke and
Godt.9 Further purification was achieved by column chromatography. 5,6-Diamino-1-alkyluracils were
selected as starting compounds for 1,1’-disubstituted hydurilic acids. Since the reaction of 1-methyl- or
1-propyl-5,6-diaminouracil (46 and 47) with concentrated formic acid did not lead to hydurilic acids (see
Scheme 1) the reaction was performed with an excess of hydrochloric acid under reflux conditions. After
reaction times of less than 1 h the crude hydurilic acid derivatives 48 and 49, contaminated by
corresponding pyrazine derivatives, precipitated from the cold reaction mixtures (Scheme 9). Due to its
physicochemical properties the purification of 48 (a purity of about 80 % was determined for the crude
product) proved to be extraordinary difficult and could not satisfactorily be achieved with standard
methods. In contrast, compound 49 could easily be obtained in a pure form by recrystallisation from
isopropanol. Both 1,1’-substituted hydurilic acids were obtained in moderate yields of about 20 %.
Consistent with our theory as described above, longer reaction times did not result in higher yields.
The conversion of the diaminouracil 46 confirmed our proposed reaction mechanism. Next to the desired
compound 46 and pyrazine derivatives the formation of the corresponding C5-unsubstituted barbituric
acid (50)21 and the parabanic acid derivative 5120 were observed as side-products and characterized by
comparison with literature NMR data. The small heterocyclic compounds 50 and 51 were extracted from
the crude reaction mixture with dichloromethane and subsequently purified by column chromatography
(Scheme 9).
O
pyrazine isomers
H
O
O
H
+
H2O/excess HCl
6 h reflux
H
O
NH2
NH2
N
N
N
N
N
O
O
O
*
*
H
N
R
N
50 R = Me
R
+
O
O
R
O
N
R
O
46 R = Me
48 R = Me
47 R = n-Pr
49 R = n-Pr
O
R
H
+
N
N
51 R = Me
O
O
Scheme 9. Formation of 1,1’-disubstituted hydurilic acid derivatives.

HETEROCYCLES, Vol. 79, 2009
713
The preparation of hydurilic acids from 5,6-diaminouracils was observed to be associated with a number
of difficulties: a) the yield is limited due to the reaction mechanism, b) the co-formation of pyrazine
derivatives appears to be inevitable or can at least not easily be suppressed, c) especially less lipophilic
derivatives cannot be purified easily. The easy formation of the 1,1’-di-(2-phenylethyl)hydurilic acid 5
(Scheme 1) from the corresponding 5,6-diaminouracil 3 remained an exception.
5,5’-Unsubstituted hydurilic acids show characteristic NMR spectra as discussed below. In order to
obtain a broader basis of information 5,5’-disubstituted hydurilic acid derivatives were additionally
prepared (Scheme 10). The known 5-bromo-5’-methoxytetramethylhydurilic acid (52) was obtained as
previously described starting from tetramethylhydurilic acid 13 with an excess of bromine in methanol
under reflux conditions.22 The methylation of 13 using an excess of methyl iodide in DMF in the presence
of a potassium carbonate under microwave irradiation (10 W, 80 °C, 1.5 bar, 0.5 h) yielded
hexamethylhydurilic acid (53, Scheme 10).
MeOH,
excess Br2,
1.5 h reflux
O
O
O
O
O
O
MW, 10 W, 80 °C,
1.5 bar, 0.5 h
N
N
Br
O
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
DMF, MeI,
K2CO3
O
O
O
O
O
O
13
53
52
Scheme 10. Formation of 1,1’,3,3’-tetramethyl-5,5’-substituted hydurilic acid derivatives.
The previously described hydurilic acid derivatives 13, 48, 52 and 53 as well as the new derivatives 5 and
1
1
49 were investigated by H and 13C NMR spectroscopy.22 The H NMR spectra of all N-methyl
substituted derivatives showed singlets for the N-methyl groups in the typical range from 3.08 (48) to
3.37 ppm (52). The C5 H-atom of the C5-unsubstituted derivatives were exchangeable, and appeared as
very broad singlets within a small range from 4.85 to 4.99 ppm (compounds 5, 13, 48 and 49, measured in
DMSO-d6). The NH-signals for the derivatives 5, 48 and 49 were consistently observed around 11.7 ppm.
In the 13C NMR spectra the NCH3 signals for the derivatives 13, 48, 52 and 53 appeared in the expected
region around 29 ppm. The chemical shifts for unsubstituted C5-atoms (derivatives 5, 13, 48 and 49)
were observed around 48.5 ppm, showing very little variation. One remarkable effect could be observed
comparing the spectra of tetramethylhydurilic acid 13 measured in CHCl3 and in DMSO-d6, respectively.
The peak for the C5-atoms at 48.2 ppm appeared broadened and not very clear when DMSO-d6 was used
as a solvent, while in CDCl3 the signal appeared very clear and well pronounced. This effect could be
explained by a reduced tendency of the CH-acidic compound to form enol-tautomers in the non-polar
CDCl3. The well pronounced C2 signals of all derivatives investigated did not show any significant
variations and were observed in the typical region around 150 ppm. In contrast to this the C4- and the

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HETEROCYCLES, Vol. 79, 2009
C6-signals, respectively, of the C5-unsubstituted derivatives 5, 13, 48 and 49, appeared around 166 ppm
appeared broadened and were only weak. Again, this effect could be explained by the formation of
tautomers. The spectra of the C5-substituted derivatives 52 and 53 provided the proof for this assumption:
the formation of tautomers could be blocked by substitution of the C5-positions so that the C4/C6-signals
appeared clearly and well defined.
CONCLUSIONS
A series of differently substituted hydurilic acids was prepared from 5,6-diaminouracil derivatives
including several new derivatives. The reaction mechanism was investigated in detail, and a new pathway
was postulated based on the isolation and structural determination of intermediate products. The products
were characterized by spectroscopic methods and 5,5’-unsubstituted derivatives not previously described
in the literature were shown to tautomerize in polar solvents such as DMSO.
EXPERIMENTAL
1,1’,3,3’-Tetramethyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone (13): The compound was prepared as
13
previously described.9 1H NMR (CDCl3) ppm: 3.31 (s, 12H, NCH3), 4.65 (s sharp, 2H, C5H); C NMR
(CDCl3) ppm: 29.1 (NCH3), 48.72 (s sharp, C5), 151.0 (C2), 166.28 (C4/C6); 1H NMR (DMSO-d6) ppm:
13
3.15 (s, 12H, NCH3), 4.99 (s br), 2H, C5H); C NMR (DMSO-d6) ppm: 28.6 (NCH3), 48.7 (br, C5),
151.4 (C2), 167.1 (br, C4/C6).
1,1’-Dimethyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone
(48):8,22
Freshly
prepared
5,6-diamino-1-methyluracil (46, 1 g, < 6 mmol, containing an undetermined amount of water) was
refluxed in a mixture of concentrated hydrochloric acid (5 mL) and water (5 mL). After 1 h the reaction
was stopped and the yellow solution was evaporated under reduced pressure. The residue was crystallized
from a minimum of water at 4 °C. After ca. 12 h the precipitate was filtered off under reduced pressure,
washed with little water and dried at 70 °C yielding 160 mg of a pale yellow (due to impurities of the
corresponding yellow pyrazine derivatives) solid. For the (colorless) 48 a purity of about 80 % was
determined by 1H NMR spectroscopy. Until now no satisfactory purification method could be developed.
1H NMR (DMSO-d6) ppm: 3.08 (s, 6H, CH3), 4.85 (s, 2H, C5-H), 11.72 (s, 2H, NH); 13C NMR
(DMSO-d6) ppm: 27.68, 48.31 (C5), 150.9 (C2), 167.6 and 168.4 (br, C4,C6).
1,1’-Dipropyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone
(49):
Freshly
prepared
5,6-diamino-1-propyluracil (47, ca. 850 mg, 4,6 mmol) was refluxed in a mixture of concentrated
hydrochloric acid (3 mL) and water (5 mL). After 30 min a colorless solid precipitated and the reaction

HETEROCYCLES, Vol. 79, 2009
715
was stopped. The precipitation was completed at 4 °C and the crude product (270 mg) was filtered off
under reduced pressure. The solid was washed with water and recrystallized from isopropanol yielding
155 mg of colorless crystals (20 %). Alternatively the crude product could be purified by column
chromatography on silica gel: eluting first with CH2Cl2/MeOH (5 : 1) in order to separate the impurities
1
(pyrazine derivatives) and finally with CH2Cl2/MeOH (3 : 1): mp 215 °C; H NMR (DMSO-d6) ppm:
0.81 (br s, 6H, CH3), 1.48 (br s , 4H, CH2), 3.65 (br s, 4H, NCH2), 4.87 (s, 2H, C5-H), 11.68 (s, 2H, NH);
13C NMR (DMSO-d6) ppm: 11.0 (CH3) , 20.8 (CH2), 42.3 (NCH2), 48.5 (C5), 150.7 (C2), 167-169 (br,
C4,C6); EIMS (m/z, %) 338 (M+ , 10) 170 (M/2H+, 100). Anal. Calcd for C14H18N4O6: C, 49.7; H, 5.36;
N, 16.56. Found: C, 49.6; H, 5.33; N, 16.53.
1,1’-Diphenylethyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone (5): 5,6-Diamino-3-(2-phenethyl)uracil
(3, 1.2 g, 4.9 mmol) was suspended in 30 mL of formic acid (98%). The mixture was refluxed for 28 h.
The excess of formic acid was distilled off and the residue was suspended in water. The precipitate was
collected by filtration and washed with water. Further purification was achieved by dissolution of the
compound in 1 M NaOH solution, precipitation by acidification using acetic acid and crystallization from
a small amount of CHCl3 yielding colorless crystals (66 % yield): mp 195 °C; 1H NMR (CDCl3): 2.87 (m,
4H, PhCH2), 4.05 (m, 4H, NCH2), 4.53 (s, 2H, C5-H), 7.17-7.30 (m, 10H, Harom.), 8.61 (s, 2H, NH) ppm;
13C NMR (CDCl3) ppm: 33.8, 43.3, 48.2, 126.8, 128.6, 128.88, 128.92, 138.44, 137.50, 149.2 (C2), 166.0
(br, C4,C6) ppm; EIMS (m/z, %) 462 (M+, 9) 104 ([CH2CH2Ph]+, 100), FDMS (m/z, %) 462 (M+ , 100);
Anal. Calcd for C24H22N4O6: C, 62.3; H, 4.79; N, 12.1. Found: C, 62.2; H, 4.73; N, 12.2. TLC analysis:
(CHCl3 : MeOH = 3:1, Rf = 0.95).
5-Bromo-5’-methoxy-1,1’,3,3’-tetramethyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone
(52):
The
compound was prepared from 13 as previously described22 (mp ca. 240 °C (dec.); lit mp 245-247 °C).22
1H NMR (CDCl3) ppm: 3.31 (s, 3H, OCH3), 3.36 (s, 6H, NCH3), 3.37 (s, 6H, NCH3). 13C NMR (CDCl3)
ppm: 29.6 (NCH3), 30.4 (NCH3), 56.9 (OCH3), 64.9 (C5), 84.9 (C5), 150.2 and 150.5 (C2 or C2’), 161.5
and 162.8 (C4/C6 or C4’/C6’).
1,1’,3,3’,5,5’-Hexamethyl[5,5’]bipyrimidinyl-2,4,6,2’,4’,6’-hexaone (53):22 A suspension of 13 (60 mg,
0.19 mmol), K2CO3 (0.055 g, 0.38 mmol) and methyl iodide (1 mL, 16 mol) in DMF (1 mL) was placed
in a 10 mL pressure tube and irradiated by microwave for 0.5 h (10 W, 80 °C, 1.5 bar). Subsequently the
mixture was evaporated under reduced pressure. After the addition of water (75 mL) the residue was
extracted twice, with 50 mL CH2Cl2 each. The organic extracts were dried over K2CO3, filtered,
evaporated and concentrated. The product was crystallized with Et2O: 50 mg colorless crystals (77 %),

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HETEROCYCLES, Vol. 79, 2009
1
mp 258.7-259.1 °C; H NMR (CDCl3) ppm: 1.86 (s, 6H, C5CH3), 3.25 (s, 12 H, NCH3); 13C NMR
(CDCl3) ppm: 21.5 (C5CH3), 29.1 (NCH3), 55.7 (C5), 150.3 (C2), 170.6 (C4/C6); EIMS (m/z, %) 338
(M+ , 2) 170 (M/2H+, 100). Anal. Calcd for C14H18N4O6: C, 49.7; H, 5.36; N, 16.56. Found: C, 49.5; H,
5.61; N, 16.60.
1,3-Dimethylpyrimidine-2,4,5,6-tetraone-5-oxime
(22):
A
suspension
of
6-amino-5-nitroso-1,3-dimethyluracil 18 (4.6 g, 25 mmol) in 35 mL of diluted hydrochloric acid (2 M)
was heated under reflux until an almost decolorized mixture was obtained (ca. 10 min). The colorless
product was crystallized from the reaction mixture at 4 °C, filtered off under reduced pressure, washed
with water and dried at 70 °C (84 % yield): mp 144.9-145.5 °C (lit.23, mp 141 °C). 1H NMR (CDCl3): (a
single tautomer) 3.38 (s, 3H, NCH3), 3.41 (s, 3H, NCH3), 15.91 (br s, 1H) ppm; 13C NMR (CDCl3): 27.9
(NCH3), 29.0 (NCH3), 135.5, 149.2, 156.2, 160.4 ppm; 1H NMR (DMSO-d6): 3.12 (s, 3H, NCH3), 3.17 (s,
3H, NCH3), 14.70 (br s, 1H) ppm; 13C NMR (DMSO-d6): 27.7 (NCH3), 28.4 (NCH3), 135.8, 150.8, 153.7,
158.3 ppm.
1-Methylpyrimidine-2,4,5,6-tetraone-5-oxime (24): A suspension of 6-amino-5-nitroso-3-methyluracil
20 (2.1 g, 12 mmol) in 15 mL of diluted hydrochloric acid (2 M) was heated under reflux until an almost
decolorized mixture was obtained (ca. 10 min). The colorless product was crystallized from the reaction
mixture at 4 °C, filtered off under reduced pressure, washed with water and dried at 70 °C (39 % yield):
mp 208.3 °C (lit.24, mp 202-203 °C (dec.)); 1H NMR (DMSO-d6): (mixture of two tautomer forms ca. 1 :
13
0.9) 3.05 (s, 3H, NCH3), 3.11 (s, 3H, NCH3), 11.51 (br s, 1H), 11.06 (s, 1H), 14.70 (br s, 2H) ppm; C
NMR (DMSO-d6) ppm: 26.8 (NCH3), 27.5 (NCH3), 135.9, 136.4, 150.18, 150.24, 154.1, 154.8, 158.3,
159.1 ppm.
1,3-Dibutylpyrimidine-2,4,5,6-tetraone-5-oxime
(23):25
A
mixture
of
finally
ground
6-amino-1,3-dibutyl-5-nitrosouracil 19 (3.2 g, 12 mmol) and 30 mL of diluted hydrochloric acid was
heated under stirring and vigorous reflux. After cooling to rt the mixture was diluted with 100 mL of
water and extracted with 150 mL of Et2O. The ether extract was filtered, dried over MgSO4, filtered again
1
and evaporated. The product was crystallized from petroleum ether (82 % yield): mp 74.5-75.2 °C; H
NMR (CDCl3) ppm: (a single tautomer) 0.94 (m, 6H, CH3), 1.36 (m, 4H, CH2), 1.36 (m, 4H, CH2), 1.60
13
(m, 4H, CH2), 3.93 (m, 4H, NCH2), 16.00 (br s, 1H), C NMR (CDCl3) ppm: 13.56, 13.62, 20.0, 29.7,
29.8, 41.6, 42.5, 135.5, 148.8, 156.0, 160.4.

HETEROCYCLES, Vol. 79, 2009
717
1-Prop-2-ynylpyrimidine-2,4,5,6-tetraone-5-oxime
(25):
A
suspension
of
6-amino-5-nitroso-3-prop-2-ynyluracil 21 (1.2 g, 6 mmol) in 9 mL of diluted hydrochloric acid (2 M) was
heated under reflux for 10 min. The hot solution was filtered in order to remove a small amount of
decomposed material. Subsequently the off-white solid was allowed to crystallize at 4 °C, filtered under
1
reduced pressure, washed with water and dried at 70 °C (39 % yield): mp > 173 °C (dec.); H NMR
(DMSO-d6): (mixture of two tautomers, ca. 1 : 0.9) 3.13 (t, J = 2.5 Hz, 1H), 3.14 (t, J = 2.5 Hz, 1H), 4.41
(d, J = 2.5 Hz, 2H), 4.47 (d, J = 2.5 Hz , 2H), 11.64 ( br s, 1H), 11.73 (s, 1H), 14.76 (br s, 2H) ppm; 13C
NMR (DMSO-d6): 29.6, 30.2, 73.62, 73.64, 78.86, 78.88, 135.64, 136.30, 149.3, 149.4, 153.2, 163.7,
158.1, 158.3 ppm; EIMS (m/z, %) 195 (M+ , 100).
5-Amino-1,3-dimethylpyrimidine-2,4,6-trione
(7):12
A
deep-purple
solution
of
1,3-dimethylpyrimidine-2,4,5,6-tetraone-5-oxime 22 (1 g, 5.4 mmol) in 20 mL 12.5% aq NH4OH was
prepared and heated at 60 °C. Subsequently sodium dithionite (ca. 2.5 g) was rapidly added under stirring
until the color turned yellowish. The solution was concentrated under reduced pressure to two-thirds of
the original volume. After cooling to rt the air-sensitive, colorless crystals were filtered off and washed
1
with water, EtOH and Et2O and directly used for following steps (56 % yield): mp 200 °C; H NMR
13
(DMSO-d6): 3.08 (s, 6H, NCH3), 8.12 (s br, 3H, NH2, OH) ppm; C NMR (DMSO-d6): 26.9 (NCH3),
83.3, 152.1, 158.6 ppm.
5-Amino-1,3-dibutylpyrimidine-2,4,6-trione
(26):
A
deep-purple
mixture
of
1,3-dibutylpyrimidine-2,4,5,6-tetraone-5-oxime 23 (1 g, 3.9 mmol) in 30 mL 12.5% aq NH4OH was
prepared and heated at 80 °C. Subsequently the solution was decolorized by the addition of sodium
dithionite (2.7 g) upon stirring. The mixture was heated at 60 °C for additional 10 min, filtered to remove
some unconverted starting material and concentrated under reduced pressure to two-thirds of the original
volume. After cooling to rt colorless needles were rapidly filtered off, washed with water and directly
used for following steps (yield: 1.0 g, max. 3.7 mmol, containing an undetermined percentage of water).
Due to its extreme air-sensitivity compound 26 was only characterized by derivatization with benzoyl
chloride yielding 4,6-dibutyl-2-phenyl-4H,6H-oxazolo[5,4-d]pyrimidine-5,7-dione (29).
4,6-Dimethyl-2-phenyl-4H,6H-oxazolo[5,4-d]pyrimidine-5,7-dione (28): The compound was prepared
as previously described:14 mp 234 °C (lit., mp 247 °C;15 240-242 °C26).
1H NMR (CDCl3): 3.42 (s, 3H, NCH3), 3.63 (s, 3H, NCH3) 7.46-7.48 (m, 3H, Harom.), 8.01-8.04 (m, 2H,
Harom.) ppm; 13C NMR (CDCl3): 28.8 (NCH3), 30.6 (NCH3), 112.6 (C3a), 125.5, 126.5, 129.0, 131.3
(Carom.), 150.2, 154.4, 156.5, 156.6 (C2, C4, C6, C7a) ppm.

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HETEROCYCLES, Vol. 79, 2009
4,6-Dibutyl-2-phenyl-4H,6H-oxazolo[5,4-d]pyrimidine-5,7-dione (29): A mixture of freshly prepared
5-amino-1,3-dibutylpyrimidine-2,4,6-trione 26 (1 g, 3.7 mmol) was refluxed with an excess of benzoyl
chloride (3 mL, 25.8 mmol) for 0.5 h, cooled to rt, treated with 5% NaOH solution (50 mL), refluxed
again for 10 min and finally stirred at rt until the viscous residue turned into a solid. The solid was
extracted twice with 50 mL CH2Cl2 each, dried over K2CO3, filtered over silica gel and concentrated
under reduced pressure leading to a highly pure product. Colorless needles were obtained by
1
recrystallization from CH2Cl2 : petroleum ether (1 : 6) (ca. 30 % yield): mp 91 °C, H NMR (CDCl3):
0.93 (t, J = 7.6 Hz, 3H, CH3), 0.99 (t, J = 7.6 Hz, 3H, CH3), 1.37 (m, 2H, CH3CH2), 1.42 (m, 2H,
CH3CH2), 1.63 (m, 2H, CH2CH2CH2), 1.80 (m, 2H, CH2CH2CH2), 4.02 (m, 2H, NCH2), 4.08 (m, 2H,
NCH2), 7.45-7.50 (m, 3H, Harom.), 8.00-8.05 (m, 2H, Harom.) ppm; 13C NMR (CDCl3): 13.6, 13.8, 19.9,
20.1, 29.9, 30.3, 42.0 (NCH2), 44.5 (NCH2), 112.7 (C3a), 125.7, 126.5, 129.0, 131.3 (Caromat), 149.7,
154.3, 156.4, 156.5 (C2, C4, C6, C7a) ppm; EIMS (m/z, %) 341 (M+ , 100).
Reaction of 5-amino-1,3-dimethylpyrimidine-2,4,6-trione (7) with hydrochloric acid: Typical
procedure: Freshly prepared 7 (1,1 g, ca. 6 mmol) was dissolved in a mixture of concentrated
hydrochloric acid (10 mL) and water (10 mL) and heated under reflux. After 3 h the reaction was stopped.
The colorless solution was cooled to rt, diluted with a concentrated aqueous solution of NaCl (50 mL) and
extracted four times, with 50 mL CH2Cl2 each. The organic extracts were dried over MgSO4, filtered and
evaporated. The colorless solid residue (300 mg) was investigated by NMR spectroscopy indicating the
formation of 35 (88 %) and 36 (12 %). Recrystallisation with CH2Cl2/Et2O (1 : 5) afforded pure 35 ( 220
mg, 32 %).
1
3-Methyloxazolidine-2,4-dione (35): mp 133 °C; H NMR (CDCl3): 3.08 (s, 3H, CH3), 4.68 (s, 2H,
13
CH2), ppm; C NMR (CDCl3): 25.9 (NCH3), 68.0 (CH2), 156,0 (C2), 170.4 (C4) ppm; EIMS (m/z, %)
155 (M+, 100).
Reaction of 5,6-diamino-1,3-dimethyl-1H-pyrimidine-2,4,dione (15) with hydrochloric acid: Typical
procedure: Freshly prepared 15 (0.5 g, ca. 6 mmol) was dissolved in a mixture of concentrated
hydrochloric acid (3 mL) and water (3 mL) and heated under reflux. After 1 h the yellow solution was
cooled to rt and extracted three times, with 75 mL CH2Cl2 each. The organic extracts were dried over
MgSO4, filtered and evaporated. The product (260 mg) was separated by column chromatography on
silica gel (eluent: CH2Cl2 /MeOH 7 : 1). The separated products 13, 16, 17, 42 and 45 were characterized
by their physico-chemical properties (TLC, mp, fluorescence) and NMR spectroscopy followed by
comparison with literature data as far as accessible. Since part of the individual compounds remained in

HETEROCYCLES, Vol. 79, 2009
719
the aqueous phase yields could not be precisely determined. Due to the extractive method which was
selected for separation only qualitative results could reliably be obtained.
1,3,7,9-Tetramethyl-(1H,3H,7H,9H)-pyrimido[5,4-g]pteridine-2,4,6,8-tetrone
(16):27
colorless
1
crystals: mp > 360 °C; H NMR (CDCl3) 3.52 (s, 6H, NCH3), 3.72 (s, 6H, NCH3) ppm, 13C NMR
(CDCl3): 29.1 (NCH3), 29.9 (NCH3), 123.6, 149.4, 150.3, 157.9 ppm.
1,3,6,8-Tetramethyl-(1H,3H,6H,8H)-pyrimido[4,5-g]pteridine-2,4,7,9-tetrone (17):11 blue fluorescent
yellow crystals: 1H NMR (CDCl3) 3.55 (s, 6H, NCH3), 3.80 (s, 6H, NCH3) ppm, 13C NMR (CDCl3): 29.4
(NCH3), 30.1 (NCH3), 129.0, 144.3, 150.0, 158.6 ppm.
ACKNOWLEDGMENTS
We gratefully acknowledge support for our studies by the Fonds der Chemischen Industrie and the
Bundesministerium für Bildung und Forschung. We thank Dr. Joachim C. Burbiel and Dr. Andreas
Brunschweiger for fruitful discussions.
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