Novel derivatives of 1,3-dimethyl-5-methylenebarbituric acid

Article abstract of DOI:10.2174/157017809790442934

The ability of the pyridinium adduct of 1,3-dimethyl-5-methylenebarbituric acid (2) to undergo nucleophilic substitution reaction has been examined. Various types of nucleophiles, including cyanide, barbiturate, sulfide anions and 1,2-bis(diphenylphosphin

Full text of DOI:10.2174/157017809790442934

Letters in Organic Chemistry, 2009, 6, 669-672
669
Novel Derivatives of 1,3-Dimethyl-5-methylenebarbituric Acid
Kamal Sweidan*,a, Qutaiba Abu-Salemb, Ahmed Al-Sheikhc and Ghassan Abu Sheikhaa
aFaculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
bInstitut für Anorganische Chemie der Universität Tübingen, Auf der Morgenstelle 18, D-72076, Germany
cFaculty of Pharmacy, the University of Petra, Amman, Jordan
Received March 14, 2009: Revised November 05, 2009: Accepted November 05, 2009
Abstract: The ability of the pyridinium adduct of 1,3-dimethyl-5-methylenebarbituric acid (2) to undergo nucleophilic
substitution reaction has been examined. Various types of nucleophiles, including cyanide, barbiturate, sulfide anions and
1,2-bis(diphenylphosphino)ethane substitute the pyridinium fragment in 2 leading to synthesis of new organic derivatives.
Keywords: 1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1,3-dimethylbarbituric acid), zwitterionic pyridinium adduct,
nucleophilic substitution reaction.
INTRODUCTION
barbituric acid by applying the nucleophilic substitution
reaction at the pyridinium fragment in 2. We examined the
reactions of 2 with different types of nucleophiles, including
cyanide and sulfide anions, sodium barbiturate and 1,2-
bis(diphenylphosphino)ethane. The synthesis of 5,5'-
methylene bis-derivatives of uracils by acidic hydrolysis of
bis-[4-methylamino-2,6-dioxo-1,3-dimethyltetrahydropyrimi-
dinyl]methane was reported in the literature [6]. In addition,
the reduction of 5-arylidene barbiturates by thiols in the
presence of triethylamine followed by oxidation process led
to the formation of 5-benzyl-5-hydroxy-1,3-dimethyl-
2,4,6(1H,3H,5H)-pyrimidinetrion [7].
Derivatives of 1,3-dimethylbarbituric acid (1) play an
important role in the pharmaceutical chemistry [1,2]. The
condensation of 1 with aqueous formaldehyde solution in
pyridine afforded the zwitterionic pyridinium adduct 2,
which was first prepared and characterized by our group [3].
Compound 2 may be considered as an important precursor in
organic synthesis since the exocyclic methylene carbon atom
exhibits electrophilic properties, which enhance the
substitution of a pyridinium fragment with various types of
nucleophiles. For example, novel zwitterionic compounds
were prepared by reactions of 2 with triphenylphosphine and
2,3-dihydro-1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene
to produce 1,3-dimethyl-2,4,6-trioxo-5-triphenylphospho-
niomethyl-1,3-perhydrodiazin-5-yl-phosphonium and 1,3-
dimethyl-2,4,6-trioxo-5-(1,3-diisopropyl-4,5-dimethylimida-
zoliomethyl)-1,3-perhydrodiazin-5-yl-imidazoliumylides, res-
pectively, in good yields [3].
Zoorob et al. [8] reported a procedure for monoacylation
at C5 of 1,3-dimethylbarbituric acid by the reaction of
sodium derivatives of barbiturate (act as nucleophiles) with
acyl chlorides. This procedure is limited only for sensitive
acyl chlorides compounds (act as electrophiles). In addition,
the conversion of carbonyl functionality at C5 into a
methylene group requires a further reduction step. In
contrast, the advantage of the proposed procedure is that a
wide range of nucleophiles can react at the electrophilic
center of the exo-methylene group under mild conditions in a
single step.
Introduction of sulfur atom in the exomethylene fragment
of uracil (pyrimidine derivative) was achieved by the
reaction of 1-(5-uraciylmethylene)pyridinium chloride or
iodide with (4-nitrophenyl)methanethiol in the light to
process the resulted formation of the thymine via exocyclic
methylene intermediate [4]. The concurring displacement of
sulfur with cyano group took place by free radical alkylation
of 1,3-dimethyluracil with benzoyl peroxide in acetonitrile
[5].
Reaction of 2 with sodium cyanide and sodium 1,3-
dimethylbarbiturate produced 3 and 4, respectively, (Scheme
1). In spite of the localization of negative charge at the
cyanide carbon atom or its delocalization at the barbiturate
ring, the substitution of the pyridinium occurred readily. The
reaction of barbituric acid derivatives and bis(dialkyl-
amino)malononitrile afforded a mixture of salts in which the
cyano group is attached directly at the exo-methylene carbon
atom of the 5-methylenebarbituric acid [9].
Continuing our previous study, this work investigates the
ability of pyridinium fragment substitution in 2 using
different nucleophiles.
RESULTS AND DISCUSSION
1
The H-NMR spectrum of 4 reveals that the barbiturate
We extended our previous work [3] concerning the
synthesis of novel derivatives of 1,3-dimethyl-5-methylene
ring is connected to the methylene carbon atom of 2 through
carbon atom (C5) rather than its oxygen atoms at C4 or C6.
Changing the solvent from water to chloroform led to the
same result. The neutral barbituric ring in 4 adopted a keto
form which was confirmed by DEPT-NMR analysis. It was
reported that two symmetrical 1,3-dimethylbarbituric rings
*Address correspondence to this author at the Faculty of Pharmacy, Al-
Zaytoonah University, P.O. Box 130 Amman, Jordan; Fax: + 962-6-
4291432, E-mail: kamal_sweidan@hotmail.com
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

670 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Sweidan et al.
were connected through methylene fragment by synthesis of
6-amino-1,3-dimethyluracil followed by a reaction with
formaldehyde under neutral or basic conditions. Acidic
hydrolysis of the resulted compounds gave the desired
product [10]. On the other hand, unsymmetrical barbituric
rings may be prepared by the reaction of N-methyl-o-
nitroaniline hydrochloride, diethoxymethane and 1,3-
dimethylbarbituric acid [11].
triphenylphosphine [3]. On the other hand, reaction of 2 and
1,2-bis(diphenylphosphino)ethane in a stoichiometric ratio
led to a mixture of unidentified products.
Bis[1,3-dimethylbarbituryl(5)]sulfide, in which a sulfur
atom is connected directly with two barbiturate rings was
prepared and characterized by using X-ray diffraction
analysis [12]. Similarly, the reaction of 2 with sulfide anion
produced 6 in which a sulfur atom is attached with two 5-
methylenebarbituric acid rings. Apparently, 6 consists of two
additional methylenebarbituric fragments attached at C5
atoms of the di-anion salt which formed initially. To verify
this result, the protonation of 6 with aqueous hydrochloride
1,2-Bis(diphenylphosphino)ethane reacts readily with
two equivalents of 2 forming 5 which was the expected
product according to the formation of the stable zwitterionic
phosphonium compound from the reaction of 2 with
O
N
O
N
O
1
N
37 % aq. H2CO
, r.t
O
O
Na
N
N
Na
O
O
Na
O
O
O
O
O
N
N
O
N
N
N
N
N
NaCN
H2O, r.t
O
O
O
H2O, r.t
O
CN
N
N
H
3
2
O
4
Ph2PCH2CH2PPh2
O
CH2Cl2, r.t
O
H2O, r.t
Na
Na2S
O
N
N
N
N
S
O
Ph
Ph
O
O
O
N
P
P
N
O
N
N
Ph
Ph O
O
O
N
O
5
O
O
N
O
O
N
Na
O
N
O
6
r.t
aq. HCl
O
N
O
O
N
O
N
H
S
O
N
O
O
N
H
O
N
O
O
O
N
O
N
7
Scheme 1.

Novel Derivatives of 1,3-Dimethyl-5-methylenebarbituric Acid
Letters in Organic Chemistry, 2009, Vol. 6, No. 8
671
solution produces 7 which was characterized by NMR, MS
and elemental analysis. The DEPT-NMR analysis of 7
showed that protonation occurred at each C5 atom of the
barbiturate rings rather than at oxygen atoms (Scheme 1)
leading to a keto-form tautomer which was reported formerly
[13]. Other nucleophiles including iodide anion, phenol and
thioanisol failed to substitute the pyridinium fragment in 2
even under reflux.
(C6H6N2O3)], 323 (9) [M+]. Anal. Calcd. for C13H15N4O6Na:
C, 45.1; H, 4.4; N, 16.2. Found: C, 44.7; H, 4.8; N, 16.0%.
1,3-dimethyl-5-{[{2-[[(1-methyl-6-oxido-2,4-dioxo-1,2,3,4-
tetrahydro-5-pyrimidinyl) methyl](diphenyl)phosphonio]
ethyl}(diphenyl)phosphonio]methyl}-2,6-dioxo-1,2,3,6-tetr-
ahydro-4-pyrimidinolate (5)
3.0 mmol (0.74 g) of 2 was dissolved in 15.0 mL of
CH2Cl2, and then 1.5 mmol (0.59 g) of 1,2-
bis(diphenylphosphino)ethane was added in one portion to
the solution which was stirred at r.t overnight. The
precipitate was filtered off, washed with CH2Cl2 and dried
under vacuum.
EXPERIMENTAL
Materials and Instruments
All experiments have been performed in purified solvents
under argon. 1,3-Dimethylbarbituric acid (B), formaldehyde
solution (37%), sodium cyanide, sodium hydroxide, 1,2-
bis(diphenylphosphino)ethane, and sodium sulfide were
purchased from Aldrich and used without further
purification. Nuclear magnetic resonance (NMR) spectra
were acquired by a Bruker DRX 400 NMR spectrometer
with tetramethylsilane (1H, 13C) and 85% H3PO4 (31P) as
external standards. The FAB-mass spectra were obtained on
a Finnigan TQS 70 by 70 eV in 3-nitrobenzylalcohol (NBA)-
matrix at 30°C. Elemental analyses were determined by
Carlo Erba Company, model 1106. Melting points were
obtained by the device from Büchi, model 510.
Yield: 80%; m.p. 253-256 °C (decomp.); 1H NMR
(400.13 MHz, CDCl3): 3.01 (m, 4H, P-(CH2)2-P), 3.09 (s,
12H, 1,3B-Me); 3.99 (d, 4H, B-CH2-P, J= 7.5 Hz); 7.58-7.77
(m, 20 H, Ph) ppm. 13C NMR (100.62 MHz, CDCl3): 15.9
(d, B-CH2-P, Jpc = 47.9 Hz); 20.7 (d, CH2-P, Jpc = 47.7 Hz);
27.6 (1,3B-Me); 72.7 (C5 ); 119.5 (d, Carom, Jpc = 79.8 Hz),
B
130.0 (Cm), 132.9 (Co), 134.6 (Cp); 153.1 (C2 ); 163.8 (C4,6
)
B
B
ppm. 31P NMR (161.98 MHz, CDCl3): 23.9 ppm. MS (FAB):
m/z (%)
=
399 (100) [Ph4P2C2H4], 567 (49) [M+-
(C7H8N2O3)], 734 (3) [M+]. Anal. Calcd. for C40H40N4O6P2:
C, 65.4; H, 5.5; N, 7.6. Found: C, 65.0; H, 5.9; N, 7.8%.
Disodium 5-[(5-{[({5-[(1,3-dimethyl-6-oxido-2,4-dioxo-1,2,
3,4-tetrahydro-5-pyrimidinyl) methyl]-1,3-dimethyl-2,4,6-
trioxohexahydro-5-pyrimidinyl}methyl) sulfanyl]methyl}-
1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl)methyl]-
1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-4-pyrimidinolate
(6)
Sodium 5-(cyanomethyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-
tetrahydro-4-pyrimidinolate (3)
2.5 mmol (0.62 g) of 2 was dissolved in 20.0 mL of H2O,
and then 2.3 mmol (0.11 g) of NaCN was added in one
portion to the aqueous solution which was stirred at r.t
overnight. The solvent was removed under vacuum; the
residue was then washed with CHCl3, filtered and dried
under vacuum.
To a suspended solution of 3.0 mmol (0.74 g) of 2 in 25.0
mL of THF, 12.0 mmol (0.94 g) of sodium sulfide was added
in one portion to the solution which was stirred at r.t for 72
h. The solvent was removed under vacuum; the residue was
washed with CH2Cl2, filtered and dried under vacuum.
Yield: 85%; m.p. 307-309 °C (decomp.); 1H NMR
(400.13 MHz, D2O): 3.14 (s, 6H, 1,3B-Me); 3.35 (s, 2H,
CH2) ppm. 13C NMR (100.62 MHz, D2O): 12.7 (CH2); 27.8
Yield: 70%; m.p. 223-226 °C (decomp.); 1H NMR
(400.13 MHz, D2O): 2.85 (s, 4H, B-CH2-S); 3.04 (s, 12H,
1,3B-Me); 3.08 (s, 12H, 1,3B(-ve)-Me); 3.29 (s, 4H, B-CH2-B)
ppm. 13C NMR (100.62 MHz, D2O): 27.8 (1,3B(-ve)-Me); 28.8
(1,3B-Me); 36.1 (CH2); 37.9 (CH2); 60.3 (C5 ); 83.1 (C5
(1,3B-Me); 80.6 (C5 ); 121.0 (CN); 153.9 (C2 ); 164.1 (C4,6
)
B
B
B
ppm. MS (FAB): m/z (%) = 168 (21) [M+ - CN], 194 (100)
[M+]. Anal. Calcd. for C8H8N3O3Na: C, 44.3; H, 3.7; N,
19.4. Found: C, 43.9; H, 4.1; N, 19.1%.
B
B(-
B(-
ve)); 153.2 (C2 ); 154.4 (C2B(-ve)); 164.2 (C4,6B); 171.6 (C4,6
B
ve)) ppm. MS (FAB): m/z (%) = 391 (63) [(M++Na)-
C7H8N2O3], 599 (100) [(M++Na)-C7H8N2O3], 727 (13)
[M++Na]. Anal. Calcd. for C28H32N8O12SNa2: C, 44.8; H,
4.3; N, 14.9. Found: C, 44.4; H, 4.1; N, 15.1%.
Sodium 5-[(1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimi-
dinyl)methyl]-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-4-
pyrimidinolate (4)
3.2 mmol (0.79 g) of 2 was dissolved in 15.0 mL of H2O,
and then 2.8 mmol (0.50 g) of sodium 1,3-dimethyl-2,6-
dioxo-1,2,3,6-tetrahydro-4-pyrimidinolate was added in one
portion to the aqueous solution which was stirred at r.t
overnight. The solvent was removed under vacuum; the
residue was washed with CHCl3, filtered and dried under
vacuum.
5-[(1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimidinyl)met-
hyl]-5-{[({5-[(1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrimi-
dinyl)methyl]-1,3-dimethyl-2,4,6-trioxohexahydro-5-pyrim-
idinyl} methyl)sulfanyl]methyl}-1,3-dimethyl-2,4,6(1H,3H,
5H)-pyrimidinetrione (7)
To a clear aqueous solution of 1.8 mmol (1.35 g) of 6,
3.6 mmol (0.36 ml of 10 M HCl ) was added in one portion
followed by stirring at r.t for 30 min. The resulting
precipitate was filtered off, washed with distilled H2O and
dried under vacuum.
Yield: 80%; m.p. 237-240 °C (decomp.); 1H NMR
(400.13 MHz, D2O): 2.90 (t, 1H, C5 , J= 6.5 Hz); 2.98 (s,
B
6H, 1,3B-Me); 3.09 (s, 6H, 1,3B(-ve)-Me); 3.26 (d, 2H, CH2, J=
6.5 Hz) ppm. 13C NMR (100.62 MHz, D2O): 27.8 (1,3B(-ve)
-
Me); 28.8 (1,3B-Me); 40.0 (CH2); 55.2 (C5 ); 82.7 (C5B(-ve));
B
Yield: 83%; m.p. 129-132 °C; 1H NMR (400.13 MHz,
CDCl3): 2.80 (s, 4H, B-CH2-S); 3.23 (s, 12H, 1,3B-Me); 3.27
(s, 12H, 1,3B-Me); 3.59 (d, 4H, B-CH2-B, J= 6.7 Hz); 4.10 (t,
154.0 (C2 ); 164.4 (C4,6B); 173.2 (C4,6B(-ve)) ppm. MS (FAB):
B
m/z (%) = 153 (100) [NBA matrix], 169 (9) [M+-
2H, CB H, J= 6.7 Hz) ppm. 13C NMR (100.62 MHz, CDCl3):
5

672 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Sweidan et al.
28.5 (1,3B-Me); 28.8 (1,3B-Me); 35.2 (B-CH2-S); 42.9 (B-
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CH2-B); 44.5 (C5 H); 55.6 (C5 ); 150.8 (C2 ); 170.4 (C4,6
)
B
B
B
B
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In summary, 1,3-dimethylbarbituric acid pyridinium
adduct is considered an excellent organic precursor for
synthesis of new organic derivatives of 1,3-
dimethylbarbituric acid; based on the readily substitution of
its pyridinium fragment different types of nucleophiles may
applied under mild experimental conditions.
[5]
[6]
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ACKNOWLEDGEMENTS
Financial support by the Deutsche Forschungsgeme-
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of Jordan is gratefully acknowledged.
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