Formation of aryl-bis (6-amino-1,3-dimethyluracil-5-yl) methanes by reaction of 6-amino-1,3-dimethyluracil with aromatic aldehydes

Article abstract of DOI:10.1002/jhet.5570450636

(Chemical Equation Presented) The synthesis of aryl-bis(6-amino-1,3- dimethyluracil-5-yl)-methanes 3a-m by condensation of 6-amino-1,3-dimethyluracil (1) with aromatic aldehydes 2a-m at room temperature is reported. The structures of the compounds were es

Full text of DOI:10.1002/jhet.5570450636

Nov-Dec 2008
1789
Formation of Aryl-bis (6-Amino-1,3-Dimethyluracil-5-yl) Methanes
by reaction of 6-Amino-1, 3-Dimethyluracil with Aromatic
Aldehydes
Ranju Bansal a*, R. Sunil Kumar a, Gulshan Kumar a , Sridhar Thota a ,
S. Thamotharan b, V. Parthasarathi c and Anthony Linden d
a University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India
b Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560 012,India
c School of Physics, Bharathidasan University, Tiruchirappalli-620024, India
d Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190,CH-8057 Zürich, Switzerland
*ranju29in@yahoo.co.in
Received November 26, 2007
O
AcOH
MeOH
H
R
O
O
C
O
H3C
O
N
H3C
O
CH3
C
7
+
4
2
3N
4'
N 3'
5
5'
R
N
NH2
H
-H2O
1
N
1'
N
6
2
2'
O
NH2 H2N 6'
CH3
CH3
CH3
The synthesis of aryl-bis(6-amino-1,3-dimethyluracil-5-yl)-methanes 3a-m by condensation of 6-amino-
1,3-dimethyluracil (1) with aromatic aldehydes 2a-m at room temperature is reported. The structures of the
compounds were established using various spectroscopic analyses and X-ray crystallography. The crystal
structures of two aryl-bis (6-amino-1,3-dimethyluracil-5-yl) methanes are presented.
J. Heterocyclic Chem., 45, 1789 (2008).
Scheme I
INTRODUCTION
O
The role of methylxanthines as phosphodiesterase
(PDE) inhibitors is well established and theophylline is
now routinely used as a phosphodiesterase inhibitor for
the treatment of asthma [1–5]. In order to investigate the
minimal structural requirements for inhibiting phospho-
diesterases by xanthines, a series of uracil derivatives
have been synthesized and studied by Garst et al. [6]. The
uracil ring of the xanthine nucleus plays a vital role in
phosphodiesterase inhibition and the imidazole portion is
insufficient to maintain inhibition of phosphodiesterase
[7]. The present study was also aimed at the synthesis of a
new series of 6-amino-1,3-dimethyluracil derivatives in
order to investigate their PDE inhibitory effects.
However, during the synthesis of these compounds some
interesting bis-products were obtained, which we report
herein.
H3C
O
O
C
N
2
+
N
NH2
R
H
CH3
2a-m
1
AcOH
MeOH
-H2O
R
H
O
O
H3C
CH3
O
C
7
4
3 N
4'
N3'
5
5'
1
1'
2'
6
2
6'
H2N
NH2
N
N
O
CH3
CH3
3a-m
R
R
10
11
12
9
h
i
a
8
N
13
RESULTS AND DISCUSSION
OMe
OMe
OH
OH
While synthesizing a series of 6-amino-1,3-dimethyl-
uracil derivatives, condensation of 6-amino-1,3-dimethyl-
uracil (1) [8] with various aromatic aldehydes such as
benzaldehyde, veratraldehyde, 3,4,5-trimethoxybenzal-
dehyde, p-anisaldehyde, piperonal, cuminaldehyde,
pyridine-4-carboxaldehyde, pyridine-2-carboxaldehyde,
vanillin and 3-hydroxybenzaldehyde (2a-j) in the
presence of glacial acetic acid and methanol at room
temperature led to the formation of the respective aryl-
bis(6-amino-1,3-dimethyluracil-5-yl)methanes 3a-j as
outlined in Scheme I.
OMe
OMe
OMe
OMe
b
c
j
OMe
N
OCH2CH2
OMe
OCH2CH2
OMe
OCH2CH2CH2
k
d
e
OMe
O
O
CH2Cl
l
CH3
CH3
f
N
N
m
N
g

1790
R. Bansal, R. S. Kumar, G. Kumar, S. Thota, S. Thamotharan,
V. Parthasarathi and A. Linden
Vol 45
For the preparation of 3k and 3l, vanillin was
substituents in the compounds 3a-m were also observed at
the appropriate places. In order to further confirm the
carbon skeleton, 13C NMR spectra of some of the bis-
products were also studied. The 13C NMR spectra showed
characteristic peaks near ꢀ 27.7 (C(7)), 29.4 (Me-N(3, 3'),
34.4 (Me-N(1,1'), 153.5 (C(2,2'), C=O), 162.9 (C(4,4'),
C=O) and for aromatic carbons between 125-126 ppm.
The proposed structures were also confirmed by X-ray
crystallographic studies for 3a and 3i. The formation of
the bis-methanes could be explained by the mechanism
illustrated in Scheme II. The electrophile generated by
condensed with 1-(2-chloroethyl)pyrrolidine hydro-
chloride and 1-bromo-3-chloropropane in ethyl methyl
ketone in the presence of anhydrous potassium carbonate
to get oily residues, which were used as such and treated
with 6-amino-1,3-dimethyluracil by using a similar
procedure. Further fusion of chloro derivative 3l with
imidazole at 110 °C for 2 h yielded the target imidazole
derivative 3m. Most of the bis-methanes were isolated as
crystalline materials in good yields by stirring the
reactants overnight at room temperature.
Scheme II Mechanism illustrating the formation of bis-methanes
O
O
OCH3
CH3O
O
C
H
+
H
H
CH3
CH3
R
C
N
N
+
C
CH3OH
-H2O
+
H
R
H
+
R
H
N
N
H2N
O
O
H2N
CH3
CH3
NH2
NH2
+
O
R
H
R
O
N
H
CH3
H3C
H3C
N
+
CH3
N
C
H
N
C
N
N
O
O
H
N
N
O
O
O
H2N
CH3
O
H2N
CH3
CH3
CH3
NH2
N
OCH3
H
NH2
O
N
O
N
R
C
H
R
CH3
H3C
CH3
C
+
H3C
N
N
N
H
O
N
O
N
O
O
H2N
O
H2N
O
CH3
CH3
CH3
CH3
However pyridyl substituted derivatives 3g and 3h
could be obtained within 2 h of stirring the corresponding
reactants but in lower yields. Detailed spectroscopic
studies of the obtained bis-products confirmed their
structures. Characteristic asymmetrical and symmetrical
stretching for free amino groups were observed at 3470
and 3350 cm-1, respectively, in the infrared spectra of all
the bis-products 3a-m. Proton NMR spectra of 3a-m
showed four singlets, each integrating for 3 protons of
four N-methyls, which indicated the presence of two
uracil nuclei. A singlet appeared at ꢀ 5.75 ppm for the H–
C(7) of bis-methanes through which the two nuclei are
connected to each other. Two exchangeable free amino
groups appeared as broad singlets ranging from ꢀ 6.50 -
7.25 ppm in the proton NMR spectra of all of the
products. Signals for various protons of the respective
acid catalysed reaction of aldehyde with methanol attacks
the electron rich center of 6-aminouracil, which is
stabilized by free amino and carbonyl group. Removal of
methanol followed by rearrangement leads to the
formation of another electron deficient carbonium ion,
which combines with one more nucleophilic uracil
nucleus to form bis-methanes.
6-Aminouracils are key intermediates in the synthesis
of a number of xanthine based drug molecules and also
act as starting compounds for the synthesis of new
condensed heterocycles exhibiting intriguing pharma-
cological activities [9-11], the formation of interesting
aryl-bis (6-amino-1,3-dimethyluracil-5-yl) methanes by
acid catalysed condensation of 6-amino-1,3-dimethyl-
uracil with aromatic aldehydes with stirring at room
temperature in methanol could be a key step for the

Nov-Dec 2008
Formation of Aryl-bis (6-Amino-1,3-Dimethyluracil-5-yl) Methanes
1791
formation of novel pharmacologically attractive
heterocyclic structures.
Compound 3i crystallizes as a methanol hemisolvate, in
which the methanol molecule is disordered over two
positions close to an inversion center. The bond lengths
and angles in 3a and 3i have normal values in each
structure; the orientations of the pyrimidinedione rings
relative to the phenyl rings are different. The dihedral
angles between the plane of the phenyl ring and those of
the two-pyrimidinedione rings are 76.6(1) and 66.2(1)° in
3a. The corresponding angles in 3i are 69.1(1) and
80.7(1)°. The dihedral angle between the planes of the
two-pyrimidine rings is 64.4(1)° in 3a and 54.2(1)° in 3i.
Crystallography. Views of the asymmetric units in the
structures of 3a and 3i, with atomic numbering schemes,
are shown in Figures 1a and 1b, respectively.
The structures of 3a and 3i are stabilized by series of
N–H…O hydrogen bonds (Table 1 & 2). In 3a, atoms
N(16) and N(26) act as donors for intramolecular
hydrogen bonds with carbonyl atoms O(22) and O(12),
respectively. Each interaction can be described by a
graph-set motif of S(8) [12]. In addition, atom N(16) [via
H(162)] is involved in an intermolecular N–H…O
hydrogen bond with carbonyl atom O(22) of
a
neighboring centro- symmetrically related molecule.
Taken together, the intra- and intermolecular hydrogen
bonds involving N(16)…O(22) interactions generate
dimers across an inversion center and create a ring motif
which can be described by a graph-set motif of R 24 (8)
(Figure 2).
1a
1b
Figure 1. ORTEP representation of the asymmetric unit in the structure
of compound 3a (a) compound 3i.0.5MeOH (b), showing the atom-
labeling scheme (Displacement ellipsoids are drawn at the 50%
probability level and H atoms are represented by circles of arbitrary
radii).
Figure 2. The hydrogen bonding in 3a, showing the formation of a
centrosymmetric dimmer and the R24 (8) ring motif (Atoms marked with
a hash (#) are at the symmetry positions (-x,1-y,1-z)).

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V. Parthasarathi and A. Linden
Vol 45
Table 1
Hydrogen-bond parameters (Å, °)
ꢀD–H…A
D–H…A
d(D–H)
d(H…A)
d(D…A)
Compound 3a
N16–H161…O22
0.92(2)
0.88(2)
0.95(2)
2.04(2)
2.06(2)
1.82(2)
2.951(2)
2.863(2)
2.749(2)
171(2)
151(2)
164(2)
N16–H162…O22i
N26–H261…O12
Compound 3i.0.5MeOH
O4–H4…O22ii
0.89(3)
0.86(3)
0.89(3)
0.85(3)
1.00(4)
0.98
1.91(3)
2.04(3)
2.40(3)
2.55(3)
1.81(4)
2.34
2.737(3)
2.883(3)
3.276(3)
3.338(3)
2.755(3)
3.154(3)
3.409(4)
154(3)
168(2)
167(3)
155(3)
156(3)
140
N16–H161…O22
N16–H162…O4iii
N26–H261…O12iv
N26–H261…O12
C25–H251…O12iv
C51–H512…O24v
0.98
2.56
145
Symmetry codes: (i) -x,-y+1,-z+1; (ii) -x,-y,-z+2; (iii) x+1/2,-y-1/2,z+1/2; (iv) -x+1/2,y+1/2,-z+3/2;
(v) -x,-y+1,-z+2
Table 2
Crystallographic Data of compounds 3a and 3i
3a
3i
Empirical formula
Mr
C19H22N6O4
398.4
C20H24N6O6, 0.5(CH3OH)
460.5
Crystal color, habit
Crystal dimensions [mm]
Temperature [K]
Crystal system
Space group
colourless, prism
0.25 x 0.25 x 0.18
160(2)
colourless, prism
0.25 x 0.20 x 0.18
160(2)
Monoclinic
Monoclinic
P2 /n
P2 /n
1
1
Z
4
4
Reflections for cell determination
4565
3879
2ꢁ Range for cell determination [°]
4–55
4–50
Unit cell parameters
a [Å]
b [Å]
c [Å]
ꢂ [°]
12.2918(3)
8.1130(2)
19.3728(4)
105.5443(15)
1861.26(8)
1.422
14.3616(5)
9.4789(3)
15.1782(5)
94.463(2)
2059.98(12)
1.485
V [Å3]
Dx [g cm-3]
μ [mm-1]
0.103
0.113
Scan type
2ꢂ(max) [°]
ꢀ and ꢁ
55
ꢀ and ꢁ
50
Total reflections measured
47241
4263
3248
4263
282
26753
3642
2724
3642
334
Symmetry-independent reflections
Reflections with (I > 2ꢃ(I))
Reflections used in refinement
Parameters refined
Final
R(F) (I > 2ꢃ(I) reflections
0.0492
0.1348
1.066
0.000
0.26; -0.27
0.0548
0.1603
1.026
0.000
0.27; -0.27
wR(F2) (all data)
Goodness of fit
Final ꢃmax/ꢃ
ꢄꢄ (max; min) [e Å3]
Weights: For 3a w = [ꢃ2(F o2 ) +(0.0687P)2+0.4769P)]-1; for 3i w = [ꢃ2 (F 2o )+(0.0856P)2+1.0009P)]-1; where P = (F o2 +2 F 2o )/3
Surprisingly, the second H-atom on atom N(26) is not
involved in any hydrogen bonds, thus precluding the
presence of an anticipated ladder structure. In case of 3i,
one of the amino groups [N(26)] forms bifurcated
hydrogen bonds. One of these is intramolecular and
involves the carbonyl O-atom, O(12), of one of the
pyrimidine rings. The second interaction is also with
O(12), but in an adjacent molecule. The intramolecular
interaction generates an S(8) motif, while the
intermolecular interaction links the molecules into which
run parallel to the crystallographic b axis (Fig. 3) and can
be described by a graph-set motif of C(8). One H atom of
the other amino group (N16) forms an intramolecular
hydrogen bond with the carbonyl O atom, O(22), to give

Nov-Dec 2008
Formation of Aryl-bis (6-Amino-1,3-Dimethyluracil-5-yl) Methanes
1793
FT-IR spectrophotometer (Huenenberg, Switzerland). KBr
pellets; ꢀmax in cm-1. 1H- and 13C-NMR spectra: Bruker AC-300F
(300 MHz) instrument (Bruker AG, Fällanden, Switzerland);
Me4Si as the internal standard; chemical shifts ꢀ in ppm, J in Hz.
Elemental analyses (C, H, N): Perkin-Elmer-2400 apparatus.
General Procedure. Compounds 3a-l were prepared by
treating equimolar quantities (2.58 mmol) of 6-amino-1,3-
dimethyluracil and the requisite aromatic aldehyde in methanol
(16.0 mL) and glacial acetic acid ( 4.0 mL ) with constant
stirring. Although pyridyl substituted derivatives 3g and 3h
could be isolated within 2 h of stirring the corresponding
reactants, formation of rest of the bis-products required
overnight stirring. The completion of the reaction was monitored
by TLC. The reaction was worked up by addition of water and
further basification with aqueous sodium hydroxide. The
precipitate obtained was collected by filtration, washed
thoroughly with water, dried and recrystallized using appropriate
solvents. For the synthesis of 3h and 3l, aromatic aldehydes,
an S(8) motif. The other H atom forms an intermolecular
hydrogen bond with the hydroxyl O atom, O(4), of a
neighboring molecule and thereby links the molecules
into chains which run parallel to the crystallographic c
axis and can be described by a graph-set motif of C(10).
Atom C(25) is involved in a weak intermolecular C–
H…O interaction with carbonyl atom O(12). This weak
interaction links the molecules into a chain, which runs
parallel to the axis and has a graph-set motif of C(9).
3-methoxy-4-(2-pyrrolidin-1yl-ethoxy)
benzaldehyde
and
3-methoxy-4-(3-chloropropoxy) benzaldehyde were prepared by
adding 1-(2-chloroethyl) pyrrolidine hydrochloride (1.0 g) and
1-bromo-3-chloropropane (1.0 mL, 9.76 mmol) to
a
magnetically stirred slurry of vanillin (1.0 g, 6.57 mmol) and
anhydrous potassium carbonate (2.0 g) in ethyl methyl ketone
(50.0 mL) and further stirring and refluxing the reaction mixture
for 6 h. The completion of the reaction was monitored by TLC.
The cooled reaction mixture was filtered and the solvent was
removed under reduced pressure to obtain the oily residue of the
corresponding aldehyde, which was used as such for further
reaction. Compound 3m was obtained by thermally fusing
chloro-derivative 3l with imidazole.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(phenyl)-methyl]-1,3-dimethyl-1,2,
3,4-tetrahydro-2,4-pyrimidinedione (3a). Recrystallization
(chloroform and methanol); Yield 0.38 g (74.5%). mp 260-262
°C. ir (KBr): 3457.0, 3386.2, 3001.3, 1694.6, 1586.2, 1502.5,
1
1375.7, 1247.6, 1051.6, 835.5. H nmr (300 MHz, CDCl3): 3.27
(s, 6H, 2 N-CH3), 3.44 (s, 6H, 2 N-CH3), 5.75 (s, 1H, 7-H), 7.11
(m, 4H, ArH), 7.15-7.22 (m, 3H, ArH and NH2), 7.24 (br, 2H,
NH2). Anal. Calcd. for C19H22N6O4 (398.42) : C, 57.2; H, 5.57;
N, 21.0. Found: C, 56.9; H, 5.4; N, 20.9.
Figure 3. The crystal structure of 3i. 0.5 MeOH projected onto the ac
plane, showing the hydrogen bonding (for clarity, H atoms not involved
in the hydrogen bonding have been omitted).
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(3,4-di-methoxyphenyl)methyl]-
1,3-dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione (3b).
Recrystallization (ether and methanol); Yield 0.37 g (62.71%).
mp 220-222 °C. ir (KBr): 3450.2, 3373.7, 3050.0, 1680.0,
Atom C(51) has also weak intermolecular C–H…O
interaction with atom O(24) of a neighboring centro-
symmetrically-related molecule. This interaction produces
a R 22 (24) loop.
1
1601.0, 1502.0, 1249.4, 762.1. H nmr (300 MHz, CDCl3): 3.35
(s, 6H, 2 N-CH3), 3.76 (6H, 2 N-CH3), 3.76 (s, 3H, OCH3), 3.83
(s, 3H, OCH3), 5.75 (s, 1H, 7-H), 6.50 (br, 2H, NH2), 6.67 (br,
2H, NH2), 6.67 (d, 1H, Jo=10.1 Hz, ArH), 6.75 (d, 2H, Jo =8.1
Hz, ArH); Anal. Calcd. for C21H26N6O6 (458.47): C, 55.0; H,
5.72; N, 18.3. Found: C, 54.8; H, 5.5; N, 17.9.
EXPERIMENTAL
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(3,4,5-trimethoxy-phenyl)methyl]-
1,3-dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione (3c).
Recrystallization (ether and acetone); Yield 0.28 g (45.16%). mp
268-270 °C. ir (KBr): 3354.5, 3100.0, 1685.2, 1594.4, 1498.0,
1234.8. 1H nmr (300 MHz, CDCl3): 3.37 (s, 6H, 2 N-CH3), 3.47
(s, 6H, 2 N-CH3), 3.76 (s, 6H, OCH3), 3.82(s, 3H, OCH3), 5.75
(s, 1H, 7-H), 6.36 (s, 2H, ArH), 6.48 (br, 2H, NH2), 6.71 (br, 2H,
NH2). Anal. Calcd. for C22H28N6O7 (488.49): C, 54.09; H, 5.78;
N, 17.21. Found: C, 54.19; H, 5.39; N, 17.33.
Materials obtained from the commercial suppliers were used
without further purification. Anhydrous Na2SO4 was used as a
drying agent. The purity of the compounds was established by
TLC and elemental analyses. TLC: plates (E. Merck, Darmstadt,
Germany) were prepared according to Stahl (activated at 110°C
for 30 min.); AcOEt as a solvent; visualization by I2 vapors.
M.p.: MP1-Veego instrument (Veego Instruments, Mumbai,
India); uncorrected. IR spectra: Perkin-Elmer spectrum RX 1,

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R. Bansal, R. S. Kumar, G. Kumar, S. Thota, S. Thamotharan,
V. Parthasarathi and A. Linden
Vol 45
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
7.11 (t, 1H, Jo=6.1 Hz, pyrid H), 7.19 (d, 1H, Jo =6.2 Hz, pyrid
H), 7.60 (t, 1H, Jo =1.6 Hz, pyrid H), 8.53 (d, 1H, Jo =3.8 Hz,
pyrid H). Anal. Calcd. for C18H21N7O4 (399.41): C, 54.13; H,
5.30; N, 24.55; Found: C, 53.93; H, 5.21; N, 24.25.
tetrahydro-5'-pyrimidinyl(4-methoxyphenyl)methyl]-1,3-
dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione (3d).
Recrystallization (chloroform and methanol); Yield 0.37g
(67.27%), mp 256-258 °C. ir (KBr): 3352.0, 3050.0, 1686.5,
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(4-hydroxy-3-methoxyphenyl)-
methyl]-1,3-dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione
(3i). Recrystallization (chloroform and methanol); Yield 0.42 g
(73.68%), mp 240-242°C. ir (KBr): 3432.9, 3050.0, 1694.2,
1
1592.6, 1502.3, 1242.2, 788.7. H nmr (300 MHz, CDCl3): 3.33
(s, 6H, 2 N-CH3), 3.46 (s, 6H, 2 N-CH3), 3.77 (s, 3H, OCH3)),
5.74 (s, 1H, 7-H), 6.49 (br, 2H, NH2), 6.70 (br, 2H, NH2), 6.79
(d, 2H, Jo=8.6 Hz, ArH), 7.03 (d, 2H, Jo=8.6 Hz, ArH), 13C nmr
(CDCl3, 300 MHz): 27.77 (7-C), 29.47 (2 N-CH3), 34.42 (2 N-
CH3), 54.53 (O-CH3), 85.87 (5,5'-C), 112.68 (2ArC), 127.17
(2ArC), 130.57 (ArC), 150.52 (6,6'-C), 153.47 (2,2'-C, C=O ),
156.69 (ArC) and 162.9 (4,4'-C, C=O). Anal. Calcd. for
C20H24N6O5 (428.44): C, 56.1; H, 5.6; N, 19.62. Found: C, 55.8;
H, 5.3; N, 19.28.
1
1599.8, 1504.6, 1377.7, 1259.9, 1031.3, 936.7 785.6. H nmr
(300 MHz, CDCl3): 3.18 (s, 6H, 2 N-CH3), 3.40 (s, 6H, 2 N-
CH3), 3.72 (s, 3H, O-CH3), 5.62 (s,1H, 7-H), 6.54 (d, 1H, Jo=8.2
Hz, ArH), 6.61 (s, 1H, ArH), 6.66 (d, 1H, Jo=8.1Hz, ArH), 7.41
(br, 4H, 2 NH2); Anal. Calcd. for C20H24N6O6 (444.44): C, 54.05;
H, 5.44; N, 18.91. Found: C, 53.85; H, 5.55; N, 18.63.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(benzo-[d][1,3]dioxol-5-yl)methyl]-
1,3-dimethyl-1,2,3,-tetra-hydro-2,4-pyrimidinedione (3e).
Recrystallization (chloroform and methanol); Yield 0.35 g
(61.4%), mp 238-240°C. ir (KBr): 3357.4, 3050.0, 1686.6,
1596.8, 1239.2, 931.6, 1H nmr (300 MHz, CDCl3): 3.27 (s, 6H, 2
N-CH3), 3.45 (s, 6H, 2 N-CH3), 5.70 (s, 1H, 7-H), 5.91 (s, 2H,
O-CH2-O), 6.46 (br, 2H, NH2), 6.58 (m, 2H, ArH), 6.59 (m, 3H,
ArH and NH2). Anal. Calcd. for C20H22N6O6 (442.43): C, 58.5;
H, 5.4; N, 20.48. Found: C, 58.16; H, 5.3; N, 20.19.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(3-hydroxyphenyl)methyl]-1,3-
dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione (3j).
Recrystallization (acetone and petroleum ether); Yield 0.30 g
(56.6%), mp 262-264°C. ir (KBr): 3395.5, 3100.0, 1690.0,
1
1611.8, 1500.0, 1210.5, 810.5, 791.5, 695.9. H nmr (CDCl3):
3.28 (s, 6H, (s, 6H, 2 N-CH3), 3.45 (s, 6H, 2 N-CH3), 5.71 (s,1H,
7-H), 6.62 (m, 3H, ArH), 7.03 (t, 1H, ArH), 7.25 (br, 4H, 2
NH2); Anal. Calcd. for C19H22N6O5 (414.42): C, 55.06; H, 5.35;
N, 20.28. Found: C, 54.86; H, 4.91; N, 19.92.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(4-isopropylphenyl)methyl]-1,3-
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl{4-[2-(1-pyrrolidinyl)ethoxy]-3-
methoxyphenyl}methyl)-1,3-dimethyl-1,2,3,4-tetrahydro-2,4-
pyrimidinedione (3k). Recrystallization (acetone); Yield 0.20 g
(28.98%), M.p. 235-238°C. ir (KBr): 3423.7, 2952.9, 1688.0,
1614.3, 1498.1, 1261.5, 1214.6, 757.9. 1H nmr (CDCl3+DMSO-
d6): 1.95 (s, 4H, 2 CH2), 2.97 (s, 4H, N(CH2)2), 3.16 (s, 2H,
NCH2), 3.38 (s, 6H, 2 N-CH3), 3.48 (s, 6H, 2 N-CH3), 3.73 (s,
3H, O-CH3), 4.27 (s, 2H, O-CH2), 5.75 (s, 1H, 7-H), 6.5 (br,
2H, NH2), 6.67 (m, 4H, 2 ArH and NH2), 6.81 (d, 1H, Jo =8.92
Hz, ArH). Calcd. for C26H35N7O6 (541.60): C, 57.65; H, 6.51; N,
18.11; Found: C, 57.38; H, 6.36; N, 17.90.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl[4-(3-chloropropoxy)-3-methoxy-
phenyl]methyl]-1,3-dimethyl-1,2,3,4-tetrahydro-2,4-pyrimi-
dinedione (3l). Recrystallization (ethylacetate) ; Yield 0.54 g
(80.59%), mp 155-157°C . ir (KBr): 3392.5, 3111.5, 2980.0,
1680.4, 1499.2, 1252.7, 787.8. 1H nmr (CDCl3+DMSO-d6): 2.33
(p, 2H, -OCH2CH2CH2Cl), 3.33 (s, 6H, 2 N-CH3), 3.46 (s, 6H, 2
N-CH3), 3.61 (t, 2H, -CH2Cl), 3.73 (s, 3H, O-CH3), 4.11 (t, 2H,
O-CH2), 5.75 (s, 1H, 7-H), 6.48 (br, 2H, NH2), 6.66 (m, 4H, 2
ArH and NH2), 6.79 (d, 1H, Jo=8.9 Hz, ArH). Calcd. for
C23H29N6O6Cl (520.96): C, 53.02; H, 5.61; N, 16.13; Found: C,
52.85; H, 5.32; N, 16.24.
dimethyl-1,2,3,4-tetrahydro-2,4-pyrimidinedione
Recrystallization (chloroform and methanol); Yield 0.32 g
(3f).
(56.3%), mp 255-257°C. ir (KBr): 3377.6, 3115.0, 2957.3,
1
1691.4, 1593.5, 1498.2, 1360.0, 1055.4, 928.9. H nmr (300
MHz, CDCl3): 1.21 (d, 6H, -CH(CH3)2), 2.58 (q, 1H,
-CH(CH3)2), 3.27 (s, 3H, N-CH3), 3.38-3.45 (br, 9H, 3 N-CH3),
5.73 (s, 1H, 7-H), 6.63 (br, 2H, NH2), 6.85 (br, 2H, NH2), 7.03
(d, 2H, Jo=8.2 Hz, ArH), 7.12 (d, 2H, Jo=8.3 Hz, ArH). 13C nmr
(CDCl3, 300 MHz,): 23.86 (2 CH3), 29.26 (4 N-CH3), 33.35 (7-
C), 35.24 (CH), 86.60 (5 or 5'-C), 88.16 (5 or 5'-C), 125.97 (2
ArC), 126.54 (2 ArC), 135.59 (ArC), 145.90 (ArC), 150.65
(6,6'-C), 153.47 (2 or 2'-C, C=O ), 154.75 (2 or 2'-C, C=O ),
162.66 (4 or 4'-C, C=O) and 164.50 (4 or 4'-C, C=O). 13C nmr
DEPT 90: 33.35 (7-C), 35.24 (CH), 125.97 (2 ArC), 126.54 (2
ArC). 13C nmr DEPT 135: 23.86 (2 CH3), 29.26 (4 N-CH3),
33.35 (7-C), 35.24 (CH), 125.97 (2 ArC), 126.54 (2 ArC). EI-
MS: 440.4 [M+.]. Anal. Calcd. for C22H28N6O4 (440.49): C,
59.98; H, 6.41; N, 19.08. Found: C, 59.66; H, 6.05; N, 18.83.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(4-pyridyl)methyl]-1,3-dimethyl-1,2,
3,4-tetrahydro-2,4-pyrimidinedione (3g). Recrystallization (ether
and acetone); Yield 0.09 g (17.6%), mp 260-262°C. ir (KBr):
3390.9, 3151.1, 1690.1, 1595.2, 1500.0, 1213.5, 1054.7, 852.1,
765.5. 1H nmr (300 MHz, CDCl3): 3.18-3.39 (m, 12H, 4 N-
CH3), 5.73 (s, 1H, 7-H); 7.16 (d, 2H, Jo =5.1 Hz, pyrid H); 7.25
(br, 2H, NH2); 7.43 (br, 2H, NH2); 8.44 (d, 2H, Jo =4.2 Hz, pyrid
H); Anal. Calcd. for C18H21N7O4 (399.41): C, 54.12; H, 5.30;
24.55. Found: C, 54.69; H, 4.93; N, 24.25.
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl{4-[3-(1H-1-imidazolyl)propoxy]-3-
methoxyphenyl}methyl]-1,3-dimethyl-1,2,3,4-tetrahydro-2,4-
pyrimi-dinedione (3m). The chloro derivative 3l (0.5 g, 0.96
mmol) and imidazole (0.1 g, 1.47 mmol) were fused together at
110° for 2 h. The completion of reaction was monitored by TLC.
To the fused mixture, ice cold water was added and the mixture
was kept in the freezer for complete precipitation. The
precipitate obtained was collected by filtration, washed
thoroughly with water and dried. Recrystallization (ether); Yield
0.2 g (37.70%), mp 180-182 °C. ir (KBr): 3422.0, 3350.0,
6-Amino-5-[6'-amino-1',3'-dimethyl-2',4'-dioxo-1',2',3',4'-
tetrahydro-5'-pyrimidinyl(2-pyridyl)methyl]-1,3-dimethyl-1,2,
3,4-tetrahydro-2,4-pyrimidinedione (3h). Recrystallization (ether
and acetone); Yield 0.12g (23.52%), mp 262-264°C. ir (KBr):
3550.0, 3365.1, 3159.7, 1680.9, 1594.9, 1500.9, 1058.9, 843.6,
1
1
768.5. H-NMR (300 MHz, CDCl3): 3.33 (s, 6H, 2 N-CH3),
1686.8, 1600.2, 1501.3, 1248.7, 1141.2, 787.3, 753.0. H nmr
3.42 (s, 6H, 2 N-CH3), 5.87 (s, 1H, CH), 6.52 (br, 4H, 2 NH2),
(CDCl3+DMSO-d6): 2.22 (p, 2H, OCH2CH2CH2N), 3.32 (s, 6H,

Nov-Dec 2008
Formation of Aryl-bis (6-Amino-1,3-Dimethyluracil-5-yl) Methanes
1795
2 N-CH3), 3.47 (s, 6H, 2 N-CH3), 3.76 (s, 3H, -O-CH3), 3.92 (t,
2H, N-CH2), 4.20 (t, 2H, O-CH2), 5.75 (s, 1H, 7-H), 6.56 (br,
2H, NH2), 6.72 (m, 5H, 3 ArH and NH2), 6.93 (s, 1H, imid-H),
7.04 (1H, s, imid-H), 7.49 (1H, s, imid-H). Calcd. for
C26H32N8O6 (552.59): C, 56.51; H, 5.84; N, 20.28; Found: C,
56.26; H, 5.45; N, 20.07.
Data Collection, Structure Solution and Refinement. X-ray
intensity data were collected for compounds 3a and 3i at 160 K
on a Nonius Kappa CCD diffractometer [13] using graphite-
monochromated MoKꢀ radiation (ꢀ = 0.71073 Å) and an Oxford
Cryosystems Cryostream 700 cooler. The data reduction was
performed with HKL Denzo and Scalepack [14]. The intensities
were corrected for Lorentz and polarization effects, but not for
absorption.
REFERENCES
[1] Gupta, R.; Kumar, G.; Sunil Kumar, R. Methods Find. Exp.
Clin. Pharmacol. 2005, 27, 101.
[2] Barnette, M. S. Prog. Drug. Res. 1999, 53, 195.
[3] Wells, J. N.; Garst, J. E.; Kramer, G. L. J. Med. Chem. 1981,
24, 954.
[4] Nicholson, C. D.; Jackman, S. A.; Wilke, R. Br. J.
Pharmacol. 1989, 97, 889.
[5] Buckle, D. R.; Arch, J. R. S.; Connolly, B. J.; Fenwick, A. E.;
Foster, K. A.; Murray, K. J.; Readshaw, S. A.; Smallridge, M.; Smith, D.
G. J. Med.Chem.1994, 37, 476.
[6] Garst, J. E.; Kramer, G. L; Wu Y. J.; Wells J. N. J. Med.
Chem. 1976,19, 499.
Both structures were solved by direct methods using SIR92
[15]. The non-hydrogen atoms were refined anisotropically
using SHELXL-97 [16]. In 3a and 3i, the positions of the amino
H atoms were determined from a difference Fourier map and
refined freely along with their isotropic displacement
parameters. The methyl H atoms were constrained to an ideal
geometry (C–H=0.98 Å), with Uiso(H)=1.5Ueq(C), but were
allowed to rotate freely about the C–C bonds. All remaining H
atoms were placed in geometrically calculated positions and
refined using a riding model where each H-atom was assigned a
fixed isotropic displacement parameter with a value equal to
1.2Ueq of its parent C-atom. The asymmetric unit of 3i includes a
MeOH molecule, which is disordered across two positions close
to a center of inversion. The site occupation factors of the
MeOH atoms were fixed at 0.5. The position of the hydroxy H
atom of the MeOH molecule could not be located from a
difference map. The reflection 002 in both 3a and 3i was
partially obscured by the beam stop and was omitted during the
final refinement. Figures were prepared using ORTEP-3 [17]
and PLATON [18].
[7] Buchmann, R.; Heinstein, P. F.; Wells, J. N. J. Med. Chem.
1974, 17, 1168.
[8] Papesch, V.; Schroeder, E. F. J. Org. Chem. 1951, 16, 1879.
[9] Zhi, C.; Long, Z. Y.; Gamine, J.; Xu, W. C.; Brown, N. C.;
Barnes M.; Butler, M.; LaMarr, W.; Wright, G. E. J. Med. Chem. 2003,
46, 2731.
[10] Ali, A.; Taylor, G. E.; Ellsworth, K.; Harris, G.; Painter, R.;
Silver, L. L.; Young, K. J. Med. Chem. 2003, 46, 1824.
[11] Muller, C. E.; Shi, D.; Manning, M.; Daly, J. W. J. Med.
Chem. 1993, 36, 3341.
[12] Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang N.-L., Angew
Chem. Int. Ed. Engl. 1995, 34, 1555.
[13] Nonius. COLLECT. Kappa CCD Collect Software, Nonius
BV, Delft, 2000.
[14] Otwinowski, Z.; Minor, W. In Methods in Enzymology, C. W.
Carter Jr., R. M. Sweet Ed, Academic Press, New York, 1999,Vol 276,
P-307.
[15] Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435.
[16] G. M. Sheldrick, SHELXL97 (1997) (University of
Göttingen, Germany).
Acknowedgements. The authors thank University Grants
Commission, India for financial assistance. Special thanks are
due to Dr. Vasundhara Singh for her valuable suggestions.
[17] Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
[18] Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.