New results on the reactivity of 5,6-diamino-4-hydroxy-2-mercaptopyrimidine

Article abstract of DOI:10.1002/jhet.5570410606

The reaction of 5,6-diamino-4-hydroxy-2-mercaptopyrimidine with mono- and α,ω-dihalocompounds has been reinvestigated. Alkyl derivatives of 5-amino group, not previously described, have been obtained as reaction products. A comparison with the reactivity of 6-amino-4-hydroxy-2- mercaptopyrimidine has been also performed.

Full text of DOI:10.1002/jhet.5570410606

Nov-Dec 2004
883
New Results on the Reactivity of 5,6-Diamino-4-hydroxy-
2-mercaptopyrimidine
Barbara Cosimelli [a]*, Manuela Iadanza [a], Raffaella Spisani [b]
and Ettore Novellino [a]
[a] Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli "Federico II",
Via D. Montesano, 49, I-80131 Napoli, Italy
[b] Dipartimento di Chimica Organica "A. Mangini", Università di Bologna,
Via S. Donato 15, I-40127 Bologna, Italy
Received February 19, 2004
The reaction of 5,6-diamino-4-hydroxy-2-mercaptopyrimidine with mono- and α,ω-dihalocompounds
has been reinvestigated. Alkyl derivatives of 5-amino group, not previously described, have been obtained as
reaction products. A comparison with the reactivity of 6-amino-4-hydroxy-2-mercaptopyrimidine has been
also performed.
J. Heterocyclic Chem., 41, 883 (2004).
Introduction.
ring by using NaNO and HCl (Scheme 1). We attempted to
2
generalize the procedure employing α,ω-dihalogenoalka-
nes with increased chain length to obtain a thiazepine ring
as well as monoalogenoalkanes with the aim to obtain
alkylated at sulfur and at ring nitrogen structures.
In the framework of our studies on polycyclic molecular
structures suitable as adenosine receptor antagonists [1,2]
we were interested to synthesize and to test 6,7-dihy-
dro[1,3]thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidin-
9(1H)-one (6) and 7,8-dihydro-6H-[1,2,3]triazolo-
[4',5':4,5]pyrimido[1,2-b][1,3]thiazin-10(1H)-one (7). A
described procedure [3] gave the desired compounds start-
ing from 5,6-diamino-4-hydroxy-2-mercaptopyrimidine (1)
and α,ω-dihalogenoalkanes to give the pyrimidothiazoline
or pyrimidothiazino moiety and then obtaining the triazole
Results and Discussion.
First, we confirmed that 1 reacts with the dihaloderiva-
tive 2 (or 3) to give 6 (or 7) by the way of 4 (or 5).
Successively, we allowed 1 to react with 1,4-dibromobu-
tane (8) to obtain the seven membered thiazepine ring.
Marumoto and coworkers asserted [4] that the cyclization
at S and N-3 of 2-mercaptopyrimidine moiety "decreases
as the chain length of α,ω-dihalogenoalkanes increases"
and on their substrates the 1,4-dibromobutane is a border-
line reagent because they obtained the desired thiazepine
derivative together with 1,4-bis(2-thioinosinyl)butane.
Scheme 1
Scheme 2
i) NaOH 2M, n-propanol. ii) NaNO , HCl
2

884
B. Cosimelli, M. Iadanza, R. Spisani and E. Novellino
at different distances from the pyrimidinone ring.
Vol. 41
So we attempted, in our standard conditions (NaOH 2
M, 2-propanol), the reaction between 1 and 8, but we
obtained (Scheme 2) a complex mixture, in which we only
recovered the unexpected derivatives 10 and 11 (6% and
2%, respectively), instead of the desired compound 9. The
nature of compounds 10 and 11 was determined on the
We ascertained the structure of compound 14 on the
basis of spectroscopic data and on the basis of a chemical
proof. So, following the previously described procedure
(NaOH 1 M) and starting from compound 14 we obtained
13 in 51% yield (see Experimental) by reaction with ben-
zyl bromide (12). The alkylation site of compound 15 was
also confirmed by reactivity. The reaction of 15 with 1,4-
dibromobutane (8) gave compound 17 (Scheme 4) in 47%
yield, thus confirming that the first alkylation has been on
S atom.
1
13
basis of their H, C, and mass spectra.
Another procedure, described by Pecoraro and cowork-
ers, [5] reported the synthesis of some thio- and 3-nitro-
gen-dialkyl derivatives of 1 by reaction with mono-
halogenoalkanes in NaOH 1 M.
Following these reaction conditions, we obtained a com-
plex mixture in which we recovered once again the com-
pounds 10 (6%) and 11 (2%) in very small amount.
The starting material 1, is a polyfunctional compound
and is very difficult to handle because it is insoluble in
commonly used solvents for workup of reactions; its NMR
Scheme 3
This result although not unexpected, on the basis of the
previous reaction, has been very intriguing for us, espe-
cially because the possibility of a different mechanism by
using monohalogenoalkanes instead of 1,4-dibromobutane
is not obvious. So, we repeated the reaction of 1 with ben-
zyl bromide (12) as described by the Authors [5]. In our
hands, the crude, after flash-chromatography, furnished
compounds 13, 14 and 15 in ratio 2.5:2:1, respectively
(Scheme 3) in overall yield 30% and not the compound 16
in yield 60-80% as previously reported [5].
Scheme 4
1
The H NMR spectra (see Experimental) are consistent
with the proposed structures. It can be noticed that in com-
pound 13 the two CH groups of the dibenzylamino sub-
2
stituent appear as isochronic AB systems. This finding is
reasonable on the basis of both scale models and the
results of MM calculations (program PCModel, Serena
Software) showing that the dimethyleneamino moiety is
perpendicular to the pyrimidinone ring and that, within
each methylene group, the two protons are steadily located

Nov-Dec 2004
New Results on the Reactivity of 5,6-Diamino-4-hydroxy-2-mercaptopyrimidine
885
(6.3 mL) was then added. 1,4-Dibromobutane (7.6 mmol) was
then slowly added into the reaction mixture at room temperature,
stirring continuing at the same temperature for 2 h and then at 60-
70 °C for a further 5 h. The reaction mixture was extracted with
spectrum is not fully satisfactory because the molecule
possess only exchangeable protons and, finally, the reac-
tivity is probably strongly influenced by pH.
In the sodium hydroxide solution the reactive atoms are
CHCl (3x20 mL); the combined organic layers were dried over
3
S>5-NH >>N-3 as summarized in Schemes 2 and 3. This
2
anhydrous Na SO and evaporated in vacuo. The residue was
2
4
is a new result, because previously the S and N-3 have
been reported as the reactive atoms.
purified by flash-chromatography (eluant: CHCl /MeOH=97:3);
3
the faster running band gave pure 11 (6%; mp: 176-178 °C), the
slower one gave compound 10, which was crystallized from
water (2%; mp: 272-273 °C).
To confirm the high reactivity of the 5-NH group we
2
repeated the reaction starting from 6-amino-4-hydroxy-2-
mercaptopyrimidine (18) and 1,4-dibromobutane (8) in
NaOH 1 M. The reaction product was the bis(2-thio-6-
aminouracyl)butane 19 (57%) without traces of a thi-
azepine derivative (Scheme 5). Finally, for sake of
research, we repeated the reaction between 1 and 12 in
NaOH 2M/2-propanol solvent obtaining compounds 13
and 14 in 5:1 ratio and overall yield 30%. The monoben-
zylderivative 15 was present only in TLC traces.
6-Amino-2-[(4-{[4-amino-6-oxo-5-(1-pyrrolidinyl)-1,6-dihydro-
2-pyrimidinyl]thio}butyl)thio]-5-(1-pyrrolidinyl)-4(3H)-
pyrimidinone (10).
Compound 10 has the following spectroscopic properties: ir
–1
1
(KBr): 3454, 3284, 3188, 3151, 2962, 1652, 1600, 783 cm ; H
nmr (dimethyl sulfoxide-d ) δ 11.40 (1H, bs exch., NH), 6.13
6
(2H, bs exch., NH ), 3.06 (2H, m, SCH ), 2.92 (4H, m,
2
2
13
2xNCH ), 1.76 (4H, m, 2xCH ), 1.68 (2H, m, CH ); C nmr
2
2
2
(dimethyl sulfoxide-d ) δ 161.2 (C), 160.0 (C), 156.9 (C), 104.5
6
(C), 49.2 (2xCH N), 30.0 (CH S), 28.1 (CH ), 25.1 (2xCH );
2
2
2
2
Scheme 5
+
ESI-MS (MeOH): 501 (10+Na ).
Anal. Calcd for C N O S : C, 50.19; H, 6.32; N, 23.41.
H
20 30
8 2 2
Found: C, 50.20; H, 6.33; N, 23.38.
2-Amino-3-(1-pyrrolidinyl)-6,7,8,9-tetrahydro-4H-pyrimido-
[2,1-b][1,3]thiazepin-4-one (11).
Compound 11 has the following spectroscopic properties: ir
-1
1
(KBr): 3417, 3275, 3144, 2952, 1642, 1594, 775 cm ; H nmr
(dimethyl sulfoxide-d ) δ 6.23 (2H, bs exch., NH ), 4.19 (2H, m,
6
2
NCH ), 3.04 (2H, m, SCH ), 2.95 (4H, m, 2xNCH ), 1.92 (2H,
2
2
2
13
m, CH ), 1.80 (4H, m, 2xCH ), 1.79 (2H, m, CH ); C nmr
2
2
2
(dimethyl sulfoxide-d ) δ 159.4 (C), 159.0 (C), 158.0 (C), 106.0
6
(C), 48.9 (2xCH N), 43.7 (CH N), 31.5 (CH S), 27.6 (CH ),
2
2
2
2
+
26.2 (CH ), 25.1 (2xCH ); ESI-MS (MeOH): 289 (11+Na ).
2
2
Anal. Calcd for C
H N OS: C, 54.11; H, 6.81; N, 21.03.
12 18 4
Found: C, 54.13; H, 6.81; N, 21.03.
Reaction of 5,6-Diamino-4-hydroxy-2-mercaptopyrimidine with
Benzyl Bromide.
Benzyl bromide (62 mmol) was added dropwise into a solu-
tion of 5,6-diamino-4-hydroxy-2-mercaptopyrimidine (5 g, 31
mmol) in NaOH 1 M (62 mL). The reaction mixture was kept,
under stirring, for 7 h at 50-55 °C and then left overnight at
room temperature. The precipitate, collected by filtration and
dried on KOH was purified by flash chromatography (eluant:
EXPERIMENTAL
Melting points were determined using a Büchi apparatus and
are uncorrected. Ir spectra were obtained by a Perkin-Elmer FT-
IR Spectrometer Spectrum 2000. NMR spectra were recorded on
a Varian Mercury 400 Instrument in the Fourier transform mode
CHCl /MeOH=97:3) to give, in order of elution, the following
3
three pure compounds: 13 (14%; mp: 189-190 °C); 14 (11%;
mp: 172-175 °C); 15 (5%; mp: 148-151 °C).
1
13
at 21 ± 0.5 °C. H (400 MHz) and C NMR (100 MHz) chemi-
cal shifts (δ) are in ppm relative to TMS as secondary reference
standard; coupling constants are in Hz. ESI-MS spectra were
obtained on a micromass ZMD Waters instrument (3.2kV and
30V). Silica gel (Merck F254) and silica gel 60 (Merck 230-400
mesh) were used for analytical tlc and flash chromatography,
respectively. Compounds 6 and 7 were obtained according to
published procedures [3].
6-Amino-2-(benzylthio)-5-(dibenzylamino)-4(3H)-pyrimidinone
(13).
Compound 13 has the following spectroscopic properties: ir
(KBr): 3497, 3382, 3254, 3187, 3028, 2929, 1626, 1580, 786
-1
1
cm ; H nmr (dimethyl sulfoxide-d ) δ 11.67 (1H, bs exch.,
6
NH), 7.38-7.19 (15H, m, H-Ar), 6.16 (2H, bs exch., NH ), 4.23
2
13
(2H, s, CH S), 4.03 (4H, 2 AB systems, 2xCH N); C nmr
2
2
Reaction of 5,6-Diamino-4-hydroxy-2-mercaptopyrimidine with
1,4-Dibromobutane.
(dimethyl sulfoxide-d ) δ 160.8 (C), 160.7 (C), 157.0 (C), 139.5
6
(2xC), 137.3 (C), 130.0 (2xCH), 128.7 (4xCH), 128.3 (2xCH),
127.9 (4xCH), 127.1 (CH), 126.7 (2xCH), 104.7 (C), 55.3
5,6-Diamino-4-hydroxy-2-mercaptopyrimidine (1 g, 6.3
mmol) was dissolved in NaOH 2 M (6.3 mL) and propan-2-ol
+
(2xCH N), 33.4 (CH S); ESI-MS (MeOH): 451 (13+Na ).
2
2

886
B. Cosimelli, M. Iadanza, R. Spisani and E. Novellino
Vol. 41
Anal. Calcd for C
Found: C, 70.09; H, 5.65; N, 13.05.
H
N OS: C, 70.07; H, 5.64; N, 13.07.
137.9 (C), 129.2 (2xCH), 128.4 (2xCH), 127.1 (CH), 104.6 (C),
49.2 (2xCH N); 33.4 (CH S), 25.1 (2xCH ); ESI-MS (MeOH):
325.0 (17+Na ).
25 24
4
2
2
2
+
5,6-Diamino-3-benzyl-2-(benzylthio)-4(3H)-pyrimidinone (14).
Anal. Calcd for C
H N OS: C, 59.58; H, 6.00; N, 18.53.
15 18 4
Compound 14 has the following spectroscopic properties: ir
Found: C, 59.61; H, 6.00; N, 18.51.
(KBr): 3440, 3366, 3326, 3172, 3025, 2862, 1608, 1577, 781
Reaction of 6-Amino-4-hydroxy-2-mercaptopyrimidine with 1,4-
Dibromobutane.
-1
1
cm ; H nmr (dimethyl sulfoxide-d ) δ 11.75 (1H, bs exch.,
6
NH), 7.44-7.17 (10H, m, H-Ar), 6.12 (2H, bs exch., NH ), 4.30
2
13
(2H, s, CH S), 3.96 (2H, s, CH N), 3.60 (1H, bs exch., NH);
C
1,4-Dibromobutane (7.44 mmol) was added dropwise into a
solution of 6-amino-4-hydroxy-2-mercaptopyrimidine monohy-
drate 18 (1 g, 6.2 mmol) in NaOH 1 M (12.4 mL). The reaction
mixture was kept, under stirring, for 3 h at 50-55 °C. After cool-
ing, the resultant precipitate was collected by filtration. The solu-
tion was cooled to 0 °C and acidified to pH=3 with AcOH; the
solid was then collected by filtration. The combined precipitates
2
2
nmr (dimethyl sulfoxide-d ) δ 160.2 (C), 155.4 (C), 153.2 (C),
140.9 (C), 137.8 (C), 129.0 (2xCH), 128.3 (2xCH), 127.9
(4xCH), 127.1 (CH), 126.5 (CH), 105.6 (C), 49.8 (CH N), 33.4
6
2
+
(CH S); ESI-MS (MeOH): 361 (14+Na ).
2
Anal. Calcd for C
Found: C, 63.83; H, 5.35; N, 16.52.
H N OS: C, 63.88; H, 5.36; N, 16.55.
18 18 4
were purified by flash chromatography (CHCl /MeOH=95:5) to
yield compound 19 (57%; mp: 176-178 °C).
3
5,6-Diamino-2-(benzylthio)-4(3H)-pyrimidinone (15).
Compound 15 has the following spectroscopic properties: ir
-1
1
6-Amino-2-({4-[4-amino-6-oxo-1,6-dihydro-2-pyrimidinyl]-
thio}butyl)thio)-4(3H)-pyrimidinone (19)
(KBr): 3462, 3351, 3292, 3027, 2920, 1636, 1535, 751 cm ; H
nmr (dimethyl sulfoxide-d ) δ 11.80 (1H, bs exch., NH), 7.43-
6
7.20 (5H, m, H-Ar), 5.81 (2H, bs exch., NH ), 4.29 (2H, s,
2
Compound 19 has the following spectroscopic properties: ir
13
CH S), 3.58 (2H, bs exch., NH ); C nmr (dimethyl sulfoxide-
2
2
(KBr): 3468, 3410, 3326, 3202, 3018, 2922, 1617, 1576, 803
d ) δ 157.2 (C), 148.7 (C), 148.0 (C), 138.1 (C), 129.0 (2xCH),
-1
1
6
cm ; H nmr (dimethyl sulfoxide-d ) δ 11.40 (1H, bs exch.,
6
128.3 (2xCH), 127.0 (CH), 106.4 (C), 33.5 (CH S); ESI-MS
2
NH), 6.41 (2H, bs exch., NH ), 4.90 (1H, s, H-5), 3.10 (2H, m,
2
+
(MeOH): 271 (15+Na ).
13
CH S), 1.72 (2H, m, CH ); C nmr (dimethyl sulfoxide-d ) δ
2
2
6
Anal. Calcd for C H N OS: C, 53.21; H, 4.87; N, 22.56.
11 12
4
164.2 (C), 163.5 (C), 162.1 (C), 81.3 (C), 28.8 (CH S), 28.1
2
Found: C, 53.18; H, 4.89; N, 22.54.
+
(CH ); ESI-MS (MeOH): 363 (19+Na ).
2
Anal. Calcd for C
H N O S : C, 42.34; H, 4.74; N, 24.69.
Reaction of 14 with Benzyl Bromide.
12 16 6 2 2
Found: C, 42.31; H, 4.75; N, 24.67.
Operating as above, but starting from compound 14 (1 g, 3
mmol) and benzyl bromide (3 mmol) we obtained the derivative
13 (51%; mp: 189-190 °C).
Acknowledgment.
The authors thank one of the referee for her\his suggestions.
Reaction of 15 with 1,4-Dibromobutane.
1,4-Dibromobutane (4 mmol) was added dropwise into a solu-
tion of 15 (1 g, 4 mmol) in NaOH 1 M (8 mL). The reaction mix-
ture was kept, under stirring, for 2 h and then at 60-70 °C for a
further 5 h. The reaction mixture was then kept, under stirring,
for 7 h at 50-55 °C and finally left overnight at room temperature.
The precipitate, collected by filtration and dried on KOH, was
REFERENCES AND NOTES
*
Corresponding Author: Tel.: +39-081678614; fax: +39-
081678630; e-mail: barbara.cosimelli@unina.it
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Martini J. Med. Chem., 44, 316 (2001).
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purified by flash-chromatography (eluant: CHCl /MeOH=98:2)
3
to yield compound 17 (47%; mp: 184-186 °C).
6-Amino-2-(benzylthio)-5-(1-pyrrolidinyl)-4(3H)-pyrimidinone
(17).
Compound 17 has the following spectroscopic properties: ir
(KBr): 3440, 3272, 3183, 3125, 2962, 2912, 1605, 1557, 783
-1
1
cm ; H nmr (dimethyl sulfoxide-d ) δ 11.65 (1H, bs exch.,
6
NH), 7.46-7.26 (5H, m, H-Ar); 6.29 (2H, bs exch., NH ), 4.34
2
13
(2H, s, SCH ), 2.97 (4H, m, 2xNCH ), 1.81 (4H, m, 2xCH );
C
[5] P. Pecorari, M. Melegari, M. Rinaldi, M. P. Costi, and A.
Provvisionato Boll. Chim. Farm., 127, 71 (1988).
2
2
2
nmr (dimethyl sulfoxide-d ) δ 161.2 (C), 160.2 (C), 156.7 (C),
6