Reactions with 2-thiothymine; selective cyclization of S-substituted 2-thiothymine

Article abstract of DOI:10.1080/10426500307818

2-Thiothymine (I) undergoes S-alkylation when treated with some halo compounds such as methyl and ethyl iodides. The S-alkyl derivatives II are treated with hydrazine hydrate to produce the hydrazine derivative III, which condensed with p-chlorobenzaldehyde to give p-chlorobenzaldehydepyrimidinehydrazone derivative IV. Compound II_a reacts with phosphorus oxychloride to give 4-chloro derivative V. The chlorine atom in V undergoes nucleophilic substitution with p-chloroaniline and anthranilic acid to produce drivatives VI_a,b. Dehydrative cyclization of VI_b yields the pyrimido[6,1-b]quinazolin-10-one derivative VII. Treatment of V with ammonia solution gives the diamino derivative VI_d. Reaction of V with sodium azide produces the tetrazolo[1,5-c]pyrimidine derivative VIII. Compound I undergoes S-alkylation with α-haloketones followed by cyclization to produce the thiazolo[3,2-a]pyrimidine derivatives X_a-c. Reaction of I with bromomalononitrile produces thiazolo[3,2-a]pyrimidine-2-carbonitrile derivative XII. Treatment of XII with formic acid, formamide and ammonium thiocyanate produces thiazolo[3,2-a:4,5-d]dipyrimidine derivatives XIII_a-c. Finally, reacting XII with malononitrile yields ppyrido[2′,3′:4,5]thiazolo[3,2-a]pyrimidine-3-carbonitrile derivative XIV.

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Reactions with 2-Thiothymine; Selective Cyclization of
S-Substituted 2-Thiothymine
Mohamed M. Youssef a & Ayman M. S. Youssef a
a Cairo University, Giza, Egypt
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:67–81
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DOI: 10.1080/10426500390170174
REACTIONS WITH 2-THIOTHYMINE; SELECTIVE
CYCLIZATION OF S-SUBSTITUTED 2-THIOTHYMINE
Mohamed M. Youssef and Ayman M. S. Youssef
Cairo University, Giza, Egypt
(Received March 2, 2002; accepted June 18, 2002)
2-Thiothymine (I) undergoes S-alkylation when treated with some
halo compounds such as methyl and ethyl iodides. The S-alkyl
derivatives II are treated with hydrazine hydrate to produce the hy-
drazine derivative III, which condensed with p-chlorobenzaldehyde
to give p-chlorobenzaldehydepyrimidinehydrazone derivative IV. Com-
pound IIa reacts with phosphorus oxychloride to give 4-chloro deriva-
tive V. The chlorine atom in V undergoes nucleophilic substitution
with p-chloroaniline and anthranilic acid to produce drivatives
VIa,b. Dehydrative cyclization of VIb yields the pyrimido[6,1-
b]quinazolin-10-one derivative VII. Treatment of V with ammo-
nia solution gives the diamino derivative VId. Reaction of V with
sodium azide produces the tetrazolo[1,5-c]pyrimidine derivative VIII.
Compound I undergoes S-alkylation with -haloketones followed
by cyclization to produce the thiazolo[3,2-a]pyrimidine derivatives
X
a–c. Reaction of I with bromomalononitrile produces thiazolo[3,2-
a]pyrimidine-2-carbonitrile derivative XII. Treatment of XII with
formic acid, formamide and ammonium thiocyanate produces
thiazolo[3,2-a:4,5-d]dipyrimidine derivatives XIIIa–c
. Finally, re-
acting XII with malononitrile yields ppyrido[20,30:4,5]thiazolo[3,2-
a]pyrimidine-3-carbonitrile derivative XIV.
Keywords: 2-Thiothymine; active chloro derivative; nucleophilic
substitution; pyridothiazolopyrimidine; pyrimidoquinazoline; tetra-
zolopyrimidine; thiazolodipyrimidine; thiazolopyrimidine
In spite of the fact that much literature is published on 2-thiouracil, very
few communications are published regarding 2-thiothymine. Only one
of these publications discussed chemical reactions of 2-thiothymine.1
All the others reported its uses in the formation of nucleosides2–6 and
as anti-HIV agents.7,8
Address correspondence to M. M. Youssef, Department of Chemistry, Faculty of
Science, Cairo University, Giza, Egypt. E-mail: mmmyousef@yahoo.com
67

68
M. M. Youssef and A. M. S. Youssef
Because of its potential biological importance and the lack of work
published dealing with its chemistry, we would like here to report some
reactions of 2-thiothymine as well as its uses as a precursor for the syn-
thesis of some biologically important bi- and tricyclic fused heterocycles
such as thiazolopyrimidine and thiazolodipyrimidine derivatives.
2-Thiothymine(I) was synthesized after a method published in 19109
by formylation of ethyl propionate with ethyl formate in presence of
sodium metal. The produced ethyl 2-formylpropionate underwent cyclo-
condensation with thiourea to give I.
Compound I undergoes S-alkylation when it is treated with some
halo compounds. Thus, treatment of I with methyl or ethyl iodide
yielded the corresponding S-alkyl derivatives IIa,b respectively. That
alkylation took place at the sulphur atom could be proved by reacting
each of IIa,b with hydrazine hydrate in boiling dioxane to produce, the
same sulphur free compound, 2-hydrazino derivative III.
1
Analytical, IR, and H-NMR spectral data are in agreement with
the proposed structure II. The hydrazino derivative III displayed IR
1
absorption bands at 3321, 3205, 3151 cm (NH2 and NH) and 1685
(CO). Its 1H-NMR spectrum (DMSO-d6) showed signals at 1.77 ppm (s,
3H, CH3), 4.48 (s, 2H, NH2, D2O exchangeable), 7.39 (s, 1H, pyrimidine

Reactions with 2-Thiothymine
69
H6), 8.26 (s, 1H, NH, D2O exchangeable), and 8.65 (bs, 1H, NH, D2O
exchangeable).
The hydrazino derivative III condensed with p-chlorobenzaldehyde
to give the p-chlorobenzaldehydepyrimidylhydrazone derivative IV.
Analytical and spectral data of IV are in agreement with the proposed
structure (Experimental).
The S-methyl derivative IIa, containing only one active hydrogen
atom, reacts smoothly with phosphorus oxychloride, in dry dioxane,
to give 4-chloro-5-methyl-2-methylthiopyrimidine (V), which gave com-
patible elemental analyses. Its IR spectrum revealed the disappearance
of both NH and CO groups.
The chlorine atom at position 4 in compound V shows high activity
towards some nucleophiles.
Thus, reaction of V with some weak nucleophiles such as aro-
matic amines, namely, p-chloroaniline and anthranilic acid yielded the
4-(p-chlorophenylamino)- and the 4-(o-carboxyphenylamino)pyrimi-
dine derivatives VIa,b
.
Compound VIa gave compatible elemental analyses and IR data. The
1H-NMR spectrum (DMSO-d6) of VIa showed signals at 2.14 ppm
(s, 3H, CH3), 2.41 (s, 3H, SCH3), 7.37 (d, 2H, aromatic protons), 7.74
(d, 2H, aromatic protons), 8.01 (s, 1H, pyrimidine H6), and 8.63 (s, 1H,
NH, D2O exchangeable). The IR spectrum of VIb displayed absorption
bands at 3200–2800 cm 1 (br, OH + NH) and 1685 (CO). The mass spec-
trum of VIb showed the molecular ion peak at m/z 275 (100%).

70
M. M. Youssef and A. M. S. Youssef
Compound VIb underwent cyclization by dehydration upon fusion at
270 C to produce 4-methyl-1-methylthio-10H-pyrimido[6,1-b]quinazo-
lin-10-one (VII). The IR spectrum of VII revealed the disappearance of
any absorption bands at 3200–2800 cm 1, except for the expected OH
absorption (Experimental). Its mass spectrum showed the molecular
ion peak at m/z 257 (100%).
Compound V undergoes nucleophilic substitution with thioglycolic
acid to produce 2-methylthio-5-methylpyrimidine-4-ylthioacetic acid
(VIc), which displayed IR absorption bands at 3200–2900 cm 1 (br, OH)
and 1690 (CO).
Diaminopyrimidines are known in literature to have biological
12
activity.10
Therefore, we tried to synthesize a pyrimidine deriva-
tive containing two amino groups. Thus, treatment of V with con-
centrated ammonia solution (strong nucleophile) resulted in replace-
ment of both chlorine atom at 4-position, and the methylthio group
at 2-position, to produce 5-methylpyrimidine-2,4-diamine (VId) in poor
yield.
The produced diaminopyrimidine derivative VId displayed IR ab-
1
sorption bands at 3330–3170 cm
(NH2). Its 1H-NMR spectrum
(DMSO-d6) showed signals at 1.82 ppm (s, 3H, CH3), 3.43 (s, 2H,
NH2, D2O exchangeable), 4.45 (s, 2H, NH2, D2O exchangeable), and
7.53 (s, 1H, pyrimidine H6).
Similarly, compound V reacted with hydrazine hydrate in boiling
dioxane and gave the corresponding 2,4-dihydrazino derivative VIe.
1
Analytical, IR, and H-NMR spectral data are in agreement with the
proposed structure VIe (Experimental).

Reactions with 2-Thiothymine
71
Compound V reacted with sodium azide in dimethyl-formamide to
produce 8-methyl-5-methylthiotetrazolo[1,5-c]pyrimidine (VIII).
The mass spectrum of VIII revealed the molecular ion peak at m/z
181 (82.9%) and the base peak at m/z 86.
In continuation, alkylation of I with -haloketones yielded the
corresponding S-alkylated derivatives. Thus, treatment of I with
each of chloroacetone, phenacyl bromide, and 3-chloropentan-2,4-
dione in ethanolic sodium ethoxide solution yielded the corresponding
S-acetonyl-, S-phenacyl-, and S-diacetylmethyl derivatives IXa–c re-
spectively.
Compounds IXa–c gave compatible data in elemental analyses, IR
and 1H-NMR spectra (Experimental).
Dehydration of IXa–c by polyphosphoric acid gave the correspond-
ing substituted thiazolo[3,2-a]pyrimidine derivatives Xa–c, respectively,
rather than the isomeric structure X0.
The IR spectra of compounds X showed the absence of any absorp-
tion bands in the NH region and absorptions near 1640 cm 1 (CO). The
1H-NMR spectrum of Xa, as an example, showed signals at 1.95 ppm
(s, 3H, CH3), 2.36 (s, 3H, CH3), 6.94 (s, 1H, thiazole H5), and 8.02

72
M. M. Youssef and A. M. S. Youssef
(s, 1H, pyrimidine H6). The mass spectrum of Xa showed the molec-
ular ion peak at m/z 180 (100%).
1
Preferring structure X over X0 was based on H-NMR studies (see
later).
Furthermore, compound I was treated with a mixture of chloroacetic
acid, acetic anhydride, and the proper aromatic aldehyde, in acetic
acid containing anhydrous sodium acetate, to produce the 2-arylidene
thiazolo[3,2-a]pyrimidinedione derivatives XIa–d
.
Analytical, IR, and 1H-NMR spectral data are in agreement with the
proposed structure XI.
Reaction of compound I with monobromomalononitrile, in alcoholic
potassium hydroxide, produced 3-amino-6-methyl-5-oxo-thiazolo[3,2-a]
pyrimidine-2-carbonitrile (XII), most probably via the formation of XII0.
The IR spectrum of compound XII displayed absorption bands at
1
3354, 3301 cm
(NH2), 2200 (CN), and 1674 (CO). Its 1H-NMR
(DMSO-d6) showed signals at 1.90 ppm (s, 3H, CH3), 7.81 (s, 1H,

Reactions with 2-Thiothymine
73
pyrimidine H7), and 8.50 (s, 2H, NH2, D2O exchangeable). The mass
spectrum of XII showed the molecular ion peak at 206 (100%).
The presence of the enaminonitrile moiety in compound XII could be
proved by its reactions with each of formic acid, formamide and ammo-
nium thiocyanate to produce thiazolo[3,2-a:4,5-d]dipyrimidine deriva-
tives XIIIa–c respectively.
Agreeable analytical and spectral data are obtained for XIII
(Experimental).
Reactions of XII with formic acid and formamide may be take place
as shown in Scheme 1.
SCHEME 1
Ultimately, compound XII reacted with malononitrile in ethanol con-
taining a catalytic amount of piperidine to yield 2,4-diamino-8-methyl-
9-oxopyrido[20,30:4,5]Thiazolo[3,2-a]pyrimidine-3-carbonitrile (XIV).
Analytical and spectral data of XIV are in agreement with the proposed
structure (Experimental).

74
M. M. Youssef and A. M. S. Youssef
Structure X could be preferred over X0 by comparing chemical shifts
( ) of pyrimidine H-6 proton in IIa,b (7.72 ppm) with those for each of
the cyclized products Xa (8.02 ppm), XIb (7.72 ppm), XII (7.81 ppm),
and XIIIb (7.81 ppm). It is clear that values for H-7 proton in the cy-
clized structures X, XI, XII, and XIII did not suffer from any significant
changes from the pyrimidine H-6 in the open structure II (difference is
within 0.3 ppm). We previously reported13 that in pyrimidines, cycliza-
tion involving a certain nitrogen atom causes a high field shift for its
neighboring proton by a value of >1 ppm, whereas cyclization involv-
ing the other nitrogen atom would not affect value of the same proton.
Consequently, we could conclude that cyclization reactions carried out
in this article involves N-3 rather than N-1 and thus sructure X and
the related cyclized products could be preferred.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded (KBr)
1
on a Pye Unicam SP-1000 spectrophotometer. H-NMR were obtained
with a Varian 1H-Gemini 200 spectrometer and chemical shifts are
expressed in (ppm) using TMS as the internal standard. The ele-
mentary analyses were performed by the Microanalytical Data Center,
Cairo University, Egypt.
Compounds I were prepared according to literature procedure.9
2-Alkylthio-3,4-dihydro-5-methylpyrimidin-4-ones IIa,b
A mixture of an equimolar amounts of I (1.42 g, 0.01 mmol), alkyliodide
and potssium hydroxide (0.65 g, 0.01 mmol) in 30 ml absolute ethanol
was heated under reflux for 2 h, cooled, and then poured into water
(70 ml). The precipitated solid was collected and crystallized from diox-
ane to give IIa,b. Compound IIa was obtained in 90% yield; m.p. 247 C;
1
1
IR spectrum: 3136 cm (NH), 2974 (CH), and 1652 (CO). H-NMR
spectrum (DMSO-d6): 1.85 ppm (s, 3H, CH3), 2.11 (s, 3H, SCH3),
3.55 (bs, 1H, NH, D2O exchangeable), and 7.72 (s, 1H, pyrimidine H6).

Reactions with 2-Thiothymine
75
Analysis: C6H8N2OS (156.31). Requires: C, 46.10; H, 5.15; N, 17.99; S,
20.51%. Found: C, 46.1; H, 5.1; N, 17.8; S, 20.4%.
Compound IIb was obtained in 85% yield; m.p. 185 C; IR spectrum:
1
3145 cm (NH), 2980 (CH), and 1650 (CO). 1H-NMR (DMSO-d6):
1.26 ppm (t, 3H, CH3), 1.85 (s, 3H, CH3), 4.20 (q, 2H, CH2), 4.52 (bs,
1H, NH, D2O exchangeable), and 7.72 (s, 1H, pyrimidine H6). Analysis:
C7H10N2OS (170.34). Requires: C, 49.35; H, 5.91; N, 16.51; S, 18.86%.
Found: C, 49.3; H, 5.8; N, 16.5; S, 18.9%.
3,4-Dihydro-2-hydrazino-5-methylpyrimidin-4-one (III)
A mixture of each of IIa,b (0.01 mmol) and hydrazine hydrate (1.5 ml,
0.03 mmol) in dioxane (30 ml) was heated under reflux for 5 h, the
reaction mixture was poured into cold water, whereby the solid so-
precipitated was filtered off, dried, and crystallized from dilute dioxane.
The yield of compound III was 61%; m.p. 230 C; IR spectrum: 3321,
1
1
3205, 3151 cm (NH2 and NH), 2985 (CH), and 1685 (CO). H-NMR
spectrum (DMSO-d6): 1.77 ppm (s, 3H, CH3), 4.48 (s, 2H, NH2, D2O
exchangeable), 7.39 (s, 1H, pyrimidine H6), 8.26 (s, 1H, D2O exchange-
able), and 8.65 (bs, 1H, NH, D2O exchangeable). Analysis: C5H8N4O
(140.13). Requires: C, 42.85; H, 5.74; N, 39.98%. Found: C, 42.7; H, 5.7;
N, 39.9%.
2-(4-Chlorophenyl)methylenehydrazino-3,4-dihydro-
5-methylpyrimid-in-4-ones (IV)
A mixture of 0.01 mmol of III and an equimolar amount of p-chloro-
benzaldehyde in 50 ml of absolute ethanol was refluxed for 3 h, the solid
that formed on dilution with water, was collected, dried, and crystallized
1
from acetic acid; m.p. 243 C; IR spectrum: 3310, 3130 cm (NH) and
1680 (CO). Analysis: C12H11ClN4O (262.68). Requires: C, 54.86; H, 4.21;
N, 21.32; Cl, 13.49%. Found: C, 54.9; H, 4.2; N, 21.1; Cl, 13.3%.
4-Chloro-5-methyl-2-methylthiopyrimidine (V)
A mixture of IIa (1.56 g, 0.01 mmol) in dry dioxane (10 ml) and phos-
phorus oxychloride (2.5 ml) was heated under reflux for 2 h, cooled, and
poured into ice. The precipitated solid was collected, dried, and crystal-
lized from methanol to give 1.04 g (60%) of V; m.p. 35 C; IR spectrum:
1
2980 cm (CH). Analysis: C6H7ClN2S (174.60). Requires: C, 41.27; H,
4.01; N, 16.04; S, 18.36; Cl, 20.30%. Found: C, 41.3; H, 4.0; N, 16.1; S,
18.2; Cl, 20.3%.

76
M. M. Youssef and A. M. S. Youssef
4-(p-Chlorophenylamino)-5-methyl-
2-methylthiopyrimidine VIa,b
A mixture of V (0.01 mmol) and an appropriate primary aromatic amine
(0.01 mmol) in dry dioxane (20 ml) was heated under reflux for 1 h,
the reaction mixture was poured onto cold water, whereby the solid
produced so precipitated was filtered off, dried, and crystallized from
dioxane/water.
4-(p-Chlorophenylamino)-5-methyl-
2-methylthiopyrimidine (VIa)
1
Yield (80%); m.p. 140 C; IR spectrum: 3228 cm (NH) and 2975 (CH).
1H-NMR spectrum (DMSO-d6): 2.14 ppm (s, 3H, CH3), 2.41 (s, 3H,
SCH3), 7.37 (d, 2H, aromatic protons), 7.74 (d, 2H, aromatic protons),
8.01 (s, 1H, pyrimidine H6), and 8.63 (s, 1H, NH, D2O exchangeable).
Analysis: C12H12ClN3S (265.75). Requires: C, 54.23; H, 4.54; N, 15.80;
S, 12.06; Cl, 13.33%. Found: C, 54.3; H, 4.5; N, 15.7; S, 12.1; Cl, 13.3%.
4-(o-Carboxyphenylamino)-5-methyl-
2-methylthiopyrimidine (VIb)
1
Yield (80%); m.p. 255 C; IR spectrum: 3200–2800 cm (br, OH + NH)
and 1685 (CO). 1H-NMR spectrum (DMSO-d6): 2.14 ppm (s, 3H, CH3),
2.14 (s, 3H, SCH3), 8.02 (s, 1H, pyrimidine H6), 8.61 (s, 1H, NH, D2O
exchangeable), and 10.73 (s, 1H, COOH, D2O exchangeable). Analysis:
C13H13N3O2S (275.31). Requires: C, 56.71; H, 4.75; N, 15.26; S, 11.65%.
Found: C, 56.6; H, 4.7; N, 15.3; S, 11.7%.
4-Methyl-1-methylthio-10H-pyrimido-
[6,1-b]quinazoline-10-one (VII)
Compound VIb (0.01 mmol) was heated at 270 C on an oil bath for half
an hour, the reaction mixture was then triturated with absolute ethanol.
The solid product, so formed, was filtered off, dried, and crystallized
1
from dioxane to yield (80%) of VII; m.p. 283 C; IR spectrum 1690 cm
(CO). Analysis: C13H11N3OS (257.29). Requires: C, 60.68; H, 4.30; N,
16.33; S, 12.46%. Found: C, 60.7; H, 4.2; N, 16.3; S, 12.5%.
4-Carboxymethylthio-5-methyl-2-methylthiopyrimidine
(VIc)
A mixture of V (0.01 mmol) and thioglycollic acid (0.01 mmol) in dry
dioxane (20 ml) was heated under reflux for 3 h then cooled. The

Reactions with 2-Thiothymine
77
precipitated solid was collected, dried, and crystallized from dioxane
to give (70%) of VIc; m.p. 245 C; IR spectrum 3200–2900 cm 1 (br, OH)
and 1690 (CO). Analysis: C8H10N2O2S2 (230.29). Requires: C, 41.72; H,
4.37; N, 12.16; S, 27.84%. Found: C, 41.7; H, 4.3; N, 12.2; S, 27.9%.
5-Methylpyrimidine-2,4-diamine (VId)
A mixture of V (0.01 mmol) and concentrated ammonia solution was
heated under reflux for 2 h, the solid thus formed after evaporation,
was collected, dried, and crystallized from ethanol to give (30%) of VId;
1
1
m.p. 190 C; IR spectrum 3330–3170 cm (NH2). H-NMR spectrum
(DMSO-d6): 1.82 ppm (s, 3H, CH3), 3.43 (s, 2H, NH2, D2O exchange-
able), 4.45 (s, 2H, NH2, D2O exchangeable), and 7.53 (s, 1H, pyrimidine
H6). Analysis: C5H8N4 (124.13). Requires: C, 48.37; H, 6.48; N, 45.13%.
Found: C, 48.4; H, 6,6; N, 45.1%.
2,4-Dihydrazino-5-methylpyrimidine (VIe)
A mixture of V (0.01 mmol) and Hydrazine hydrate (0.05 mmol) in
dioxane (20 ml) was heated under reflux for 5 h, the reaction mixture
was evaporated, cooled, whereby the solid so-precipitated was filtered
off, dried, and crystallized from water. The yield of compound VIe was
1
1
60%; m.p. 183 C; IR spectrum 3320–3180 cm (NH2). The H-NMR
spectrum (DMSO-d6): 1.83 ppm (s, 3H, CH3), 3.47 (s, 2H, NH2, D2O
exchangeable), 4.12–4.31 (bs, 3H, NH2 + NH, D2O exchangeable), 7.35
(s, 1H, NH, D2O exchangeable), and 7.52 (s, 1H, Pyrimidine H6). Anal-
ysis: C5H10N6 (154.16). Requires: C, 38.95; H, 6.53; N, 54.51%. Found:
C, 38.8; H, 6.5; N, 54.5%.
8-Methyl-5-methylthiotetrazolo[1,5]pyrimidine (VIII)
A mixture of V (0.01 mmol) and sodium azide (0.01 mmol) in dimethyl
formamide (20 ml) was stirred at room temperature for 12 h, the re-
action mixture was heated on a water bath for 1 h, then poured onto
ice/water whereby the solid product that precipitated, was filtered off,
dried, and crystallized from methanol. Compound VIII was obtained in
64% yield; m.p. 100 C; IR spectrum 2950 cm 1 (CH). Analysis: C6H7N5S
(181.20). Requires: C, 39.76; H, 3.88; N, 38.64; S, 17.69%. Found: C, 39.7;
H, 3.8; N, 38.5; S, 17.7%.
Alkylation of I. Preparation of IXa–c
A mixture of an equimolar amounts of I (0.01 mmol) and an appropriate
-haloketone in ethanolic sodium ethoxide solution (20 ml) was heated,

78
M. M. Youssef and A. M. S. Youssef
TABLE I Characterization Data of Compounds IXa–c and Xa–c
Analysis
Calc. Found
%C
%H
%N
%S
%C
%H
%N
%S
Molecular
formula
m.p. C
Solvent
IR (KBr)
cm
1
Compound
Yield %
70
IXa
C8H10N2O2S
(198.22)
195
Ethanol
48.47
5.08
48.4
5.1
3417, 3008 (NH),
1631 (CO)
14.13
16.17
59.98
4.64
10.76
12.31
49.99
5.02
11.65
13.34
53.02
5.00
15.45
17.69
64.18
4.55
14.1
16.1
60.0
4.6
10.7
12.3
49.9
5.0
11.7
13.2
53.0
5.0
15.3
17.7
64.2
4.5
1566 (CO)
IXb
IXc
Xa
C13H12N2O2
(260.28)
80
75
60
72
58
230
Ethanol
3421, 3213 (NH),
1685 (CO),
1639 (CO)
C10H12N2O3S
(240.23)
190
Ethanol
3031 (NH),
1631 (CO),
1587 (CO)
C8H9N2OS
(181.20)
196
Dioxane
1640 (CO)
Xb
C13H11N2OS
(243.27)
262
Dioxane
1635 (CO)
11.51
13.18
54.04
4.53
11.5
13.1
54.1
4.5
Xc
C10H10N2O2S
(222.24)
202
Ethanol
1650 (CO),
1642 (CO)
12.60
14.42
12.6
14.5
IXb: 1H-NMR spectrum (DMSO-d6): 1.82 ppm (s, 3H, CH3), 4.78 (s, 2H, CH2),
7.30–8.04 (m, 6H, 5 aromatic protons + pyrimidine H6) and 8.30 (bs, 1H, NH, D2O
exchangeable).
Xa: 1H-NMR spectrum (DMSO-d6): 1.95 ppm (s, 3H, CH3), 2.36 (s, 3H, CH3), 6.94
(s, 1H, thiazole H5) and 8.02 (s, 1H, pyrimidine H6).
under reflux for 3 h, the reaction mixture was poured onto water, the
solid product formed was filtered off, and crystallized from the proper
solvent (Table I).
Cyclization of IXa–c. Synthesis of Xa–c
A suspension of 1 g of each of IXa–c in 10 g of polyphosphoric acid
was heated at 100–120 C on an oil bath for 1 h, the solution was
left to cool, poured with stirring into ice/water, and basified with

Reactions with 2-Thiothymine
79
ammonium hydroxide solution. The solid that formed was collected,
washed with water, and crystallized from the proper solvent to give Xa–c
(Table I).
2-Arylidene Thiazolo[3,2-a]pyrimidinedione XIa–d
A mixture of 0.01 mmol of each of I (1.42 g), (1.04 g) of chloroacetic acid,
an appropriate aldehyde, and (2 g) of anhydrous sodium acetate was
refluxed in 30 ml of glacial acetic acid and 15 ml of acetic anhydride for
3 h, the reaction mixture was poured into water. The precipitate that
formed was filtered off, washed with water, dried, and crystallized from
the proper solvent to produce XIa–d (Table II).
3-Amino-6-methyl-5-oxothiazolo[3,2-a]pyrimidine-
2-carbonitrile (XII)
A mixture of 0.01 mmol of each of I (1.42 g) and monobromomalononi-
trile was heated under reflux for 1 h in alcoholic potassium hydroxide
TABLE II Characterization Data of Compounds XIa–d
Analysis
Calc. Found
%C
%H
%N
%S
%C
%H
%N
%S
Molecular
formula
m.p. C
Solvent
IR (KBr)
cm
1
Compound
Yield %
80
XIa
C14H9ClN2O2S
(304.73)
280
Acetic acid
55.17
2.97
55.0
2.9
1720 (CO),
1681 (CO)
9.19
9.2
10.52
59.99
4.02
10.6
60.0
4.0
XIb
XIc
XId
C15H12N2O3S
(300.01)
83
70
78
290
dilute
Acetic acid
1684 (CO),
1670 (CO)
9.32
9.2
10.67
52.16
2.91
10.13
23.20
56.95
3.81
10.7
52.1
3.0
10.2
23.1
56.9
3.8
C12H8N2O2S2
(276.30)
340
DMF
1715 (CO),
1640 (CO)
C15H12N2O4S
(316.31)
305
Acetic acid
3340–3210 (OH),
1710 (CO),
8.85
8.8
1680 (CO)
10.13
10.1
XIa: Cl, Requires: 11.63; Found: 11.5%.
XIb: 1H-NMR spectrum (DMSO-d6): 1.98 ppm (s, 3H, CH3), 3.89 (s, 3H, CH3),
7.15–7.74 (q, 4H, aromatic protons), 7.72 (s, 1H, pyrimidine-H6) and 8.1 (s, 1H, CH).

80
M. M. Youssef and A. M. S. Youssef
solution (20 ml). The reaction mixture was poured onto water. The
precipitate, thus formed, was filtered off, washed with water, dried,
and crystallized from dilut dimethylformamide. Compound XII was
1
obtained in 70% yield; m.p. 282 C; IR spectrum 3354, 3301 cm
1
(NH2), 2200 (CN) and 1674 (CO). The H-NMR spectrum (DMSO-d6):
1.90 ppm (s, 3H, CH3), 7.81 (s, 1H, pyrimidine H7) and 8.50 (s, 2H,
NH2, D2O exchangeable). Analysis: C8H6N4OS (206.19). Requires: C,
46.59; H, 2.92; N, 27.16; S, 15.54%. Found: C, 46.5; H, 2.9; N, 27.1; S,
15.5%.
8-Methylthiazolo[3,2-a: 4,5-d]dipyrimidine-4,9-dione
(XIIIa)
A mixture of compound XII (1 g) and formic acid (10 ml) was heated
under reflux for 10 h, the solid product that separated upon cooling was
filtered off and crystallized from dimethyl formamide in 64% yield; m.p.
1
315 C; IR spectrum 3178 cm (NH) and 1670, 1612 (2CO). Analysis:
C9H6N4O2S (234.15). Requires: C, 46.16; H, 2.56; N, 23.92; S, 13.69%.
Found: C, 46.2; H, 2.6; N, 23.8; S, 13.5%.
4-Amino-8-methylthiazolo[3,2-a: 4,5-d]dipyrimidine-
9-one (XIIIb)
A mixture of compound XII (1 g) and formamide (10 ml), in presence
of formic acid (5 ml) and dimethyl formamide (5 ml), was heated under
reflux for 6 h, the solid product that separated upon cooling was filtered
off and crystallized from dilute dimethyl formamide in 58% yield; m.p.
1
1
340 C; IR spectrum 3269, 3039 cm (NH) and 1660 (CO). H-NMR
spectrum (DMSO-d6): 1.86 ppm (s, 3H, CH3), 3.41 (s, 2H, NH2, D2O
exchangeable), 7.21 (s, 1H, Pyrimidine H2), and 7.81 (s, 1H, Pyrimidine
H7). Analysis: C9H7N5OS (233.21). Requires: C, 46.34; H, 3.01; N, 30.02;
S, 13.74%. Found: C, 46.3; H, 2.9; N, 30.0; S, 13.6%.
Reaction of XII with Ammonium Thiocyanate.
Preparation of XIIIc
A mixture of XII (1 g) and an excess amount of ammonium thiocyanate
(3 g) was heated under reflux for 6 h in acetic acid (20 ml). The reaction
mixture poured onto ice/water; the solid that separated was filtered off,
dried, and crystallized from dilute dimethyl formamide, in 48% yield;
m.p. 330 C; IR spectrum 3309, 3163 cm 1 (NH) and 1643 (CO). Analysis:
C10H8N6OS2 (292.30). Requires: C, 41.09; H, 2.75; N, 28.74; S, 21.93%.
Found: C, 41.0; H, 2.6; N, 28.7; S, 21.8%.

Reactions with 2-Thiothymine
81
2,4-Diamino-8-methyl-9-oxopyrido[2‘,3‘:4,5]thiazolo-
[3,2-a]pyrimidine-3-carbonitrile (XIV)
A mixture of (0.01 mmol) of each of XII and malononitrile was heated
under reflux for 2 h in ethanol (20 ml) containing 3 drops of piperi-
dine. The reaction mixture poured onto water; the solid so formed, was
filtered off, dried, and crystallized from dilute dimethyl formamide, in
1
60% yield; m.p. 260 C; IR spectrum 3280, 3160 cm (NH2), 2230 (CN)
and 1650 (CO). Analysis: C11H8N6OS (272.25). Requires: C, 48.52; H,
2.95; N, 30.86; S, 11.77%. Found: C, 48.5; H, 2.9; N, 30.8; S, 11.7%.
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