One-pot synthesis of fused 2-thiouracils: Pyrimidopyrimidines, pyridopyrimidines and imidazolopyrimidines

Article abstract of DOI:10.1515/znb-2008-0709

Several 6-substitued-1-methyl-2,5,7,8-tetrahydro-2-thiopyrimido[4,5-d] pyrimidine-4-ones and ethyl 7-amino-5-aryl-1-methyl-4-oxo-1,2,3,4-tetrahydro-2- thiopyrido[2,3-d]pyrimidines-6-carboxylates were synthesized by treatment of 6-amino-1-methyl-2-thiourac

Full text of DOI:10.1515/znb-2008-0709

One-pot Synthesis of Fused 2-Thiouracils: Pyrimidopyrimidines,
Pyridopyrimidines and Imidazolopyrimidines
Shaker Youssifa and Fatmah Agilib
a Medical Chemistry Division, Faculty of Medicine, University of Jazan, P. O. Box: 114 Jazan,
Saudi Arabia; on leave from Chemistry Department, Faculty of Science, Zagazig University, Egypt
b Department of Chemistry, Faculty of Education for Girls, University of Jazan, Saudi Arabia
Reprint requests to Dr. Shaker Youssif. Fax: +96673217540. E-mail: syoussif@hotmail.com
Z. Naturforsch. 2008, 63b, 860 – 864; received March 4, 2008
Several 6-substitued-1-methyl-2,5,7,8-tetrahydro-2-thiopyrimido[4,5-d]pyrimidine-4-ones and
ethyl 7-amino-5-aryl-1-methyl-4-oxo-1,2,3,4-tetrahydro-2-thiopyrido[2,3-d]pyrimidines-6-carbox-
ylates were synthesized by treatment of 6-amino-1-methyl-2-thiouracil with primary amines and
formalin (40 %), and with ethyl 3-aryl-2-cyanoacrylate respectively. 8-Substituted-7-hydroxy-3-
methyl-2-thioxanthines were synthesized by the treatment of 6-amino-1-methyl-5-nitroso-2-thio-
uracil with benzylidene-anilines. Elemental and spectral analyses were performed for the new
compounds.
Key words: 6-Amino-1-methyl-2-thiourail and Nitroso Analogs, 6-Substituted-1-methyl-pyr-
imido[4,5-d]pyrimidines, 1,2,3,4-Tetrahydropyrido[2,3-d]pyrimidine-6-carboxylates,
8-Aryl-7-hydroxy-3-methyl-2-thiopurines
Introduction
Chemotherapeutically valuable pyrimidopyrimid-
inedione derivatives have been reported in the patent
literature [1]. The synthesis of pyrimidine via Man-
nich bases has been carried out [2]. The Mannich reac-
tion of 3(5)-arylaminopyrazoles with primary amines
has been described [3] as a route to pyrazolo[3,4-d]
pyrimidines. 6-Amino-1-methyl- or 1-(2-chlorobenz-
yl)- or 1,3-dimethyl-uracil were the key intermedi-
ates for the synthesis of pyrimido[4,5-d]pyrimidines
via a Mannich base [4, 5]. A literature survey revealed
no previous reports on 2-thiopyrimido[4,5-d]pyrimid-
ines. Due to the importance of thiopurines and thio-
pyrimidines as potential biological agents [6 – 10], we
now report the synthesis of 2-thiopyrimidopyrimid-
ines, pyrido[2,3-d]pyrimidine-6-carboxylates and 7-
hydroxy-2-thioxanthines .
Compound
R
-C6H5
2
3
4
5
6
7
8
9
-C6H4-4-CH3
-C6H4-4-NO2
-C6H4-4-OCH3
-naphthyl-2
-C2H5
-C6H4-3-OCH3
-C6H4-3-Cl
Scheme 1.
[D6]DMSO) for 4 revealed the absence of proton 5-H
of uracil (1) at δ = 4.88 and the appearance of a triplet
at 7.59 characteristic for N8-H and the appearance of a
singlet at 4.63 and of a doublet at 5.38 ppm character-
istic for the methylene group at C-5 and C-7, respec-
tively. Characteristic IR absorptions were observed at
ν = 3356 (NH) and 1643 cm−1 (C=O).
Results and Discussion
In a one-pot synthesis, 6-amino-1-methyl-2-thio-
uracil [11] (1) in methanol was treated with acetic acid
at 40 ◦C, then a primary aliphatic or aromatic amine in
methanol (1 equivalent) and formalin (40%) (4 equiva-
The importance of pyrido[2,3-d]pyrimidines as bi-
lents) were added at r. t. This provided the correspond- ologically active compounds includes their use as an-
ing pyrimido[3,4-d]pyrimidines 2 – 9 (Scheme 1) in titumor [12], antibacterial [13 – 15] and anticonvulsive
1
excellent yield. The H NMR spectrum (300 MHz, agents [16]. The treatment of 1 with ethyl 3-phenyl-
c
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S. Youssif – F. Agili · One-pot Synthesis of Fused 2-Thiouracils
861
Compound
R
15
16
17
18
19
H
4-OH
4-Br
4-Cl
2-OCH3
Scheme 2.
Compound
R
27
28
29
30
31
32
H
4-OH
2-OH
4-Cl
4-Br
4-F
Scheme 3.
2-cyanoacrylates 10 – 14 in absolute ethanol and in the obtained for the solid state in potassium bromide discs using
a Perkin-Elmer model 1430 spectrometer. 1H and 13C NMR
presence of triethylamine (TEA) (3 mL) by heating un-
spectra were recorded on a Varian Gemini-300 spectrome-
ter at 300 and 75 MHz, respectively, using tetramethylsil-
ane (TMS) as internal standard and [D6]DMSO as solvent.
Mass spectra were recorded on an VG-7035 instrument at 70
or 15 eV. Elemental analyses were determined at the Micro-
analytical Center of Cairo University (Giza, Egypt).
der reflux afforded pyrido[2,3-d] pyrimidines 15 – 19
(Scheme 2) in moderate yield. The formatiom of 15 –
19 proceeded through a Michael addition which de-
pends on the nucleophilicity of C-5 in uracil towards
1
electrophilic reagents. The H NMR spectrum for 19
showed a triplet at δ = 1.12– 1.28 characteristic for a
CH3 group, a quartet at 4.23 – 4.51 ppm characteristic
for a CH2 group, and a singlet at 6.42 ppm character-
istic for a NH2 group.
General procedure for 6-substitued-1-methyl-2,5,7,8-tetra-
hydro-2-thiopyrimido[4,5-d] pyrimidine-4-ones 2 – 9
A mixture of 1 (2.0 mmol) in methanol (20 mL) and acetic
acid (2 mL) was heated to 40 ◦C, and then a primary amine
(aromatic or aliphatic) (2.0 mmol) in methanol (5 mL) and
formalin (40 %, 4 equivalents) were added dropwise at r. t.
with stirring for 1 h. The resulting precipitate was filtered,
washed with ethanol and recystallized from H2O/DMF (2 : 1)
to give 2 – 9.
7-Hydroxyxanthine and its 8-alkyl or 8-aryl deriva-
tives have been prepared from 6-amino-5-nitrosour-
acils by the reaction with aliphatic or aromatic alde-
hydes [17– 21]. Due to the various biological activ-
ities [18] exhibited by these compounds, we present
herein a versatile synthetic procedure for 8-aryl-7-
hydroxy-3-methyl-2-thioxanthines [22] 27 – 32 via a
transamination process using aldehyde-anils 21 – 26.
Thus, refluxing of 21 – 26 with 6-amino-1-methyl-5-
nitroso-2-thiouracil [23] (20) in acetic acid took place
by the elimination of aniline to give 27 – 32 (Scheme 3)
in 36 – 55 % yield. The 1H NMR spectrum of 30
showed a broad singlet at δ = 13.14 characteristic for
7-OH, and a singlet at 12.33 ppm characteristic for
N1-H.
1-Methyl-6-phenyl-2,5,7,8-tetrahydro-2-thiopyrimido-
[4,5-d]pyrimidin-4-one (2)
◦
Yield 0.48 g (87 %). – M. p. > 300 C. – IR (KBr): ν =
3360 (NH), 3340 (NH), 3072 (CH ar.), 1680 (C=S), 1633
(C=O), 1604 (C=C) cm−1. – 1H NMR: δ = 4.0 (s, 3H, NMe),
4.52 (s, 5-H2, CH2), 5.08 – 5.10 (d, 7-H2, CH2), 7.54 –
7.98 (m, 5H-ar.), 8.17 (t, 1H, 8-H), 13.19 (bs, 1H, 3-H). –
13C NMR: δ = 28.79 (NCH3), 43.15 (CH2), 45.61 (CH2),
125.29, 128.53, 130.77, 133.72, 134.51, 154.53, 162.32,
166.13. – MS (70 eV): m/z (%) = 274 (37) [M]+, 174 (51),
146 (100), 132 (39), 104 (33), 91 (21), 77 (41), 60 (36). –
Experimental Section
Melting points were determined with an Electrothermal Anal. for C13H14N4OS: calcd. C 56.92, H 5.14, N 20.42;
Mel-Temp II apparatus and are uncorrected. IR spectra were found C 56.88, H 5.06, N 20.31.
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862
S. Youssif – F. Agili · One-pot Synthesis of Fused 2-Thiouracils
1-Methyl-6-(4-tolyl)-2,5,7,8-tetrahydro-2-thiopyrimido-
1-Methyl-6-ethyl-2,5,7,8-tetrahydro-2-thiopyrimido[4,5-d]-
[4,5-d]pyrimidin-4-one (3)
pyrimidin-4-one (7)
◦
Yield 0.29 g (68 %). – M. p. 210 – 12 C. – IR (KBr):
Yield 0.41 g (74 %). – M. p. 212 – 14 ◦C. – IR (KBr): ν =
3226 (NH), 3107 (CH ar.), 1642 (C=O), 1609 (C=C) cm−1. – ν = 3240 (NH), 2963 (CH aliph.), 1632 cm−1(C=O), 1616
1H NMR: δ = 2.33 (s, 3H, Me), 3.89 (s, 3H, NMe), 4.41 (s, (C=C), 1538, 1262 cm−1. – 1H NMR: δ =1.12 – 1.37 (t, 3H,
5-H2, CH2), 4.99 (d, 7-H2, CH2), 7.28 – 7.66 (dd, 4H-ar.), Me), 2.62 – 2.98 (q, 2H, CH2), 3.42 (s, 3H, NMe), 4.07 (s,
8.0 (t, 1H, 8-H), 12.89 (s, 1H, 3-H). – 13C NMR: δ = 20.82 5-H2, CH2), 4.47 – 4.49 (d, 7-H2, CH2), 8.25 (t, 1H, 8-H),
(CH3), 28.67 (NCH3), 41.73 (CH2), 45.03 (CH2), 118.34, 12.57 (bs, 1H, 3-H). – 13C NMR: δ = 14.89 (CH3), 16.51
125.19, 129.23, 132.68, 134.09, 154.32, 162.21, 165.61. – (CH2), 28.79 (NCH3), 41.00 (CH2), 43.72 (CH2), 125.29,
MS (70 eV): m/z (%) = 288 (64) [M]+, 273 (42), 244 (73), 128.53, 154.53, 160.03. – MS (70 eV): m/z (%) = 226 (17)
201 (69), 154 (61), 106 (28), 91 (100), 60 (36). – Anal. [M]+, 198 (40), 153 (71), 138 (29), 127 (100), 73 (22). –
for C14H16N4OS: calcd. C 58.32, H 5.59, N 19.43; found Anal. for C9H14N4OS: calcd. C 47.78, H 6.23, N 24.76;
C 58.02, H 5.47, N 20.10.
found C 47.71, H 6.16, N 25.30.
1-Methyl-6-(4-nitrophenyl)-2,5,7,8-tetrahydro-2-thiopyr-
1-Methyl-6-(3-methoxyphenyl)-2,5,7,8-tetrahydro-2-thio-
imido[4,5-d]pyrimidin-4-one (4)
pyrimido[4,5-d]pyrimidin-4-one (8)
◦
◦
Yield 0.50 g (82 %). – M. p. > 300 C. – IR (KBr): ν =
Yield 0.39 g (68 %). – M. p. 250 – 252 C. – IR (KBr):
3356 (NH), 3096 (CH ar.), 1680 (C=S), 1643 (C=O), 1501, ν = 3348 (NH), 3178 (CH ar.), 2939 (CH aliph.), 1651
1265, 1085 cm−1. – 1H NMR: δ = 3.78 (s, 3H, Me), 4.63 (C=O), 1620 (C=C) cm−1. – 1H NMR: δ = 3.57 (s, 3H,
(s, 5-H2, CH2), 5.38 (d, 7-H2, CH2), 6.91 – 6.94 (d, 2H, J = NMe), 3.98 (s, 3H, OMe), 4.42 (s, 5-H2, CH2), 4.87 – 4.89
7.5 Hz, 2H-ar.), 7.80 – 7.84 (d, 2H, J = 7.5 Hz, 2H-ar.), 7.59 (s, 7-H2, CH2), 6.88 – 7.76 (m, 4H-ar.), 8.05 (t, 1H, 8-H),
(t, 1H, NH), 12.23 (s, 1H, NH). – 13C NMR: δ = 28.82 13.0 (bs, NH). – 13C NMR: δ = 28.22 (NCH3), 43.11 (CH2),
(NCH3), 43.19 (CH2), 45.76 (CH2), 125.84, 128.92, 131.25, 45.40 (CH2), 54.87 (OCH3), 115.41, 119.64, 125.27, 128.47,
133.87, 134.62, 154.55, 162.63, 168.03. – MS (70 eV): 130.53, 133.23, 134.12, 154.19, 162.03, 165.80. – Anal.
m/z (%) = 319 (8) [M]+, 272 (4), 150 (100). – Anal. for for C14H16N4O2S: calcd. C 55.25, H 5.30, N 18.41; found
C13H13N5O3S: calcd. C 48.90, H 4.10, N 21.93; found C 55.12, H 5.18, N 18.07.
C 49.01, H 4.07, N 21.80.
1-Methyl-6-(3-chlorophenyl)-2,5,7,8-tetrahydro-2-thiopyr-
1-Methyl-6-(4-methoxyphenyl)-2,5,7,8-tetrahydro-2-thio-
pyrimido[4,5-d]pyrimidin-4-one (5)
imido[4,5-d]pyrimidin-4-one (9)
Yield 0.43 g (73 %). – M. p. 180 – 182 ◦C. – IR (KBr): ν =
Yield 0.46 g (79 %). – M. p. 220 – 22 ◦C. – IR (KBr): ν = 3260 (NH), 3081 (CH ar.), 2963 (CH aliph), 1639 (C=O),
3330 (NH), 3040 (CH ar.), 2906 (CH aliph.), 1640 (C=O), 1612 (C=C) cm−1. – 1H NMR: δ = 3.46 (s, 3H, NMe), 4.41
1602 (C=C), 1507 cm−1. – 1H NMR: δ = 3.76 (s, 3H, Me), (s, 5-H2, CH2), 5.02 (s, 7-H2, CH2), 6.86 – 7.23 (m, 4H-ar.),
4.09 (s, 3H, OMe), 4.53 (s, 5-H2, CH2), 5.08 – 5.10 (d, 7-H2, 8.01 – 8.06 (t, 1H, 8-H), 12.92 (s, 1H, 3-H). – 13C NMR:
CH2), 6.69 – 7.73 (dd, 4H-ar.), 7.79 (t, 1H, 8-H), 13.0 (bs, δ = 28.60 (NCH3), 43.05 (CH2), 45.11 (CH2), 125.18,
1H, 3-H). – MS (70 eV): m/z (%) = 304 (66) [M]+, 289 (15), 128.43, 129.71, 133.50, 134.51, 154.53, 162.32, 166.13. –
216 (23), 183 (12), 146 (31), 104 (33), 92 (100), 88 (39), MS (70 eV): m/z (%) = 310 (2) [M+2]+, 309 (3) [M+1]+, 308
73 (18). – Anal. for C14H16N4O2S: calcd. C 55.25, H 5.30, (7) [M]+, 292 (66), 234 (24), 204 (14), 138 (33), 102 (18),
N 18.41; found C 55.37, H 5.19, N 18.70.
75 (20), 68 (100), 53 (33). – Anal. for C13H13ClN4OS: calcd.
C 50.56, H 4.24, N 18.14; found C 50.71, H 4.11, N 18.22.
1-Methyl-6-(2-naphthyl)-2,5,7,8-tetrahydro-2-thiopyrimido-
[4,5-d]pyrimidin-4-one (6)
General procedure for ethyl 5-aryl-7-amino-1-methyl-4-oxo-
2-thio-1,2,3,4-tetra-hydropyrido[2,3-d]pyrimidine-6-carb-
oxylates 15 – 19
◦
Yield 0.44 g (71 %). – M. p. > 300 C. – IR (KBr): ν =
3333 (NH), 3171 (NH), 3063 (CH arom), 2939 (CH aliph.),
1651 (C=S), 1635 (C=O), 1620 (C=C), 1589, 1489 cm−1. –
A mixture of equimolar amounts of 1 (2.0 mmol) and the
1H NMR: δ = 3.73 (s, 3H, NMe), 4.14 (s, 5-H2, CH2), 4.63 – appropriate ethyl 3-aryl-2-cyanoacrylate 10 – 14 (2 mmol) in
4.65 (d, 7-H2, CH2), 6.59 – 7.61 (m, 7 H-ar.), 8.24 (t, 1H, absolute ethanol (10 mL) in the presence of TEA (3 mL)
8-H), 11.98 (s, 1H, 3-H). – MS (70 eV): m/z (%) = 324 was refluxed for 4 h. After cooling, the solid precipitate
(48) [M]+, 309 (42), 236 (9), 198 (11), 140 (15), 127 (100), was collected by filtration, washed with ethanol and recys-
88 (39), 73 (22). – Anal. for C17H16N4OS: calcd. C 62.95, tallized from EtOH-DMF (3 : 1), to afford the desired com-
H 4.97, N 17.27; found C 62.83, H 5.04, N 17.35.
pounds 15 – 19 in 60 – 85 % yield.
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S. Youssif – F. Agili · One-pot Synthesis of Fused 2-Thiouracils
863
Ethyl 7-amino-1-methyl-4-oxo-5-phenyl-1,2,3,4-tetrahydro- Ethyl 7-amino-1-methyl-4-oxo-5-(4-methoxyphenyl)-1,2,3,4-
2-thiopyrido[2,3-d]pyrimidine-6-carboxylate (15)
tetrahydro-2-thiopyrido[2,3-d]pyrimidine-6-carboxylate
(19)
Yield 0.57 g (84 %). – M. p. 254 – 256 ◦C. – 1H NMR: δ =
1.17 – 1.32 (t, 3H, Me), 3.89 (s, 3H, NCH3), 4.46 – 4.61 (q,
2H, CH2), 6.42 (s, 2H, NH2), 6.86 – 6.88 (m, 3H-ar.), 7.68 –
7.70 (m, 2H-ar.), 13.05 (s, 1H, 3-H). – 13C NMR: δ = 13.89
(CH3), 29.01 (NCH3), 37.12 (CH2), 91.15, 126.78, 126.93,
128.44, 128.63, 128.95, 139.21, 141.01, 156.42, 161.72,
163.53, 168.82. – MS (70 eV): m/z (%) = 356 (24) [M]+,
328 (61), 284 (18), 268 (100), 211 (41), 183 (7), 131 (29),
115 (25), 77 (48), 44 (12). – Anal. for C17H16N4O3S: calcd.
C 57.29, H 4.52, N 15.72; found C 57.08, H 4.49, N 15.80.
Yield 0.57 g (78 %). – M. p. 238 ◦C. – 1H NMR: δ = 1.12 –
1.28 (t, 3H, Me), 3.83 (s, 3H, NMe), 4.32 (s, 3H, OMe),
4.43 – 4.61 (q, 2H, CH2), 6.42 (s, 2H, NH2), 7.35 – 7.42 (d,
J = 8.8 Hz, 2H-ar.), 7.69 – 7.71 (d, J = 8.3 Hz, 2H-ar.), 12.86
(s, 1H, 3-H). – 13C NMR: δ = 13.73 (CH3), 29.06 (NCH3),
37.16 (CH2), 54.36 (OCH3), 91.18, 126.84, 127.01, 128.12,
128.47, 128.75, 140.13, 141.56, 156.21, 161.46, 163.47,
169.31. – MS (70 eV): m/z (%) = 386 (15) [M]+, 315 (22),
257 (9), 231 (100), 186 (37), 172 (79), 131 (24), 115 (13),
77 (12). – Anal. for C18H18N4O4S: calcd. C 55.95, H 4.69,
N 14.50; found C 55.81, H 4.72, N 14.39.
Ethyl 7-amino-1-methyl-4-oxo-5-(4-hydroxyphenyl)-1,2,3,4-
tetrahydro-2-thiopyrido[2,3-d]pyrimidine-6-carboxylate
(16)
General procedure for 8-substituted 3-methyl-7-hydroxy-2-
thioxanthines (27 – 32)
◦
Yield 0.65 g (91 %). – M. p. 249 – 251 C. – 1H NMR:
δ = 1.11 – 1.23 (t, 3H, Me), 3.78 (s, 3H, NMe), 4.39 – 4.47
(q, 2H, CH2), 6.33 (s, 2H, NH2), 6.79 – 6.81 (d, J = 9.0 Hz,
2H-ar.), 7.38 – 7.40 (d, J = 9.0 Hz, 2H-ar.), 11.80 (s, 1H,
OH), 12.97 (s, 1H, 3-H). – 13C NMR: δ = 13.88 (CH3),
29.11 (NCH3), 37.18 (CH2), 91.22, 126.89, 127.01, 128.14,
128.52, 128.79, 139.03, 140.76, 156.23, 161.45, 163.53,
168.75. – Anal. for C17H16N4O4S: calcd. C 54.83, H 4.33,
N 15.04; found C 54.95, H 4.23, N 14.97.
Imines 21 – 26 (2.0 mmol) were added to a solution of
compound 20 (2.0 mmol) in glacial acetic acid (10 mL)
with stirring. The reaction mixture was heated under reflux,
whereupon the color started to fade. Heating was continued
for 6 h. After cooling, the formed precipitate was filtered,
washed with ethanol and recrystallized from DMF. Com-
pounds 27 – 32 had melting points > 300 ◦C.
7-Hydroxy-3-methyl-8-phenyl-2-thioxanthine (27)
Ethyl 7-amino-1-methyl-4-oxo-5-(4-bromophenyl)-1,2,3,4-
tetrahydro-2-thiopyrido[2,3-d]pyrimidine-6-carboxylate
(17)
Yield 0.48 g (93 %). – 1H NMR: δ = 3.85 (s, 3H, NMe),
7.51 – 7.53 (m, 3H-ar.), 8.13 – 16 (m, 2H-ar.), 12.45 (s, 1H,
3-H), 14.10 (s, 1H, OH). – 13C NMR: δ = 29.06 (NCH3),
107.42, 113.29, 120.89, 127.23, 137.67, 149.81, 150.74,
154.31, 165.23. – MS (70 eV): m/z (%) = 274 (32) [M]+,
260 (51), 234 (29), 201 (14), 138 (35), 102 (21), 77 (100). –
Anal. for C12H10N4O2S: calcd. C 52.55, H 3.67, N 20.43;
found C 52.41, H 3.63, N 19.98.
Yield 0.76 g (92 %). – M. p. 266 ◦C. – 1H NMR:
δ = 1.14 – 1.26 (t, 3H, Me), 3.81 (s, 3H, NMe), 4.43 –
4.49 (q, 2H, CH2), 6.34 (s, 2H, NH2), 6.81 – 6.83 (d, J =
8.8 Hz, 2H-ar.), 7.42 – 7.44 (d, J = 8.8 Hz, 2H-ar.), 12.96
(s, 1H, 3-H). – 13C NMR: δ = 13.74 (CH3), 29.08 (NCH3),
37.07 (CH2), 91.12, 126.87, 126.01, 128.14, 128.49, 128.72,
139.01, 140.69, 156.13, 161.32, 163.49, 168.73. – Anal. for
C17H15BrN4O3S: calcd. C 46.90, H 3.47, N 12.86; found
C 46.67, H 3.44, N 12.79.
7-Hydroxy-3-methyl-8-(4-hydroxyphenyl)-2-thioxanthine
(28)
Yield 0.51 g (88 %). – 1H NMR: δ = 3.83 (s, 3H, NMe),
6.86 – 6.93 (d, 2H-ar.), 7.98 – 8.00 (d, 2H-ar.), 10.17 (s, 1H,
OH), 12.44 (s, NH), 13.80 (s, OH-7). – MS (70 eV): m/z
(%) = 290 (33) [M]+, 274 (68), 257 (41), 217 (9), 138 (12),
94 (100), 68 (8). – Anal. for C12H10N4O3S: calcd. C 49.65,
H 3.47, N 19.30; found C 49.48, H 3.42, N 19.19.
Ethyl 7-amino-1-methyl-4-oxo-5-(4-chlorophenyl)-1,2,3,4-
tetrahydro-2-thiopyrido[2,3-d]pyrimidine-6-carboxylate
(18)
◦
Yield 0.71 g (95 %). – M. p. 256 C. – 1H NMR: δ =
1.13 – 1.28 (t, 3H, Me), 3.82 (s, 3H, NMe), 4.41 – 4.49 (q,
2H, CH2), 6.37 (s, 2H, NH2), 6.83 – 6.85 (d, J = 8.3 Hz,
2H-ar.), 7.45 – 7.47 (d, J = 8.3 Hz, 2H-ar.), 12.98 (s, 1H,
3-H). – MS (70 eV): m/z (%) = 392 (17) [M+2]+, 391 (32)
[M+1]+, 390 (15) [M]+, 362 (22), 317 (67), 274 (59), 244
7-Hydroxy-3-methyl-8-(2-hydroxyphenyl)-2-thioxanthine
(29)
Yield 0.52 g (90 %). – 1H NMR: δ = 3.82 (s, 3H, NMe),
(73), 186 (18), 171 (9), 131 (24), 112 (100), 77 (73). – Anal. 6.93 – 7.01 (m, 2H-ar.), 7.33 – 7.38 (m, 1H-ar.), 8.03 – 8.05
for C17H15ClN4O3S: calcd. C 52.24, H 3.86, N 14.33; found (d, 1H-ar.), 12.50 (s, 1H, 3-H), 14.15 (bs, 1H, OH). –
C 52.05, H 3.81, N 14.29.
13C NMR: δ = 29.03 (NCH3), 107.61, 113.22, 121.09,
Unauthenticated
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864
S. Youssif – F. Agili · One-pot Synthesis of Fused 2-Thiouracils
126.95, 127.29, 128.15, 137.67, 149.81, 150.74, 154.31, (s, 1H, 3-H), 13.13 (s, 1H, OH). – 13C NMR: δ = 29.24
165.23. – Anal. for C12H10N4O3S: calcd. C 49.65, H 3.47, (NCH3), 106.83, 117.70, 125.32, 128.15, 139.15, 150.49,
N 19.30; found C 49.35, H 3.39, N 19.08.
150.74, 155.28, 167.14. – MS (70 eV): m/z (%) = 355 (7)
[M+2]+, 354 (5) [M+1]+, 353 (9) [M]+, 338 (89), 278 (23),
182 (24), 102 (23), 68 (100). – Anal. for C12H9Br N4O2S:
calcd. C 40.80, H 2.56, N 15.86; found C 40.46, H 2.44,
N 16.02.
7-Hydroxy-3-methyl-8-(4-chlorophenyl)-2-thioxanthine (30)
Yield 0.48 g (79 %). – 1H NMR: δ = 3.78 (s, 3H, NMe),
7.13 – 7.26 (dd, 2H-ar.), 7.63 – 7.65 (d, 2H-ar.), 12.33 (s,
1H, 3-H), 13.14 (s, 1H, OH). – 13C NMR: δ = 28.89
(NCH3), 112.40, 118.51, 124.17, 129.23, 141.52, 149.22,
151.63, 154.90, 166.97. – MS (70 eV): m/z (%) = 310 (3)
[M+2]+, 309 (8) [M + 1]+, 308 (12) [M]+, 292 (66), 234
(24), 204 (14), 138 (33), 102 (18), 68 (100). – Anal. for
C12H9ClN4O2S: calcd. C 46.68, H 2.93, N 18.14; found
C 46.57, H 3.01, N 18.18.
7-Hydroxy-3-methyl-8-(4-fluorophenyl)-2-thioxanthine (32)
Yield 0.45 g (77 %). – 1H NMR: δ = 3.78 (s, 3H, NMe),
7.0 – 7.04 (t, 1H-ar.), 7.12 – 7.15 (t, 1H-ar.), 7.37 – 7.44 (t,
1H-ar.), 8.18 – 8.20 (m, 1H-ar.), 12.32 (s, 1H, 3-H), 14.16
(s, 1H, OH). – MS (70 eV): m/z (%) = 294 (14) [M+2]+,
293 (20) [M + 1]+, 292 (100) [M]+, 261 (24), 234 (4), 183
(18), 157 (41), 129 (13), 57 (64). – Anal. for C12H9F N4O2S:
calcd. C 49.32, H 3.10, N 19.17; found C 49.09, H 3.15,
N 18.80.
7-Hydroxy-3-methyl-8-(4-bromophenyl)-2-thioxanthine (31)
Yield 0.58 g (83 %). – 1H NMR: δ = 3.78 (s, 3H,
NMe), 7.77 – 7.79 (d, 2H-ar.), 8.07 – 8.10 (d, 2H-ar.), 12.77
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Unauthenticated
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