New convenient synthesis of 2,3-diaminothieno[2,3-d]pyrimidin-4(3H)-one derivates from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates

Article abstract of DOI:10.1016/j.tet.2007.11.045

4,5-Disubstituted and 4-substituted alkyl 2-amino-thiophene-3-carboxylates react with triethyl orthoformate and sodium azide in acetic acid to yield new 2-(1H-tetrazol-1-yl)-4-R¹-5-R²-thiophene derivates. It was established that the

Full text of DOI:10.1016/j.tet.2007.11.045

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1430e1434
www.elsevier.com/locate/tet
New convenient synthesis of 2,3-diaminothieno[2,3-d]pyrimidin-4(3H )-one
derivates from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-
carboxylates
*
Nazariy T. Pokhodylo, Vasyl S. Matiychuk, Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla and Mefodiya St. 6, Lviv 79005, Ukraine
Received 12 August 2007; received in revised form 29 October 2007; accepted 15 November 2007
Available online 19 November 2007
Abstract
4,5-Disubstituted and 4-substituted alkyl 2-amino-thiophene-3-carboxylates react with triethyl orthoformate and sodium azide in acetic acid
to yield new 2-(1H-tetrazol-1-yl)-4-R1-5-R2-thiophene derivates. It was established that the reaction of these tetrazoles with hydrazine generates
the insufficiently studied 2,3-diaminothieno[2,3-d]pyrimidin-4(3H )-one system. It is significant that the reaction mentioned above is the unique
tetrazole ring cleavage under the action of hydrazine.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Tetrazole; Thiophene; Thieno[2,3-d]pyrimidin-4(3H )-one; Heterocyclization
N
N
N
N
1. Introduction
+
N
N
N
N
I
II
Tetrazole derivates are well known as compounds with a high
level of biological activity.1e8 The tetrazole ring is a bioisostere
of the carboxylic acid group9e12 and at the same time does
not have acidic properties. It was also noticed that toxic proper-
ties of a drug can decrease through the introduction of a tetrazole
ring into the molecule.13 Tetrazole derivatives form stable
complexes with metals.14e16 Furthermore, they have been
used as ligands for palladium-catalyzed reactions.17,18
For tetrazole ring construction the synthetic equivalents of
synthons I (sodium azide, organic azides) and II (cyanides,
isocyanides, isocyanates, isothiocyanates, and others) are
used most frequently (Fig. 1).
Figure 1.
Another method of a tetrazole ring synthesis is based on the
reaction of amines with triethyl orthoformate and sodium
azide.18,20e22 However, only arylamines were studied. In con-
trast heterocyclic amines have been used only sparingly. For
example, in a paper20 pyridinamines were converted into
tetrazolylpyridines.
In this paper we have investigated the possibility of the
synthesis of tetrazoles from 4,5-disubstituted and 4-substituted
alkyl 2-amino-thiophene-3-carboxylates, using the method
mentioned above.
They can be brought into the reaction as individual com-
pounds or generated directly in a reaction medium. The strate-
gies of the synthesis and properties of tetrazole derivates are
reported in a recent review.19
2. Results and discussion
We showed that alkyl 2-amino-thiophene-3-carboxylates
1aeh actively react with triethyl orthoformate and sodium
azide, forming an alkyl 2-(1H-tetrazol-1-yl)-4-R1-5-R2-thio-
phene-3-carboxylates 2aeh in good yields (Scheme 1, Table 1).
* Corresponding author. Tel.: þ380322728062.
E-mail address: obushak@in.lviv.ua (M.D. Obushak).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.045

N.T. Pokhodylo et al. / Tetrahedron 64 (2008) 1430e1434
1431
R3
+
R3
N
O
O
phene-3-carboxylate 1a, amino acid 6 was synthesized and
under the same conditions as in case of amino ethers, the tetra-
zole ring was formed (Scheme 3). That the yield of acid 3a was
25% proves the advantage of the first path.
R1
O
R1
O
OEt
+
NaN3
AcOH
R2
R2
EtO
OEt
NH2
N
N
S
1 a-h
S
2 a-h
N
Scheme 1.
O
O
O
OEt
NH2
OH
NH2
OH
NaN3
N
NaOH
CH(OEt)3
Table 1
Alkyl 2-(1H-tetrazol-1-yl)-4-R1-5-R2-thiophene-3-carboxylates 2aeh
N
N
N
EtOH/H2O
AcOH
S
1a
S
S
3a
Product
Yield
(%)
Product
Yield
(%)
6a
Scheme 3.
CO2Et
The experiment shown in Scheme 4 shows that the intro-
duction of a tetrazole ring into the 2-position contributes to
hydrazinolyzation of the ester group. Furthermore, under the
conditions of the reaction, the tetrazole ring cleaves and loses
a molecule of N2. The ultimate product of the reaction is
a thieno[2,3-d]pyrimidine, 7aeh (Scheme 4).
CO2Et
N
N
2a
81
84
2e
2f
83
79
N
N
N
S
N
N
S
N
Me
CO2Et
CO2Et
Me
N
N
2b
N
N
S
N
N
R3
NH2
O
O
O
N
N
NH2
N
S
R1
O
R1
N
H
R1
N
H
N2H4
- N2
F
R2
R2
N
N
N
N
N
N
N
N
R2
S
S
N
S
CO2Me
H
CO2Et
A
B
N
N
2c
72
91
2g
2h
70
87
N
S
N
N
N
O
N
S
NH2
N
R1
N
Cl
NH2
R2
N
Me
Me
CO2Me
N
S
CO2Et
7 a-h
2d
N
N
N
S
N
N
Scheme 4.
N
N
S
It is well known that 2,3-substituted thiophenes often serve
as reagents for thieno[2,3-d]pyrimidine.23e26 We established
that alkyl 2-(1H-tetrazol-1-yl)-4-R1-5-R2-thiophene-3-carbox-
ylates can be used as reagents for constructing the thieno-
[2,3-d]pyrimidine system. At the same time, the insufficiently
studied 2,3-diaminothieno[2,3-d]pyrimidin-4(3H )-ones were
prepared.27 The ability of the tetrazole ring to cleave with the
loss of nitrogen is used in this approach. Thus, the cyanamide
group formed in intermediate B reacts with the hydrazide
group, forming a pyrimidine ring. We have to point out that
in the explored reaction, the tetrazole ring cleaves under mild
conditions (hydrazine solution) unlike other known examples
(e.g., NaOH in DMSO22).
The mechanism of the reaction (Scheme 4) is confirmed by
NMR spectroscopy. In the 1H NMR spectrum of samples
selected 10 min after the beginning of reflux, the signal of a
cyanamide group proton is visible at 8.11e8.29 ppm and NH2
of hydrazide at 5.70e5.80 ppm. It is clear that cleavage of the
tetrazole ring as well as hydrazinolyzation occurs concurrently
and rapidly, while cyclization proceeds during a few hours.
The products 2aeh are white crystalline compounds. Their
structure is confirmed by NMR spectroscopy.
We also studied some properties of the compounds 2aeh. It
was established that in 0.5 M sodium hydroxide solution and
EtOH/H2O (1:1.5) 2a,b, are converted to the corresponding
acids 3a,b (Scheme 2). But in the case of compounds 2ceh
decomposition of the tetrazole ring takes place faster than the
hydrolysis of the ester group. After 2 h hydrolysis, the mixture
of products consisting of initial tetrazole 2 and cyanamide 4
was extracted from the reaction medium. More protracted re-
flux and introduction of another equivalent of base to the reac-
tion did not drive the formation of individual products to
completion. It is significant to note that at higher concentrations
of alkali a mixture of products 3, 4, 5 was obtained in all cases.
We also tried to prepare acids 3 via another path. By the
hydrolysis of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothio-
R3
O
O
R3
O
O
R1
OH
N
R1
KOH
R1
O
+
N
EtOH/H2O
N
3. Conclusion
R2
R2
N
N
N
N
R2
S
S
N
S
H
N
N
4 R3 = Et
3
2 a-h
For the first time, the hitherto rare 2,3-diaminopyrimidines
were easily prepared by the transformation of neighboring
ester group and tetrazole ring.
R
3 = H
5
Scheme 2.

1432
N.T. Pokhodylo et al. / Tetrahedron 64 (2008) 1430e1434
4. Experimental
132.2, 133.4, 135.3, 146.4, 162.0; IR (KBr): 3480, 3408, 3360,
3288, 3248, 3185, 2990, 2920, 1720, 1565, 1460, 1420, 1390,
4.1. General
1320, 1256, 1225, 1188, 1142, 1090, 1020, 956, 880 cmꢁ1
;
MS (m/z): 250 (Mþ). Anal. Calcd for C10H10N4O2S: C
47.99, H 4.03, N 22.39; found: C 47.75, H 3.96, N 22.46.
1H NMR spectra and 13C NMR spectra were recorded on
1
a Varian Mercury 400 instrument (400 MHz for H, 125 MHz
1
for 13C). The H and 13C chemical shifts are reported in parts
4.2.4. Methyl 4,5-dimethyl-2-(1H-tetrazol-1-yl)-3-
per million relativeto tetramethylsilaneor the deuterated solvent
as an internal reference. Mass spectra were run using Agilent
1100 series LC/MSD with an API-ES/APCI ionization mode.
thiophenecarboxylate 2d
Yield: 91% as white solid; mp: 86e87 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 2.32 (3H, s, CH3), 2.45 (3H, s,
CH3), 3.62 (3H, s, CH3O), 9.70 (1H, s, tetrazole); 13C NMR
(125 MHz, CDCl3): d 13.3, 13.8, 52.5, 128.4, 132.2, 133.5,
135.0, 146.3, 162.0; IR (KBr): 3488, 3360, 3280, 3248,
3176, 2992, 1720, 1564, 1472, 1416, 1288, 1256, 1192,
1168, 1088, 1024, 880, 780 cmꢁ1; MS (m/z): 238 (Mþ).
Anal. Calcd for C9H10N4O2S: C 45.37, H 4.23, N 23.51;
found: C 45.33, H 4.30, N 23.37.
4.2. General procedure for the synthesis of alkyl 2-(1H-
tetrazol-1-yl)thiophene-3-carboxylates 2aeh
A suspension of 50 mmol of the required thiophene 1,
triethyl orthoformate (37.9 mL, 0.23 mol), and sodium azide
(3.9 g, 0.06 mol) in glacial acetic acid (40 mL) was stirred
and heated at reflux for 2 h. The reaction mixture was cooled
to room temperature and 7 mL of concd HCl was added. The
solid was filtered off and the filtrate evaporated and the residue
was recrystallized from ethanol.
4.2.5. Ethyl 4-phenyl-2-(1H-tetrazol-1-yl)-3-
thiophenecarboxylate 2e
Yield: 83% as white solid; mp: 107 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 0.86 (3H, t, J 6.8 Hz, CH3), 3.99 (2H, q, J 6.8 Hz,
OCH2), 7.34e7.51 (5H, m, Ph), 7.85 (1H, s, thiophene), 9.96
(1H, s, tetrazole); 13C NMR (125 MHz, CDCl3): d 13.7,
61.7, 111.8, 115.1, 126.5, 127.5, 129.3, 132.2, 136.7, 141.1,
146.7, 161.6; IR (KBr): 3480, 3408, 3340, 3260, 3185, 2600,
1704, 1672, 1552, 1512, 1488, 1440, 1416, 1288, 1264,
1188, 1080, 1024, 1008, 864, 832, 792, 760 cmꢁ1; MS (m/z):
300 (Mþ). Anal. Calcd for C14H12N4O2S: C 55.99, H 4.03,
N 18.65; found: C 55.63, H 4.01, N 18.72.
4.2.1. Ethyl 2-(1H-tetrazol-1-yl)-4,5,6,7-tetrahydro-1-
benzothiophene-3-carboxylate 2a
Yield: 81% as white solid; mp: 88 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 1.05 (3H, t, J 7.2 Hz, CH3), 1.86 (4H, m, CH2),
2.83 (4H, m, CH2), 4.06 (2H, q, J 7.2 Hz, CH3CH2), 9.70 (1H,
s, tetrazole); 13C NMR (125 MHz, CDCl3): d 14.0, 22.2, 22.6,
24.9, 26.0, 61.2, 127.7, 133.4, 135.5, 137.8, 146.6, 161.1; IR
(KBr): 3480, 3408, 3360, 3288, 3248, 3185, 2990, 2920,
1725, 1565, 1460, 1420, 1390, 1320, 1260, 1225, 1180,
1142, 1090, 1020, 960, 880 cmꢁ1; MS (m/z): 278 (Mþ).
Anal. Calcd for C12H14N4O2S: C 51.78, H 5.07, N 20.13;
found: C 51.54, H 5.14, N 20.06.
4.2.6. Ethyl 4-(4-methylphenyl)-2-(1H-tetrazol-1-yl)-3-
thiophenecarboxylate 2f
Yield: 79% as white solid; mp: 111 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 0.94 (3H, t, J 6.8 Hz, CH3CH2), 2.39 (3H, s,
CH3), 4.02 (2H, q, J 6.8 Hz, OCH2), 7.20 (2H, d, J 8.0 Hz,
C6H4), 7.25 (2H, d, J 8.0 Hz, C6H4), 7.66 (1H, s, thiophene),
9.80 (1H, s, tetrazole); 13C NMR (125 MHz, CDCl3): d 13.8,
21.2, 61.7, 125.0, 126.1, 128.7, 128.9, 129.4, 132.3, 137.9,
141.5, 146.3, 161.8; IR (KBr): 3648, 3408, 3120, 2992, 2640,
1720, 1552, 1520, 1480, 1448, 1416, 1288, 1260, 1224, 1192,
1088, 1024, 824, 768, 656 cmꢁ1; MS (m/z): 314 (Mþ). Anal.
Calcd for C15H14N4O2S: C 57.31, H 4.49, N 17.82; found: C
57.19, H 4.31, N 17.77.
4.2.2. Ethyl 6-methyl-2-(1H-tetrazol-1-yl)-4,5,6,7-
tetrahydro-1-benzothiophene-3-carboxylate 2b
Yield: 84% as white solid; mp: 86 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 1.05 (3H, t, J 7.6 Hz, CH3CH2), 1.11 (3H, d, J
6.8 Hz, CH3), 1.38e1.49 (1H, m, cyclohexane), 1.90e2.02
(2H, m, cyclohexane), 2.39e2.45 (1H, m, cyclohexane),
2.68e2.78 (1H, m, cyclohexane), 2.89e3.03 (2H, m, cyclohex-
ane), 4.07 (2H, q, J 7.6 Hz, CH3CH2), 9.68 (1H, s, tetrazole);
13C NMR (125 MHz, CDCl3): d 14.0, 21.4, 25.7, 28.9, 30.3,
32.7, 61.2, 127.5, 133.5, 135.2, 137.4, 146.6, 161.1; IR
(KBr): 3472, 3408, 3360, 3288, 3248, 3176, 2990, 2928,
1716, 1568, 1464, 1420, 1392, 1320, 1256, 1236, 1184, 1144,
1096, 1024, 1016, 956, 780 cmꢁ1; MS (m/z): 292 (Mþ). Anal.
Calcd for C13H16N4O2S: C 53.41, H 5.52, N 19.16; found: C
53.55, H 5.44, N 19.02.
4.2.7. Ethyl 4-(4-fluorophenyl)-2-(1H-tetrazol-1-yl)-3-
thiophenecarboxylate 2g
Yield: 70% as white solid; mp: 84 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 0.91 (3H, t, J 7.8 Hz, CH3), 4.01 (2H, q, J
7.8 Hz, OCH2), 7.09 (2H, d, J 7.8 Hz, C6H4), 7.15 (2H, d, J
8.0 Hz, C6H4), 7.72 (1H, s, thiophene), 9.78 (1H, s, tetrazole);
13C NMR (125 MHz, CDCl3): d 13.7, 61,7, 115.5, 115.7,
125.7, 128.6, 131.1, 131.8, 136.3, 140.5, 146.4, 162.5 (d,
JCF 241.2 Hz, 4-C C6H4); IR (KBr): 3128, 2936, 1712,
1520, 1296, 1256, 1216, 840, 784 cmꢁ1; MS (m/z): 318
(Mþ). Anal. Calcd for C14H11FN4O2S: C 52.82, H 3.48, N
17.60; found: C 52.87, H 3.57, N 17.55.
4.2.3. Methyl 2-(1H-tetrazol-1-yl)-5,6-dihydro-4H-
cyclopenta[b]thiophene-3-carboxylate 2c
Yield: 72% as white solid; mp: 183 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 2.42e2.49 (2H, m, CH2), 2.97e
3.05 (4H, m, CH2), 3.69 (3H, s, CH3), 9.70 (1H, s, tetrazole);
13C NMR (125 MHz, CDCl3): d 25.4, 29.5, 32.9, 52.1, 127.4,

N.T. Pokhodylo et al. / Tetrahedron 64 (2008) 1430e1434
1433
4.2.8. Ethyl 4-(4-chlorophenyl)-2-(1H-tetrazol-1-yl)-3-
thiophenecarboxylate 2h
with 50 mL water. The solid was filtered and recrystallized
from ethanol.
Yield: 87% as white solid; mp: 131e132 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 0.94 (3H, t, J 6.8 Hz, CH3), 4.02
(2H, q, J 6.8 Hz, OCH2), 7.38 (2H, d, J 8.8 Hz, C6H4), 7.42
(2H, d, J 8.8 Hz, C6H4), 7.75 (1H, s, thiophene), 9.79 (1H,
s, tetrazole); 13C NMR (125 MHz, CDCl3): d 13.7, 61.7,
126.1, 128.4, 128.7, 130.8, 133.3, 134.2, 136.5, 140.3,
146.4, 161.4; IR (KBr): 3464, 3264, 3056, 1684, 1640,
1536, 1504, 1312, 1252, 1216, 1168, 1020, 968, 936, 880,
848, 766, 720, 672, 592, 544 cmꢁ1; MS (m/z): 335 (Mþ).
Anal. Calcd for C14H11ClN4O2S: C 50.23, H 3.31, N 16.74;
found: C 50.05, H 3.23, N 16.59.
4.4.1. 2,3-Diamino-5,6,7,8-tetrahydro[1]benzothieno[2,3-
d]pyrimidin-4(3H )-one 7a
Yield: 74% as white solid; mp: 281 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 1.76e1.89 (4H, m, CH2), 2.62
(2H, t, J 5.9 Hz, CH2), 2.83 (2H, t, J 5.9 Hz, CH2), 5.25
(2H, s, CNH2), 6.86 (2H, s, NNH2); 13C NMR (125 MHz,
CDCl3): d 22.4, 23.8, 24.8, 25.9, 113.2, 125.1, 130.4, 153.6,
158.1, 164.3; IR (KBr): 3472, 3320, 3200, 2928, 2856,
1660, 1632, 1596, 1504, 1456, 1352, 1304, 1248, 1176, 944,
872, 768, 476 cmꢁ1; MS (m/z): 236 (Mþ). Anal. Calcd for
C10H12N4OS: C 50.83, H 5.12, N 23.71, S 13.57; found: C
50.92, H 5.06, N 23.85, S 13.69.
4.3. Preparations of 2-(1H-tetrazol-1-yl)-3-
thiophenecarboxylic acids 3a and 3b
Compound 2a (0.01 mol) was added to a solution of 0.56 g
(0.01 mol) potassium hydroxide in 50 mL ethanol/H2O (1:1.5)
and heated at reflux for 3 h. Then, the reaction mixture was
poured into 15 mL of concd HCl. The solid formed was fil-
tered off and recrystallized from ethanol.
4.4.2. 2,3-Diamino-7-methyl-5,6,7,8-tetrahydro[1]
benzothieno[2,3-d]pyrimidin-4(3H )-one 7b
Yield: 79% as white solid; mp: 320 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 1.09 (3H, d, J 5.9 Hz, CH3), 1.32e
1.44 (1H, m, cyclohexane), 1.82e1.96 (2H, m, cyclohexane),
2.22e2.28 (1H, m, cyclohexane), 2.61e2.69 (2H, m, cyclo-
hexane), 2.97e3.06 (1H, m, cyclohexane), 5.24 (2H, s,
CNH2), 6.86 (2H, s, NNH2); 13C NMR (125 MHz, CDCl3):
d 21.8, 25.4, 29.5, 30.7, 32.8, 113.1, 124.7, 130.0, 153.7,
158.1, 164.4; IR (KBr): 3472, 3296, 3192, 2944, 2864,
1676, 1632, 1608, 1504, 1456, 1352, 1304, 1248, 1176,
1020, 944, 848, 768, 490 cmꢁ1; MS (m/z): 250 (Mþ). Anal.
Calcd for C11H14N4OS: C 52.78, H 5.64, N 22.38, S 12.81;
found: C 52.44, H 5.59, N 22.34, S 12.90.
4.3.1. 2-(1H-Tetrazol-1-yl)-4,5,6,7-tetrahydro-1-
benzothiophene-3-carboxylic acid 3a
Yield: 71% as white solid; mp: 178 ꢀC; 1H NMR (400 MHz,
DMSO-d6): d 1.74e1.80 (2H, m, CH2), 1.80e1.88 (2H, m,
CH2), 2.59e2.65 (2H, m, CH2), 2.75e2.80 (2H, m, CH2),
10.76 (1H, s, tetrazole), 11.62 (1H, s, COOH); 13C NMR
(125 MHz, CDCl3): d 21.8, 25.4, 29.5, 32.8, 113.1, 124.7,
130.0, 153.7, 158.1, 164.4; IR (KBr): 3552, 3098, 3010,
2940, 2842, 2312, 1688, 1664, 1576, 1512, 1436, 1368, 1280,
1200, 1088, 984, 880, 792, 656 cmꢁ1; MS (m/z): 250 (Mþ).
Anal. Calcd for C10H10N4O2S: C 47.99, H 4.03, N 22.39;
found: C 48.02, H 3.96, N 22.31.
4.4.3. 2,3-Diamino-3,5,6,7-tetrahydro-4H-cyclopenta
[4,5]thieno[2,3-d]pyrimidin-4-one 7c
Yield: 75% as white solid; mp: 313 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 2.30e2.40 (2H, m, CH2), 2.80
(2H, t, J 6.8 Hz, CH2), 2.86 (2H, t, J 6.8 Hz, CH2), 5.27
(2H, s, CNH2), 6.86 (2H, s, NNH2); 13C NMR (125 MHz,
CDCl3): d 25.4, 29.5, 32.9, 113.2, 124.9, 130.1, 153.4,
158.1, 164.3; IR (KBr): 3472, 3320, 3200, 2944, 2864,
1676, 1632, 1510, 1504, 1456, 1352, 1304, 1248, 1176, 944,
4.3.2. 6-Methyl-2-(1H-tetrazol-1-yl)-4,5,6,7-tetrahydro-1-
benzothiophene-3-carboxylic acid 3b
Yield: 64% as white solid; mp: 185 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 1.11 (3H, d, J 5.9 Hz, CH3), 1.38e
1.49 (1H, m, cyclohexane), 1.92e2.06 (2H, m, cyclohexane),
2.39e2.45 (1H, m, cyclohexane), 2.70e2.77 (1H, m, cyclo-
hexane), 2.89e3.06 (2H, m, cyclohexane), 10.32 (1H, s, tetra-
zole); 13C NMR (125 MHz, CDCl3): d 21.0, 26.7, 31.1, 33.3,
34.7, 123.5, 130.5, 135.2, 153.4, 158.4, 164.1; IR (KBr):
3552, 3098, 3020, 2940, 2842, 2300, 1676, 1664, 1576,
1512, 1440, 1368, 1280, 1200, 1096, 1024, 984, 880,
768 cmꢁ1
;
MS (m/z): 222 (Mþ). Anal. Calcd for
C9H10N4OS: C 48.63, H 4.53, N 25.21, S 14.43; found:
48.80, H 4.46, N 25.13, S 14.36.
4.4.4. 2,3-Diamino-5,6-dimethylthieno[2,3-d]pyrimidin-
4(3H )-one 7d
780 cmꢁ1
;
MS (m/z): 264 (Mþ). Anal. Calcd for
C11H12N4O2S: C 49.99, H 4.58, N 21.20; found: C 50.00, H
4.49, N 21.28.
Yield: 85% as white solid; mp: 285 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 2.26 (3H, s, CH3), 2.34 (3H, s,
CH3), 5.24 (2H, s, CNH2), 6.83 (2H, s, NNH2); 13C NMR
(125 MHz, CDCl3): d 12.7, 13.2, 114.2, 122.0, 128.1, 153.8,
158.4, 163.7; IR (KBr): 3472, 3304, 3240, 3152, 2950,
2864, 1680, 1616, 1512, 1460, 1368, 1336, 1252, 1196,
1020, 936, 864, 768 cmꢁ1; MS (m/z): 210 (Mþ). Anal. Calcd
for C8H10N4OS: C 45.70, H 4.79, N 26.65, S 15.25; found:
C 45.73, H 4.71, N 26.50, S 15.37.
4.4. General procedure for the synthesis of 2,3-diamino-
5-R1-6-R2-thieno[2,3-d]pyrimidin-4(3H )-ones 7aeh
A suspension of the appropriate alkyl 2-(1H-tetrazol-1-yl)-
thiophene-3-carboxylates 2aeh (0.01 mol) in 15 mL hydrazine
hydrate was heated at reflux for 7 h, then cooled and diluted

1434
N.T. Pokhodylo et al. / Tetrahedron 64 (2008) 1430e1434
4.4.5. 2,3-Diamino-5-phenylthieno[2,3-d]pyrimidin-4(3H )-
one 7e
1628, 1536, 1496, 1312, 1248, 1216, 1088, 1008, 940, 876,
768, 536, 496 cmꢁ1; MS (m/z): 293 (Mþ). Anal. Calcd for
C12H9ClN4OS: C 49.23, H 3.10, N 19.14, S 10.95; found: C
49.02, H 3.22, N 19.20, S 11.04.
Yield: 73% as white solid; mp: 227 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 5.23 (2H, s, CNH2), 6.79 (1H, s,
thiophene), 7.27e7.37 (3H, m, Ph), 7.49 (2H, d, J 6.8 Hz,
Ph); 13C NMR (125 MHz, CDCl3): d 111.8, 115.1, 127.5,
127.9, 129.5, 136.2, 138.7, 154.1, 157.7, 167.0; IR (KBr):
3490, 3390, 3296, 3264, 3010, 2860, 1680, 1636, 1548,
1488, 1332, 1304, 1176, 1096, 960, 872, 760, 576,
References and notes
1. Schmidt, B.; Schieffcr, B. J. Med. Chem. 2003, 46, 2261.
2. Bekhit, A. A.; El-Sayed, O. A.; Aboulmagd, E.; Park, J. Y. Eur. J. Med.
Chem. 2004, 39, 249.
486 cmꢁ1
;
MS (m/z): 258 (Mþ). Anal. Calcd for
C12H10N4OS: C 55.80, H 3.90, N 21.69, S 12.41; found: C
55.66, H 4.01, N 21.72, S 12.29.
3. Rajasekaran, A.; Thampi, P. P. Eur. J. Med. Chem. 2004, 39, 273.
4. Kozikowski, A. P.; Zhang, J.; Nan, F.; Petukhov, P. A.; Grajkowska, E.;
Wroblewski, J. T.; Yamamoto, T.; Bzdega, T.; Wroblewska, B.; Neale,
J. J. Med. Chem. 2004, 47, 1729.
5. Upadhayaya, R. S.; Jain, S.; Sinha, N.; Kishore, N.; Chandra, R.; Arora,
S. K. Eur. J. Med. Chem. 2004, 39, 579.
4.4.6. 2,3-Diamino-5-(4-methylphenyl)thieno[2,3-
d]pyrimidin-4(3H )-one 7f
Yield: 77% as white solid; mp: 252 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 2.35 (3H, s, CH3), 5.29 (2H, br s,
CNH2), 6.67 (1H, s, thiophene), 7.03 (2H, br s, NNH2), 7.11
(2H, d, J 7.2 Hz, C6H4), 7.37 (2H, d, J 7.2 Hz, C6H4); 13C
NMR (125 MHz, CDCl3): d 21.3, 111.9, 114.3, 128.4, 129.2,
133.7, 137.2, 139.0, 154.4, 158.8, 167.8; IR (KBr): 3496,
3392, 3368, 3272, 3104, 3048, 2888, 1680, 1636, 1616,
6. Faucher, A.-M.; White, P. W.; Brochu, C.; Grand-Maitre, C.; Rancourt, J.;
Fazal, G. J. Med. Chem. 2004, 47, 18.
7. Park, H.; Merz, K. M. J. Med. Chem. 2005, 48, 1630.
8. Bekhit, A. A.; El-Sayed, O. A.; Al-Allaf, T. A. K.; Aboul-Enein, H. Y.;
Kunhi, M.; Pulicat, S. M.; Al-Hussain, K.; Al-Khodairy, F.; Arif, J. Eur.
J. Med. Chem. 2004, 39, 499.
9. Biot, C.; Baver, H.; Schirmer, R. H.; Davioud-Charvet, E. J. Med. Chem.
2004, 47, 5972.
1552, 1496, 1320, 1296, 1248, 1184, 956, 880, 486 cmꢁ1
;
10. Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
MS (m/z): 272 (Mþ). Anal. Calcd for C13H12N4OS: C 57.34,
H 4.44, N 20.57, S 11.77; found: C 57.56, H 4.31, N 20.64,
S 11.71.
11. Schelenz, T.; Schafer, W. J. Prakt. Chem. 2000, 342, 91.
¨
12. Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka, T. J. Med.
Chem. 1996, 39, 5228.
13. Butler, R. N. Tetrazoles. Comprehensive Heterocyclic Chemistry II;
Pergamon: Oxford, 1996; Vol. 4, pp 621e678.
4.4.7. 2,3-Diamino-5-(4-fluorophenyl)thieno[2,3-
d]pyrimidin-4(3H )-one 7g
14. Grunert, M.; Weinberger, P.; Schweifer, J.; Hampel, C.; Stassen, A. F.;
Mcreiterand, K.; Linert, W. J. Mol. Struct. 2005, 733, 4113.
15. Palazzi, A.; Stagni, S.; Selva, S.; Monari, M. J. Organomet. Chem. 2003,
669, 135.
Yield: 69% as white solid; mp: 246 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 5.28 (2H, s, CNH2), 6.73 (1H, s,
thiophene), 7.02e7.11 (4H, m, NNH2þC6H4), 7.51 (2H, dd,
J 5.9, 8.8 Hz, C6H4); 13C NMR (125 MHz, CDCl3): d 111.6,
114.7, 131.4, 131.5, 132.6, 137.4, 154.1, 157.9, 162.0 (d,
JCF 242.5 Hz, 4-C C6H4), 167.3; IR (KBr): 3460, 3160,
3080, 3000, 1712, 1552, 1504, 1472, 1416, 1296, 1256,
1192, 944, 880, 796 cmꢁ1; MS (m/z): 276 (Mþ). Anal. Calcd
for C12H9FN4OS: C 52.17, H 3.28, N 20.28, S 11.61; found:
C 52.08, H 3.22, N 20.41, S 11.68.
16. Kim, Y.-J.; Kwak, Y.-S.; Lee, S.-W. J. Organomet. Chem. 2000, 603, 152.
17. Gupta, K.; Rim, C. Y.; Oh, C. H. Synlett 2004, 2227.
18. Gupta, A. K.; Song, C. H.; Oh, C. H. Tetrahedron Lett. 2004, 45, 4113.
19. Koldobskii, G. I. Russ. J. Org. Chem. 2006, 42, 469.
20. Grunert, C. M.; Weinberger, P.; Sehwcifer, J.; Hampel, C,; Stassen, A. F.;
Mereiter, K.; Linert, W. J. Mol. Struct. 2005, 733, 41.
21. Boland, Y.; Hertsens, P.; Marchand-Brynaert, J.; Garcia, Y. Synthesis
2006, 1504.
22. Vorobiov, A. N.; Gaponik, P. N.; Petrov, P. T.; Ivashkevich, O. A. Synthesis
2006, 1307.
23. El-Baih, F. E. M.; Al-Blowy, H. A. S.; Al-Hazimi, H. M. Molecules 2006,
11, 498.
4.4.8. 2,3-Diamino-5-(4-chlorophenyl)thieno[2,3-
d]pyrimidin-4(3H )-one 7h
24. Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar, R. H. Eur. J.
Med. Chem. 2003, 38, 89.
Yield: 88% as white solid; mp: 270 ꢀC; 1H NMR
(400 MHz, DMSO-d6): d 5.29 (2H, br s, CNH2), 6.77 (1H, s,
thiophene), 7.07 (2H, br s, NNH2), 7.33 (2H, d, J 7.6 Hz,
C6H4), 7.50 (2H, d, J 7.6 Hz, C6H4); 13C NMR (125 MHz,
CDCl3): d 111.5, 115.0, 127.8, 131.2, 132.3, 135.0, 137.1,
154.1, 157.9, 167.4; IR (KBr): 3416, 3380, 3096, 1672,
25. Modica, M.; Santagati, M.; Russo, F.; Selvaggini, C.; Cagnotto, A.; Men-
nini, T. Eur. J. Med. Chem. 2000, 35, 677.
26. Jennings, L. D.; Kincaid, S. L.; Wang, Y. D.; Krishnamurthy, G.; Beyer,
C. F.; Mginnis, J. P.; Miranda, M.; Discafani, C. M.; Rabindran, S. K.
Bioorg. Med. Chem. Lett. 2005, 15, 4731.
27. Modica, M.; Santagati, M.; Santagati, A. J. Heterocycl. Chem. 2001, 38,
973.