Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones

Article abstract of DOI:10.1016/j.tet.2009.01.086

New heterocyclic azides, ethyl 2-azido-4-R¹-5-R²-3-thiophenecarboxylates, were synthesized by diazotization of 2-aminothiophenes and subsequent treatment with sodium azide. The reactions of these heterocyclic azides with β-ketoesters

Full text of DOI:10.1016/j.tet.2009.01.086

Tetrahedron 65 (2009) 2678–2683
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Tetrahedron
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Synthesis of ethyl 4,5-disubstituted 2-azido-3-thiophenecarboxylates and use
in the synthesis of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones
*
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
a r t i c l e i n f o
a b s t r a c t
New heterocyclic azides, ethyl 2-azido-4-R1-5-R2-3-thiophenecarboxylates, were synthesized by di-
azotization of 2-aminothiophenes and subsequent treatment with sodium azide. The reactions of these
Article history:
Received 1 November 2008
Received in revised form 29 December 2008
Accepted 22 January 2009
heterocyclic azides with
b-ketoesters and activated acetonitriles were studied. The derivatives of
thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine, a new ring system, were prepared in high yields via an
anionic hetero-domino reaction.
Available online 29 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Triazole
Gewald 2-aminothiophenes
Thieno[3,2-e][1,2,3]triazolo[1,5-a]-
pyrimidine
Azides
Domino reaction
1. Introduction
with sodium azide are the main methods for the synthesis of such
heteroazides. Unfortunately, the difficulty in diazonium salts’
In our preceding article,1 the synthesis of tetrazole derivatives
from available Gewald 2-aminothiophenes was reported. It was
shown that such compounds have unexpected chemical properties
including cleavage of the tetrazole ring in the reaction with hy-
drazine. As a result, 2,3-diaminopyrimidines, which are not easily
available, were prepared. Such a transformation allows us to con-
tinue an investigation of the amino group modifications in alkyl 2-
aminothiophene-3-carboxylates. Moreover, the 1,2,3-triazole ring
has some similar properties to the tetrazole ring due to the iso-
structural fragment (N3), close geometry and the character of the
aromatic ring.2 From a practical point of view, triazole derivatives
exhibit diverse biological activity3 and their application in industry
and technology is being developed.4
In addition, it is of note that 1,2,3-triazoles are synthesized from
organic azides in most cases.5 Heterocyclic aromatic azides with
electron-deficient aromatic rings are most widely studied, since
such azides are synthesized by nucleophilic substitution of halogen
or another similar group by the azide ion. An electron-rich aromatic
ring is not suitable for such a reaction. Hence, diazotization of
amino derivatives and their conversion into azides by the reaction
preparation in some aminoheterocycles leads to certain restrictions
with this method.6
2. Results and discussion
In the present work, we describe diazotization of alkyl 2-
aminothiophene-3-carboxylates and their conversion into the
corresponding azides. Previously, diazotization of Gewald 2-ami-
nothiophenes was performed in concentrated hydrochloric7–9 and
sulfuric acids.10 In one paper,11 different conditions of diazotization
were discussed and the advantages of the use of sulfuric acid were
shown. The analysis of the articles cited above leads to the con-
clusion that due to the high reactivity and instability of thiophene
diazonium salts certain complications with the synthesis of azides
may appear. Taking into account this premise we prepared ethyl 2-
azido-5-R2-4-R1-3-thiophenecarboxylates from the corresponding
2-amino derivatives under various reaction conditions.
Diazotization of 4,5-disubstituted alkyl 2-aminothiophene-3-
carboxylates 1 in concentrated hydrochloric acid did not lead to the
formation of stable diazonium salts. Independent of the tempera-
ture (from ꢀ30 ꢁC to 5 ꢁC), there was a rapid cleavage of the di-
azonium salts or in some cases compounds 1 remained unreacted
after diazotization. Azide synthesis under such reaction conditions
and its extraction from the products of the cleavage were not
* Corresponding author. Tel.: þ380 322600396.
E-mail address: obushak@in.lviv.ua (M.D. Obushak).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.086

N.T. Pokhodylo et al. / Tetrahedron 65 (2009) 2678–2683
2679
possible. Instead, we prepared azides 2a–d in sulfuric acid. We
dissolved alkyl 2-aminothiophene-3-carboxylates 1a–d in con-
centrated sulfuric acid and added ice up to 40% acid solution. We
succeeded to get stable diazonium salts by further treatment of the
obtained solution with sodium nitrite. Their reaction with sodium
azide yielded the corresponding 2-azidothiophenes 2a–d (Scheme
1, Table 1).
It is well known that organic azides undergo base-catalyzed
condensation reactions with activated methylenic compounds.5
Generally, 1,2,3-triazoles form in such reactions except for some
cases when the reduction of azides to amines takes place.
We used commercially available alkyl b-oxopropanoates 3a–c as
reaction partners of ethyl 2-azido-3-thiophenecarboxylates 2a,b,d
(Scheme 3, Table 2).
R1
R2
R1
R2
OR5
COOEt
NH2
COOEt
N3
O
N
O
O
N
N
H SO , NaNO
1.
R1
R2
2
4
2
OEt
N3
O
O
MeONa
OR4
MeOH
2. NaN3
+
R1
OH
S
S
R3
R3
S
1 a-d
2 a-d
S
R2
3 a-c
Scheme 1.
2 a, b, d
4 a-g
Scheme 3.
Table 1
Azides 2a–d
Table 2
1-(3-Carboxythienyl-2)-1H-1,2,3-triazole-4-carboxylic acid 4a–g
2
R1
R2
Yield, %
a
b
c
Me
–(CH2)4–
Me
Me
Me
65
74
78
75
4
R1
R2
R3
R5
Yield, %
a
b
c
d
e
f
Me
–(CH2)4–
Me
Me
–(CH2)4–
Me
Me
Me
Me
Me
i-Pr
i-Pr
Ph
Me
H
H
H
H
65
72
75
81
83
77
85
Ac
CO2Et
d
COOH
Me
However, in the case of 4-arylthiophenes 1e–g, stable di-
azonium salts did not form under any of the tested reaction con-
ditions (Scheme 2).
Me
H
H
g
–(CH2)4–
Ph
When the solution of azides 2 was allowed to react with ethyl
COOEt
N3
Ar
COOEt
NH2
Ar
1.
H2SO4, NaNO2
NaN
acetoacetate or benzoylacetate in sodium methoxide the corre-
sponding 1,2,3-triazoles 4a–c,f,g precipitated in good yields from
the reaction medium. Reactions with methyl 4-methyl-3-oxo-
pentanoate resulted in the formation of triazoles 4d,e, which were
soluble in the reaction medium. For the reaction completion and
full hydrolysis of ester groups the reaction was heated under reflux
for 1 h; 2 equiv of base in water was needed for homogenization of
the reaction mixture. Afterwards, the mixture was boiled for one
more hour.
It is important to emphasize that compound 4a was isolated as
its monomethyl ester. Hydrolysis of the ester group in the triazole
ring occurred faster than in the thiophene one due to electron-
deficient character of the triazole ring. Therefore, different re-
activity of ester groups gives the opportunity to modify them
separately.
Aromatic azides, containing a neighbouring carboxylic or nitrile
group, were studied as reagents in domino reactions for construc-
tion of [1,2,3]triazolo[1,5-a]pyrimidine system.5 Although this type
of reaction was well described for the aromatic series, it was ap-
plied to heterocycles only in a few cases. On the other hand, it is
a versatile entry to annelated [1,2,3]triazolo[1,5-a]pyrimidines,
some of which are new heteropolycyclic systems with unstudied
properties. It makes such reactions promising for the synthesis of
new pharmaceutical substances. For instance, azides on pyrrole,13
indole,14 pyrazole,15 imidazole16 and 1,2,3-triazole17 series were
used for this type of domino reaction. Moreover, most of the articles
cited above reported interesting biological activity of annelated
[1,2,3]triazolo[1,5-a]pyrimidines. In addition, one example of use of
the thiophene derivatives in [1,2,3]triazolo[1,5-a]pyrimidine syn-
thesis was given.18 In the reaction of 3-azido-2-thio-
phenecarbaldehyde dimethyl acetal with substituted acetonitriles,
the derivatives of the thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-
5(4H)-one ring system were obtained. These compounds are iso-
mers of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-ones
discussed in the current work.
S
2.
S
3
2 e-g
1 e-g
Ar = Ph, p-MeC6H4, p-ClC6H4
Scheme 2.
The attempts to separate diazonium salts from the reaction
mixture and transform them into azides did not give a positive
result. In fact, the process of diazotization completes with the
precipitation of a black solid. We filtered the solid and found by TLC
that the precipitate was a mixture of more then five components. It
can be explained by appropriate competitive reactions. The free 5-
position in the thiophene ring was ready for attack by electrophiles,
such as diazonium or nitrous ions. Subsequently, compounds of
type I or II could be formed (Fig. 1). Similar behaviour of some 2-
aminothiophenes during the reaction of diazotization was men-
tioned in a number of articles.7,10
Ar
COOEt
NH2
COOEt
N
Ar
COOEt
NH2
Ar
O
N
N
S
I I
S
S
I
Figure 1.
2-Azidothiophenes 2a–d were separated and identified. They
were used in the reaction immediately after their formation be-
cause of their instability. Compounds 2a–d were cleaved after a few
hours at room temperature. It is also possible to assume that the
electron-rich thiophene ring decreases the stability of diazonium
salt and azide.
Similar 2-azidothiophene was previously described only in
a patent12 and was prepared by nucleophilic substitution of the
methanesulfonyl group in methyl 3-aryl-4-cyano-5-methane-
sulfonylthiophene-2-carboxylate. However, the reactions of such
azides have not been studied previously.
We found out that 2-azidothiophenes 2a–d reacted with
acetonitriles 5a–e in sodium methoxide methanol solution

2680
N.T. Pokhodylo et al. / Tetrahedron 65 (2009) 2678–2683
O
S
H
N
R3
O
O
R1
R2
OEt
H2N
R1
R2
MeONa
R1
R2
OEt
N3
N
N
+
R3
R3
N
MeOH
N
N
N
S
5 a-e
S
N
6 a-o
5
5a:
5b:
5c:
R = CN
R = MeNHCO
R = Ph
2 a-d
N
N
S
5
=
R5
=
5d: R5
5e:
5
S
Scheme 4.
(Scheme 4). The reaction was carried out using 1 equiv of sodium
methoxylate: it exhibited an appreciable exothermal effect and was
completed within 1–2 min. In general, the product of the reaction
formed immediately after mixing the reagents except for phenyl-
acetonitrile, which reacted slower. The polycyclic compounds 6a–o
were isolated in good yields (73–94%) (Table 3).
spectra (Scheme 5). Such a result is the consequence of the parallel
addition reaction of the nitrile group, activated by the electron-
deficient triazole ring, and methoxide anion.
δc
165.6 - 168.4
δc
109.0 - 112.7
O
S
δc
142.9 - 148.2
H
N
Table 3
Thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines 6a–o
N
R1
R2
R3
Yield, %
N
6
N
a
b
c
Me
Me
Me
Me
Me
Me
Me
Me
CN
83
88
75
91
δc
153.0 - 154.7
MeNHCO
Ph
Figure 2. Characteristic values of 13C NMR spectroscopic signals of thieno[3,2-e]-
[1,2,3]triazolo [1,5-a]pyrimidin-5(4H)-ones 6a–o.
d
Btha
N
e
Me
Me
94
Ph
S
f
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
C(]NH)OMe
MeNHCO
Ph
84
93
73
92
O
S
H
N
N
g
h
i
MeONa
MeOH
2 b
5 a
+
Bth
N
N
N
N
j
–(CH2)4–
Me
90
86
95
Ph
S
k
l
Ac
Ac
CN
δH
8.43
N
δC
162.8
O
Me
H
N
HN
Ph
S
OMe
m
n
Me
Me
COOEt
COOEt
CN
MeNHCO
89
82
δC
52.2
N
N
N
S
δC
124.8
N
6 f
o
Me
COOEt
94
Ph
S
Scheme 5. Synthesis and values of some NMR spectroscopic signals of compound 6f.
a
Bthd1,3-benzothiazol-2-yl.
As is obvious from the results, due to slight variations of the
experimental conditions, the method can be generally applied for
the synthesis of substituted thiophenes. In addition, it is important
to note that substituted thienopyrimidines are well known for their
diverse biological activity.19 Thus, our findings reveal a useful
synthetic approach giving access to new derivatives of this class to
be tested for biological activity.
The mechanism of such reactions includes two stages. The azido
group is supposed to attack the dipolarophile in the same way the
anion of methylene active acetonitrile does. The intermediate tri-
azole, obtained from 1,3-dipolar cycloaddition reactions, contained
amino group, which has a tendency to further react with the car-
boxylate function to provide the formation of the pyrimidine ring
(compounds 6a–o).
3. Conclusion
In order to obtain thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-
5(4H)-ones
6
from azides 2, 1,3-benzothiazol-2-yl- and (4-
Base-catalyzed cycloaddition reactions of new heterocyclic
azides with activated methylene compounds were studied. It was
shown that 1,2,3-triazole derivatives could be obtained by this
method. The application of 2-azidothiophenes in domino reactions
for the synthesis of the new ring system of thieno[3,2-e][1,2,3]tri-
azolo[1,5-a]pyrimidin-5-ones was also reported.
phenyl-1,3-thiazol-2-yl)-acetonitrile 5d,e were chosen as reactive
methylenic partners. Thus, they exhibited high reactivity, as
methylenic compounds for such anion domino reactions, for the
construction of [1,2,3]triazolo[1,5-a]pyrimidines system with het-
erocyclic substituents.
The structure of the polycyclic ring system was determined from
the NMR spectroscopic data. The range of carbon characteristic
signals in the heterocyclic skeleton of compounds 6 is shown in
Figure 2.
4. Experimental
4.1. General
It was also found that in the case of the reaction of azide 2b with
malononitrile 5a, compound 6f was isolated as a product of the
reaction and its structure was determined by mass and NMR
1H NMR spectra and 13C NMR spectra were recorded on a Varian
Mercury 400 instrument (400 MHz for 1H, 125 MHz for 13C). The 1H

N.T. Pokhodylo et al. / Tetrahedron 65 (2009) 2678–2683
2681
and 13C chemical shifts were reported in parts per million relative
to tetramethylsilane or deuterated solvent as an internal reference.
Mass spectra were run using Agilent 1100 series LC/MSD with an
API-ES/APCI ionization mode. Starting Gewald 2-aminothiophenes
1a–d,20 (1,3-benzothiazol-2-yl)-acetonitrile 5d21 and (4-phenyl-
1,3-thiazol-2-yl)-acetonitrile 5e22 were prepared according to the
procedures described in the literature. We used such abbreviations
in NMR spectra presentation: Tr¼triazole, Th¼thiophene and
Tz¼thiazole.
for C13H13N3O4S: C 50.81, H 4.26, N 13.67; found: C 50.97, H 4.34, N
13.48.
4.3.3. 5-(4-Carboxy-5-methyl-1H-1,2,3-triazol-1-yl)-3-methyl-2,4-
thiophenedicarboxylic acid 4c
Yield 2.33 g, 75%; white solid; mp: 204–205 ꢁC; IR (KBr) nmax
1702 (s, C]O), 1693 (s, C]O), 1660 (s, C]O) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
(125 MHz, DMSO-d6):
d
2.45(3H, s, Me), 2.72 (3H, s, Me); 13C NMR
10.1 (MeTr), 15.3 (MeTh), 128.8 (C), 133.1 (C),
d
137.5 (C), 140.7 (C), 142.8 (C), 144.5 (C), 159.2 (CO), 162.9 (CO), 163.3
(CO); MS (m/z): 312 (Mþþ1). Anal. Calcd for C11H9N3O6S: C 42.44, H
2.91, N 13.50; found: C 42.32, H 2.79, N 13.37.
4.2. General procedure for the synthesis of alkyl
2-azidothiophene-3-carboxylates 2a–d
4.3.4. 1-(3-Carboxy-4,5-dimethyl-2-thienyl)-5-isopropyl-1H-1,2,3-
triazole-4-carboxylic acid 4d
Appropriate 2-aminothiophene 1 (0.02 mol) was dissolved in
concentrated sulfuric acid (5 mL) and ice (15 g) was added. When
the mixture was cooled to 0 ꢁC, saturated sodium nitrite (1.73 g;
0.025 mol) aqueous solution was added keeping the temperature
below 5 ꢁC. After 10 min, resinous sediment (in case it was formed)
should be filtered. To the filtrate solution of the diazonium salt
sodium azide (1.3 g; 0.02 mol) in 5 mL of water was added drop-
wise. The solution was left for 15 min at room temperature and
azide was extracted by diethyl ether (3ꢂ10 mL). Ether was evapo-
rated in vacuo. Azides were used without subsequent cleaning: 2a,
yield 2.92 g, 65%; dark red oil; MS (m/z): 226 (Mþþ1); 2b, yield
3.71 g, 74%; dark red oil; MS (m/z): 252 (Mþþ1); 2c, yield 4.71 g,
78%; brown solid, mp: 61–62 ꢁC; MS (m/z): 284 (Mþþ1); 2d, yield
3.81 g, 75%; dark pink solid, mp: 34–35 ꢁC; MS (m/z): 254 (Mþþ1).
Identification of azides 2a–d was performed by chromatography–
mass spectrometry since they decomposed slowly during the
preparation of the analyzed samples.
Yield 2.50 g, 81%; white solid; mp: 191–192 ꢁC; IR (KBr) nmax
1718 (s, C]O), 1687 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
1.16 (6H, d, J 6.8 Hz, 2 Me), 2.22 (3H, s, Me), 2.23 (3H, s, Me), 2.98–
3.03 (1H, m, CHMe2), 12.60 (1H, s, COOH), 12.72 (1H, br s, COOH);
13C NMR (125 MHz, DMSO-d6):
12.6 (MeTh), 14.6 (MeTh), 18.9 (2
d
Mei-Pr), 37.0 (CHMe2), 114.8 (C), 123.7 (C), 123.7 (C), 130.0 (C), 144.5
(C), 158.6 (C), 166.0 (CO), 196.6 (CO); MS (m/z): 310 (Mþþ1). Anal.
Calcd for C13H15N3O4S: C 50.47, H 4.89, N 13.58; found: C 50.62, H
4.70, N 13.34.
4.3.5. 1-(3-Carboxy-4,5,6,7-tetrahydro-1-benzothien-2-yl)-5-
isopropyl-1H-1,2,3-triazole-4-carboxylic acid 4e
Yield 2.78 g, 83%; white solid; mp: 193–194 ꢁC; IR (KBr) nmax
1714 (s, C]O), 1691 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
1.16 (6H, d, J 6.8 Hz, 2Me), 1.72–1.82 (4H, m, CH2), 2.59–2.64 (2H,
m, CH2), 2.73–2.78 (2H, m, CH2), 2.98–3.03 (1H, m, CHMe2); 12.61
(1H, s, COOH), 12.63 (1H, br s, COOH); 13C NMR (125 MHz, DMSO-
4.3. General procedure for the synthesis of 1-(3-carboxy-
d6): d 18.9 (2 Me), 22.9 (CH2), 23.2 (CH2), 24.4 (CH2), 26.5 (CH2), 37.0
thienyl-2)-1H-1,2,3-triazole-4-carboxylic acids 4a–g
(CHMe2), 113.6 (C), 126.8 (C), 126.9 (C), 131.9 (C), 145.3 (C), 158.6 (C),
165.9 (CO), 196.6 (CO); MS (m/z): 336 (Mþþ1). Anal. Calcd for
C15H17N3O4S: C 53.72, H 5.11, N 12.53; found: C 53.51, H 5.27, N
12.44.
Sodium (0.23 g, 0.01 mol) was added to 20 mL of absolute
methanol.
b-Ketoester 3 (0.01 mol) and the appropriate azide 2
(0.01 mol) were slowly added (cooling by ice water) to the obtained
sodium methylate solution. The mixture was kept in ice water bath
for 30 min and then slowly heated under reflux for 1 h. The solid
sedimented. Hot water was added to dissolve the sediment (50 mL),
if necessary the solution of sodium hydroxide can be added to pH
11–12 and heated under reflux for 1 h. Hot solution was poured to
a 10 mL of concentrated HCl and left to be crystallized. The obtained
solid was filtered, washed with water twice and crystallized from
ethanol.
4.3.6. 1-(3-Carboxy-4,5-dimethyl-2-thienyl)-5-phenyl-1H-1,2,3-
triazole-4-carboxylic acid 4f
Yield 2.64 g, 77%; white solid; mp: 112–113 ꢁC; IR (KBr) nmax
1703 (s, C]O), 1686 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.22 (3H, s, Me), 2.33 (3H, s, Me), 7.32–7.42 (5H, m, Ph); 12.80 (1H,
br s, COOH); 13C NMR (125 MHz, DMSO-d6):
d
13.4 (MeTh), 13.9
(MeTh), 126.2 (C), 128.4 (CH), 128.7 (C), 129.6 (CH), 130.5 (CH), 132.8
(C), 133.3 (C), 135.1 (C), 137.1 (C), 143.5 (C), 163.0 (CO), 163.7 (CO);
MS (m/z): 344 (Mþþ1). Anal. Calcd for C16H13N3O4S: C 55.97, H 3.82,
N 12.24; found: C 55.79, H 3.94, N 12.38.
4.3.1. 1-[3-(Methoxycarbonyl)-4,5-dimethyl-2-thienyl]-5-methyl-
1H-1,2,3-triazole-4-carboxylic acid 4a
Yield 1.92 g, 65%; white solid; mp: 110–111 ꢁC; IR (KBr) nmax 1717
4.3.7. 1-(3-Carboxy-4,5,6,7-tetrahydro-1-benzothien-2-yl)-5-
phenyl-1H-1,2,3-triazole-4-carboxylic acid 4g
(s, C]O),1705 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.32
(3H, s, Me), 2.40 (3H, s, Me), 2.45 (3H, s, Me), 3.58 (3H, s, MeO); 13C
NMR (125 MHz, DMSO-d6): 10.0 (MeTr), 13.6 (MeTh), 14.0 (MeTh),
Yield 3.14 g, 85%; as a white solid; mp: 124–125 ꢁC; IR (KBr)
d
nmax 1701 (s, C]O), 1680 (s, C]O) cmꢀ1 1H NMR (400 MHz,
;
52.8 (OMe), 130.9 (C), 133.6 (C), 134.0 (C), 135.9 (C), 136.5 (C), 142.6
(C), 162.4 (CO), 162.9 (CO); MS (m/z): 296 (Mþþ1). Anal. Calcd for
C12H13N3O4S: C 48.80, H 4.44, N 14.23; found: C 48.61, H 4.57, N
14.16.
DMSO-d6):
d
1.72–1.84 (4H, m, CH2), 2.68–2.76 (4H, m, CH2), 7.32–
22.4 (CH2), 22.9
7.42 (5H, m, Ph); 13C NMR (125 MHz, DMSO-d6):
d
(CH2), 25.1 (CH2), 26.2 (CH2), 126.7 (C), 128.4 (CH), 129.7 (CH), 130.2
(C), 130.5 (CH), 132.5 (C), 132.8 (C), 135.5 (C), 137.3 (C), 143.5 (C),
163.0 (CO), 163.1 (CO); MS (m/z): 370 (Mþþ1). Anal. Calcd for
C18H15N3O4S: C 58.53, H 4.09, N 11.38; found: C 55.41, H 3.97,
N 11.31.
4.3.2. 1-(3-Carboxy-4,5,6,7-tetrahydro-1-benzothien-2-yl)-5-
methyl-1H-1,2,3-triazole-4-carboxylic acid 4b
Yield 2.21 g, 72%; white solid; mp: 147–148 ꢁC; IR (KBr) nmax 1715
(s, C]O), 1681 (s, C]O) cmꢀ1
d
;
1H NMR (400 MHz, DMSO-d6):
4.4. General procedure for the synthesis of thieno[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidines 6a–o
1.78–1.92 (4H, m, CH2), 2.41 (3H, s, Me), 2.78–2.87 (4H, m, CH2); 13
C
NMR (125 MHz, DMSO-d6): d 10.0 (Me), 22.4 (CH2), 22.9 (CH2), 25.1
(CH2), 26.3 (CH2), 130.4 (C), 134.7 (C), 135.8 (C), 136.4 (C), 138.1 (C),
To the solution of sodium methoxide (540 mg, 10.0 mmol) in dry
methanol (20 mL) substituted acetonitrile 5 (10.0 mmol) was
142.7 (C), 163.0 (CO), 163.3 (CO); MS (m/z): 308 (Mþþ1). Anal. Calcd

2682
N.T. Pokhodylo et al. / Tetrahedron 65 (2009) 2678–2683
added. To this solution 2-azidothiophene 2 (10.0 mmol) in dry
methanol (2 mL) was added dropwise and the solid started to
precipitate. The mixture was stirred for 24 h. The resulting sus-
pension was filtered and the solid product was washed with water
and methanol to give the corresponding thieno[3,2-e][1,2,3]tri-
azolo[1,5-a]pyrimidines 6a–o.
4.4.6. Methyl 5-oxo-4,5,6,7,8,9-hexahydro[1]benzothieno[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidine-3-carboximidoate 6f
Yield 2.54 g, 84%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3321
and 3225 (s, 2NH), 1653 (s, C]O), 1629 (s, C]NH) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
CH2), 2.94–3.00 (2H, m, CH2), 3.84 (3H, s, OMe), 8.43 (1H, s, NH);
13C NMR (125 MHz, DMSO-d6):
22.8 (CH2), 23.4 (CH2), 25.4
d 1.78–1.92 (4H, m, CH2), 2.64–2.70 (2H, m,
d
4.4.1. 6,7-Dimethyl-5-oxo-4,5-dihydrothieno[3,2-e][1,2,3]triazolo-
[1,5-a]pyrimidine-3-carbonitrile 6a
(CH2), 26.5 (CH2), 52.2 (MeO), 110.2 (5a-C), 121.6 (5b-C or 9a-C),
124.8 (3-C), 130.2 (5b-C or 9a-C), 145.6 (3a-C), 153.3 (10a-C), 162.8
(CNH), 165.6 (CO); MS (m/z): 304 (Mþþ1). Anal. Calcd for
C13H13N5O2S: C 51.47, H 4.32, N 23.09; found: C 51.60, H 4.21, N
23.17.
Yield 2.03 g, 83%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3325
(s, NH), 2214 (s, CN), 1650 (s, C]O) cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6):
DMSO-d6):
d
2.30 (3H, s, Me), 2.43 (3H, s, Me); 13C NMR (125 MHz,
13.4 (Me), 14.1 (Me), 103.2 (3-C), 111.8 (5a-C), 115.5
d
(CN), 122.7 (6-C or 7-C), 127.9 (6-C or 7-C), 148.2 (3a-C), 153.2 (8a-
C), 166.2 (CO); MS (m/z): 246 (Mþþ1). Anal. Calcd for C10H7N5OS: C
48.97, H 2.88, N 28.55; found: C 49.05, H 2.74, N 28.45.
4.4.7. N-Methyl-5-oxo-4,5,6,7,8,9-hexahydro[1]benzothieno-
[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine-3-carboxamide 6g
Yield 2.82 g, 93%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3356
and 3126 (s, 2NH), 1662 (s, C]O), 1637 (s, C]O) cmꢀ1 1H NMR
;
4.4.2. N,6,7-Trimethyl-5-oxo-4,5-dihydrothieno[3,2-e][1,2,3]-
triazolo[1,5-a]pyrimidine-3-carboxamide 6b
(400 MHz, DMSO-d6):
CH2), 2.96 (3H, d, 3J 4.9, CH3), 3.16–3.20 (2H, m, CH2), 8.01 (1H, q, 3J
4.9, NH); 13C NMR (125 MHz, DMSO-d6):
22.6 (CH2), 23.2 (CH2),
25.1 (Me), 25.8 (CH2), 26.3 (CH2), 110.0 (5a-C), 124.2 (5b-C or 9a-C),
124.7 (5b-C or 9a-C), 130.0 (3-C), 144.8 (3a-C), 153.0 (10a-C), 162.3
(CO), 166.0 (CO); MS (m/z): 304 (Mþþ1). Anal. Calcd for
C13H13N5O2S: C 51.47, H 4.32, N 23.09; found: C 51.35, H 4.19, N
22.93.
d 1.78–1.90 (4H, m, CH2), 2.63–2.69 (2H, m,
Yield 2.44 g, 88%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3320
d
and 3170 (s, 2NH), 1687 (s, C]O), 1661 (s, C]O) cmꢀ1
;
1H NMR
(400 MHz, DMSO-d6):
d, 3J 4.8, Me), 8.00 (1H, q, 3J 4.8, NH); 13C NMR (125 MHz, DMSO-
d6): 13.4 (Me), 14.2 (Me), 26.0 (NHMe), 111.1 (5a-C), 121.7 (6-C or
d 2.30 (3H, s, Me), 2.44 (3H, s, Me), 2.96 (3H,
d
7-C), 125.2 (3-C), 129.0 (6-C or 7-C), 144.9 (3a-C), 153.5 (8a-C),
162.3 (CO), 165.6 (CO); MS (m/z): 278 (Mþþ1). Anal. Calcd for
C11H11N5O2S: C 47.64, H 4.00, N 25.26; found: C 47.54, H 4.13,
N 25.32.
4.4.8. 3-Phenyl-6,7,8,9-tetrahydro[1]benzothieno[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one 6h
Yield 2.35 g, 73%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3310
4.4.3. 6,7-Dimethyl-3-phenylthieno[3,2-e][1,2,3]triazolo[1,5-
a]pyrimidin-5(4H)-one 6c
(s, NH), 1650 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 1.80–
1.93 (4H, m, CH2), 2.62–2.71 (2H, m, CH2), 2.97–3.03 (2H, m, CH2),
Yield 2.22 g, 75%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3305
7.13 (1H, t, 3J 7.8, 4-HPh), 7.37 (2H, t, 3J 7.8, 3,5-HPh), 8.36 (2H, d, 3J
(s, NH), 1658 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.31
7.8, 2,6-HPh); 13C NMR (125 MHz, DMSO-d6):
d 22.9 (CH2), 23.5
(3H, s, Me), 2.48 (3H, s, Me), 7.13 (1H, t, 3J 7.8, 4-HPh), 7.36 (2H, t, 3J
(CH2), 25.4 (CH2), 26.6 (CH2), 109.0 (5a-C), 123.9 (5b-C or 9a-C),
124.4 (CH), 125.7 (CH), 128.1 (5b-C or 9a-C), 129.0 (CH), 130.0 (3-C),
134.1 (CPh), 143.2 (3a-C), 153.6 (10a-C), 166.1 (CO); MS (m/z): 323
(Mþþ1). Anal. Calcd for C17H14N4OS: C 63.33, H 4.38, N 17.38;
found: C 63.45, H 4.27, N 17.51.
7.8, 3,5-HPh), 8.35 (2H, d, 3J 7.8, 2,6-HPh); 13C NMR (125 MHz,
DMSO-d6):
d 13.2 (Me), 14.0 (Me), 109.9 (5a-C), 120.8 (6-C or 7-C),
124.2 (CH), 125.5 (CH), 127.3 (3-C), 128.0 (6-C or 7-C), 128.8 (CH),
133.8 (CPh), 142.9 (3a-C), 153.7 (8a-C), 165.6 (CO); MS (m/z): 297
(Mþþ1). Anal. Calcd for C15H12N4OS: C 60.79, H 4.08, N 18.91;
found: C 60.49, H 4.20, N 18.82.
4.4.9. 3-(1,3-Benzothiazol-2-yl)-6,7,8,9-tetrahydro[1]benzothieno-
[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one 6i
4.4.4. 3-(1,3-Benzothiazol-2-yl)-6,7-dimethylthieno[3,2-e][1,2,3]-
triazolo[1,5-a]pyrimidin-5(4H)-one 6d
Yield 3.49 g, 92%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3352
(s, NH), 1678 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 1.79–
Yield 3.21 g, 91%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3390
1.93 (4H, m, CH2), 2.66–2.73 (2H, m, CH2), 2.97–3.04 (2H, m, CH2),
7.29 (1H, t, 3J 7.8, 5-HBth), 7.41 (1H, t, 3J 7.8, 6-HBth), 7.94 (1H, d, 3J 7.8,
7-HBth), 7.97 (1H, d, 3J 7.8, 4-HBth); 13C NMR (125 MHz, DMSO-d6):
(s, NH), 1677 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.34
(3H, s, Me), 2.48 (3H, s, Me), 7.28 (1H, t, 3J 7.8, 5-HBtz), 7.41 (1H, t, 3J
7.8, 6-HBtz), 7.93 (2H, d, 3J 7.8, 7-HBtz), 7.97 (2H, d, 3J 7.8, 4-HBtz); 13
NMR (125 MHz, DMSO-d6): 13.4 (Me), 14.2 (Me), 111.7 (5a-C),
C
d 22.6 (CH2), 23.3 (CH2), 25.2 (CH2), 26.3 (CH2), 110.5 (5a-C), 122.1
d
(CH), 122.2 (5b-C or 9a-C), 124.3 (CH), 125.3 (3-C), 125.4 (CH), 126.3
(CH), 130.0 (5b-C or 9a-C), 134.0 (7a-CBth), 143.7 (3a-C), 153.1 (10a-
C),154.3 (3a-CBth), 160.1 (2-CBth), 166.6 (CO); MS (m/z): 380 (Mþþ1).
Anal. Calcd for C18H13N5OS2: C 56.97, H 3.45, N 18.46; found: C
57.22, H 3.15, N 18.67.
122.2 (6-C or 7-C), 122.2 (CH), 122.4 (CH), 124.5 (CH), 125.4 (3-C),
126.6 (CH), 127.9 (6-C or 7-C), 134.0 (7a-CBth), 143.9 (3a-C), 153.4
(8a-C), 154.5(3a-CBth), 160.2 (2-CBth), 165.6 (CO); MS (m/z): 354
(Mþþ1). Anal. Calcd for C16H11N5OS2: C 54.37, H 3.14, N 19.82;
found: C 54.46, H 3.01, N 19.99.
4.4.10. 3-(4-Phenyl-1,3-thiazol-2-yl)-6,7,8,9-tetrahydro[1]-
benzothieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one 6j
Yield 3.64 g, 90%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3381
4.4.5. 6,7-Dimethyl-3-(4-phenyl-1,3-thiazol-2-yl)thieno[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one 6e
Yield 3.56 g, 94%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3384
(s, NH), 1646 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d 1.82–
(s, NH), 1680 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d
2.32
1.94 (4H, m, CH2), 2.67–2.74 (2H, m, CH2), 2.98–3.05 (2H, m, CH2),
(3H, s, Me), 2.48 (3H, s, Me), 7.29 (1H, t, 3J 7.8, 4-HPh), 7.42 (2H, t, 3J
7.30 (1H, t, 3J 7.8, 4-HPh), 7.43 (2H, t, 3J 7.8, 3,5-HPh), 7.72 (1H, s, HTz),
7.8, 3,5-HPh), 7.72 (1H, s, HTz), 8.04 (2H, d, 3J 7.8, 2,6-HPh); 13C NMR
8.06 (2H, d, 3J 7.8, 2,6-HPh); 13C NMR (125 MHz, DMSO-d6):
d 22.6
(125 MHz, DMSO-d6):
d
13.5 (Me),14.2 (Me),111.1 (5a-C),112.1 (CH),
(CH2), 23.3 (CH2), 25.2 (CH2), 26.3 (CH2), 111.0 (5a-C), 111.9 (CH),
124.8 (5b-C or 9a-C), 125.7 (3-C), 126.6 (CH), 128.2 (5b-C or 9a-C),
129.1 (CH), 130.0 (CPh), 135.1 (4-CTz), 143.4 (3a-C), 153.2 (10a-C),
154.4 (5-CTz), 159.6 (2-CTz), 166.4 (CO); MS (m/z): 406 (Mþþ1). Anal.
Calcd for C20H15N5OS2: C 59.24, H 3.73, N 17.27; found: C 59.43, H
3.70, N 17.42.
121.7 (6-C or 7-C), 125.4 (3-C), 126.8 (CH), 127.9 (6-C or 7-C), 129.4
(CH), 129.4 (CPh), 134.0 (4-CTz), 143.6 (3a-C), 153.4 (8a-C), 154.5 (5-
CTz), 159.7 (2-CTz), 166.0 (CO); MS (m/z): 380 (Mþþ1). Anal. Calcd
for C18H13N5OS2: C 56.97, H 3.45, N 18.46; found: C 56.82, H 3.29, N
18.31.

N.T. Pokhodylo et al. / Tetrahedron 65 (2009) 2678–2683
2683
4.4.11. 7-Acetyl-6-methyl-5-oxo-4,5-dihydrothieno[3,2-e][1,2,3]-
triazolo[1,5-a]pyrimidine-3-carbonitrile 6k
(3-C), 126.8 (CH), 128.3 (CPh), 129.4 (CH), 135.2 (4-CTz), 144.4 (3a-C),
145.8 (7-C), 154.3 (8a-C), 154.7 (5-CTz), 159.3 (2-CTz), 163.2 (CO),
167.9 (CO); MS (m/z): 438 (Mþþ1). Anal. Calcd for C20H15N5O3S2: C
54.91, H 3.46, N 16.01; found: C 54.95, H 3.32, N 16.15.
Yield 2.35 g, 86%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3312
(s, NH), 2220 (s, CN), 1705 (s, C]O), 1635 (s, C]O) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
(125 MHz, DMSO-d6):
d
2.46 (3H, s, Me), 2.92 (3H, s, Ac); 13C NMR
16.2 (Me), 30.7 (MeCO), 104.0 (3-C), 112.8
d
(5a-C),114.7 (CN),127.7 (6-C),143.2 (3a-C), 149.4 (7-C), 154.0 (8a-C),
168.6 (CO), 191.3 (COAc); MS (m/z): 274 (Mþþ1). Anal. Calcd for
C11H7N5O2S: C 48.35, H 2.58, N 25.63; found: C 48.17, H 2.40, N
25.78.
References and notes
1. Pokhodylo, N. T.; Matiychuk, V. S.; Obushak, M. D. Tetrahedron 2008, 64, 1430.
2. Bean, G. P. J. Org. Chem. 1998, 63, 2497; Rauhut, G. Advances in Heterocyclic
Chemistry; 2001; Vol. 81, pp 28–32.
3. Fass, R. J.; Prior, R. B. Curr. Ther. Res. 1978, 24, 352; Bohm, R.; Karow, C. Pharmazie
1981, 36, 243; Portmann, R.; Hofmeier, U. C.; Burkhard, A.; Scherrer, W.; Sze-
lagiewicz, M.; WO 98/56773; Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.;
De Clercq, E.; Perno, C.-F.; Karlsson, A.; Balzarini, J.; Camarasa, M. J. J. Med. Chem.
1994, 37, 4185; Olesen, P. H.; Sørensen, A. R.; Ursø, B.; Kurtzhals, P.; Bowler, A.
N.; Ehrbar, U.; Hansen, B. F. J. Med. Chem. 2003, 46, 3333; Bascal, Z.; Holden-Dye,
L.; Willis, R. J.; Smith, S. W. G.; Walker, R. J. Parasitology 1996, 112, 253; Biagi, G.;
Giorgi, I.; Livi, O.; Lucacchini, A.; Martini, C.; Scartoni, V. J. Pharm. Sci. 1993, 82,
893; Moltzen, E. K.; Pedersen, H.; Bøgesø, K. P.; Meier, E.; Frederiksen, K.;
Sanchez, C.; Lembøl, K. L. J. Med. Chem. 1994, 37, 4085; Chakrabarti, J. K.; Hotten,
T. M.; Pullar, I. A.; Steggles, D. J. J. Med. Chem. 1989, 32, 2375; Sanghvi, Y. S.;
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Robins, R. K.; Revankar, G. R. J. Med. Chem. 1990, 33, 336; Buckle, D. R.; Rockell,
C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986, 29, 2262; Hupe, D. J.; Boltz, R.;
Cohen, C. J.; Felix, J.; Ham, E.; Miller, D.; Soderman, D.; Van Skiver, D. J. Biol.
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4. Boddy, I. K.; Briggs, G. G.; Harrison, R. P.; Jones, T. H.; O’Mahony, M. J.; Marlow,
I. D.; Roberts, B. G.; Willis, R. J.; Bardsley, R.; Reid, J. Pestic. Sci. 1996, 48, 189;
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4.4.12. 7-Acetyl-6-methyl-3-(4-phenyl-1,3-thiazol-2-yl)thieno-
[3,2-e][1,2,3]triazolo[1,5-a]pyrimidin-5(4H)-one 6l
Yield 3.87 g, 95%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3338
(s, NH), 1718 (s, C]O), 1631 (s, C]O) cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6):
HPh), 7.43 (2H, t, 3J 7.8, 3,5-HPh), 7.76 (1H, s, HTz), 8.06 (2H, d, 3J 7.8,
2,6-HPh); 13C NMR (125 MHz, DMSO-d6):
16.2 (Me), 30.7 (MeCO),
d
2.48 (3H, s, Me), 2.97 (3H, s, Ac), 7.30 (1H, t, 3J 7.8, 4-
d
112.2 (5a-C), 112.5 (CH), 126.2 (3-C), 126.6 (CH), 126.8 (6-C), 128.3
(CPh), 129.2 (CH), 135.0 (4-CTz), 143.8 (3a-C), 144.2 (7-C), 154.6 (8a-
C), 154.6 (5-CTz), 159.1 (2-CTz), 168.0 (CO), 191.2 (COAc); MS (m/z):
408 (Mþþ1). Anal. Calcd for C19H13N5O2S2: C 56.00, H 3.22, N 17.19;
found: C 56.09, H 3.07, N 17.11.
4.4.13. Ethyl 3-cyano-6-methyl-5-oxo-4,5-dihydrothieno[3,2-e]-
[1,2,3]triazolo[1,5-a]pyrimidine-7-carboxylate 6m
Yield 2.70 g, 89%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3303
(s, NH), 2225 (s, CN), 1720 (s, C]O), 1672 (s, C]O) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6):
d
1.35 (3H, t, 3J 7.2, Me), 2.88 (3H, s, Me), 4.26
14.7 (Me), 15.7
(2H, q, 3J 7.2, CH2); 13C NMR (125 MHz, DMSO-d6):
d
(Me), 60.9 (CH2), 103.9 (3-C), 112.4 (5a-C), 114.7 (CN), 115.2 (6-C),
145.1 (3a-C), 149.4 (7-C), 153.6 (8a-C), 162.7 (CO), 168.4 (CO); MS
(m/z): 304 (Mþþ1). Anal. Calcd for C12H9N5O3S: C 47.52, H 2.99, N
23.09; found: C 47.33, H 2.84, N 23.00.
5. Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Rev. 2005, 74, 339.
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ꢀ
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phorus, Sulfur, Silicon Relat. Elem. 2003, 178, 1667.
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nandez, M. C.; Hornback, W. J.; Jimenez-Aguado, A. M.; Tromiczak, E. G.; Wu, Z.;
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J. Heterocycl. Chem. 2000, 37, 747; Lauria, A.; Diana, P.; Barraja, P.; Montalbano,
A.; Cirrincione, G.; Dattolo, G.; Almerico, A. M. Tetrahedron 2002, 58, 9723.
14. Lauria, A.; Patella, C.; Diana, P.; Barraja, P.; Montalbano, A.; Cirrincione, G.;
Dattolo, G.; Almerico, A. M. Heterocycles 2003, 60, 2669.
15. Khan, M. A.; Freitas, A. C. C. J. Heterocycl. Chem. 1980, 17, 1603.
16. Freitas, A. P.; Proenca, M. F. J. R. P.; Booth, B. L. J. Heterocycl. Chem. 1995, 32, 451.
17. L’abbe, G.; Godts, F.; Toppet, S. Bull. Soc. Chim. Belg. 1985, 94, 441; L’abbe, G.;
Godts, F.; Toppet, S. J. Chem. Soc., Chem. Commun. 1985, 589.
4.4.14. Ethyl 6-methyl-3-[(methylamino)carbonyl]-5-oxo-4,5-
dihydrothieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine-7-
carboxylate 6n
Yield 2.75 g, 82%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3320
and 3117 (s, 2NH), 1730 (s, C]O), 1690 (s, C]O), 1639 (s,
C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-d6): 1.35 (3H, t, 3J 7.2, Me),
d
2.89 (3H, s, Me), 2.94 (3H, d, 3J 4.8, MeN), 4.26 (2H, q, 3J 7.2, CH2),
7.99 (1H, q, 3J 4.8, NH); 13C NMR (125 MHz, DMSO-d6):
15.0 (Me),
d
16.1 (Me), 26.1 (MeN), 61.0 (CH2), 112.0 (5a-C), 114.5 (6-C), 125.0 (3-
C), 145.6 (3a-C), 145.8 (7-C), 154.2 (8a-C), 162.3 (CO), 162.7 (CO),
167.9 (CO); MS (m/z): 336 (Mþþ1). Anal. Calcd for C13H13N5O4S: C
46.56, H 3.91, N 20.88; found: C 46.70, H 3.79, N 20.75.
4.4.15. Ethyl 6-methyl-5-oxo-3-(4-phenyl-1,3-thiazol-2-yl)-4,5-
dihydrothieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine-7-
carboxylate 6o
18. Westerlund, C. J. Heterocycl. Chem. 1980, 17, 1765.
19. El-Baih, F. E. M.; Al-Blowy, H. A. S.; Al-Hazimi, H. M. Molecules 2006, 11, 498;
Chambhare, R. V.; Khadse, B. G.; Bobde, A. S.; Bahekar, R. H. Eur. J. Med. Chem.
2003, 38, 89; Modica, M.; Santagati, M.; Russo, F.; Selvaggini, C.; Cagnotto, A.;
Mennini, T. Eur. J. Med. Chem. 2000, 35, 677; 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.
20. Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966, 99, 94.
21. Saito, K.; Kambe, S.; Nakano, Y. Synthesis 1983, 210.
22. Volovenko, Y. M.; Resnyanska, E. V.; Tverdokhlebov, A. V. Collect. Czech. Chem.
Commun. 2002, 67, 365.
Yield 4.11 g, 94%; white solid; mp: >300 ꢁC; IR (KBr) nmax 3344 (s,
NH),1720 (s, C]O),1651 (s, C]O) cmꢀ1; 1H NMR (400 MHz, DMSO-
d6):
7.30 (1H, t, 3J 7.8, 4-HPh), 7.43 (2H, t, 3J 7.8, 3,5-HPh), 7.76 (1H, s, HTz),
8.06 (2H, d, 3J 7.8, 2,6-HPh); 13C NMR (125 MHz, DMSO-d6):
15.0
(Me),16.2 (Me), 61.0 (CH2),112.0 (CH),112.7 (5a-C),114.3 (6-C),126.3
d
1.37 (3H, t, 3J 7.2, Me), 2.94 (3H, s, Me), 4.27 (2H, q, 3J 7.2, CH2),
d