Novel selected tandem transformations of the amino and carbonyl/nitrile groups in the gewald thiophenes

Article abstract of DOI:10.1080/10426500903496739

Novel transformations of the amino and carbonyl/nitrile groups in the Gewald thiophenes were studied for thienopyrimidine synthesis. It was found that 2-amino-thiophene-3-carboxamides and ethyl 2-(acetylamino)-4,5,6,7-tetrahydro- 1-benzothiophene-3-carbo-

Full text of DOI:10.1080/10426500903496739

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Novel Selected Tandem Transformations
of the Amino and Carbonyl/Nitrile
Groups in the Gewald Thiophenes
Nazariy T. Pokhodylo a , Olga Ya. Shyyka a , Roman D. Savka a &
Mykola D. Obushak a
a Department of Organic Chemistry, Ivan Franko National University
of Lviv, Lviv, Ukraine
Version of record first published: 24 Sep 2010.
To cite this article: Nazariy T. Pokhodylo , Olga Ya. Shyyka , Roman D. Savka & Mykola D. Obushak
(2010): Novel Selected Tandem Transformations of the Amino and Carbonyl/Nitrile Groups in the
Gewald Thiophenes, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:10, 2092-2100
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Phosphorus, Sulfur, and Silicon, 185:2092–2100, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903496739
NOVEL SELECTED TANDEM TRANSFORMATIONS
OF THE AMINO AND CARBONYL/NITRILE GROUPS
IN THE GEWALD THIOPHENES
Nazariy T. Pokhodylo, Olga Ya. Shyyka, Roman D. Savka,
and Mykola D. Obushak
Department of Organic Chemistry, Ivan Franko National University of Lviv,
Lviv, Ukraine
Novel transformations of the amino and carbonyl/nitrile groups in the Gewald thiophenes
were studied for thienopyrimidine synthesis. It was found that 2-amino-thiophene-3-
carboxamides and ethyl 2-(acetylamino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carbo-
xylate did not yield tetrazole derivatives, neither in the reaction with triethyl orthoformate
and sodium azide, nor in the reaction with phosphorus oxychloride and sodium azide,
correspondingly. On the contrary, derivatives of thieno[2,3-d]pyrimidin-4(3H)-one and
thieno[2,3-d][1,3]oxazin-4-one were isolated. New 2-azidothiophenes [2-azido-4,5,6,7-tetra
hydro-1-benzothiophene-3-carbonitrile and 2-azido-4,5,6,7-tetrahydro-1-benzothiophen-3-
yl(phenyl)methanone] were synthesized and used in anionic domino reactions with activated
acetonitriles to yield thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines and/or 2-(5-amino-
1H-1,2,3-triazol-1-yl)thiophenes. Finally, a new ring system of thieno[3,2-e]pyrazolo[1,5-
a]pyrimidine was synthesized via a domino reaction of ethyl 2-[(2Z)-2-(1-chloro-2-
ethoxy-2-oxoethylidene)hydrazino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
with activated acetonitriles.
Keywords Domino reactions; thienopyrimidines, thieno[3,2-e]pyrazolo[1,5-a]pyrimidines;
thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines
INTRODUCTION
The derivatives of condensed pyrimidines have been of great interest for many years
due to the fact that many bicyclic compounds containing the pyrimidine ring play an im-
portant role in biological processes. Thienopyrimidines, as one of such ring systems, are
a focus of research because of their biological activity.1 Recently, thieno[2,3-d]pyrimidin-
4-one derivatives have been discovered as moderately potent inhibitors of TGase 2 (tissue
transglutaminase),2 novel selective and potent α1D antagonists,3 cytotoxic agents selective
for p21-deficient cells,4 highly potent dual 5-HT1A and 5-HT1B antagonists as potential an-
tidepressant drugs,5 and necroptosis inhibitors, and they have shown equipotent analgesic
and anti-inflammatory activities.7 Some derivatives of thienopyrimidines have also found
Received 18 October 2009; accepted 18 November 2009.
Address correspondence to Nazariy T. Pokhodylo, Department of Organic Chemistry, Ivan Franko National
University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine. E-mail: pokhodylo@gmail.com
2092

TANDEM TRANSFORMATIONS IN GEWALD THIOPHENES
2093
application in technical aims—as novel ionophores in plasticized poly(vinyl chloride) ma-
trix membrane sensors for uranyl ions8 and as fluorescent dyes for biomolecule detection.9
This is probably due to the fact that many compounds can be readily prepared from a
diverse array of the Gewald 2-aminothiophenes via tandem transformation of the amino
and carbonyl/nitrile groups providing annulation of new ring systems containing nitrogen
heterocycles.
We are currently interested in the novel application of the amino group in the Gewald
2-aminothiophenes, which opens access for design of the thienopyrimidine framework.10,11
In our previous articles, we described transformation of the animo group in alkyl 2-
aminothiophene-3-carboxylates I into the tetrazole ring II and the azido moiety III, and their
utilization in the synthesis of hardly available 2,3-diaminopyrimidines IV and a new ring
system of thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidines V, correspondingly (Scheme 1).
Such reactions have received attention because of their application in the synthesis of new
nitrogen-containing heterocyclic compounds in a readily synthetic protocol.
R1
R1
COOEt
COOEt
R2
N
R2
N
N
N3
S
S
N
II
III
R1
R2
COOEt
NH2
R1
O
N
O
S
R1
R2
H
NH2
NH2
N
R2
N
I
R3
S
N
N
S
N
IV
V
Scheme 1
RESULTS AND DISCUSSION
Due to the importance of thienopyrimidines and our interest in the development of
a synthetic path for their preparation, in this article we report the application of 3-(cyano,
carbamoyl and phenylcarbonyl)-2-aminothiophenes in the above mentioned approaches
and the chemoselectivity problems accompanying them.
First of all, we used cyano, carbamoyl derivatives in the reaction with triethyl ortho-
formate and sodium azide for tetrazole derivative synthesis. It was found that replacement
of the carboxylic group by the carbamoyl one did not yield the tetrazole ring due to the con-
current formation of the pyrimidine ring (Scheme 2). The internal nucleophile (a nitrogen
atom in the amide group) placed near the reaction center (an azomethine carbon atom in
intermediate A) attacks it faster than azide ion. Variation of the temperature modes of this
reaction does not lead to tetrazole compounds. Formation of the pyrimidine ring is easily
1
estimated via H NMR spectroscopic analyses. The characteristic 2-H proton signal was
found at 7.83 ppm instead of the expected tetrazole one at approximately 10 ppm.

2094
N. T. POKHODYLO ET AL.
O
NH2
R1
R2
N
N
N
N
O
S
NH2
O
NaN3
CH(OEt)3
2
R1
NH2
NH2
OEt
R1
R2
N
O
AcOH
R2
S
R1
R2
H
N
S
A
1a, b
N
1a, 3a; R1 = R2 = H
S
3a, b
1
2
-(CH ) -
1b, 3b; R + R =
2
4
Scheme 2
N
N
N
OEt
N
N
N
N
S
N
NaN3
CH(OEt)3
S
5
B
N
N
S
N
S
N
NH
AcOH
N
NH2
N
H
4
N
N
+
H
H
S
NH2
O
6
7
Scheme 3
Furthermore, in case of the compound 4 under the same conditions, 1,3-dipolar
cycloaddition of the cyano group with azide ion occurred more rapidly than the formation
of intermediate B (Scheme 3). As a result, 5-substituted tetrazoles 6 and 7 were extracted
from the reaction mixture. Obviously, formation of the electron-deficient tetrazole ring
decreases reactivity of the amino group, which is proven by low yields of the compound
7. It is noteworthy that alkyl 2-aminothiophene-3-carboxylates gave tetrazole derivatives
(type 5) in approximately 80% yields.10
Unexpectedly the reaction occurred when ethyl 2-(acetylamino)thiophene-3-
carboxylates were used for the synthesis of 1,5-disubstitutied tetrazole derivatives by the
one-pot reaction with phosphorus oxychloride and sodium azide (Scheme 4).12 It is likely
that a concurrent reaction involving the carboxylate moiety proceeded in the same manner,
as in case of the compound 3. Closure of intermolecular reaction centers in intermediate
C provided oxazinone derivative formation. In addition, the reaction was accompanied by
isolation of tarry products, which complicate separation of the product 10.
Afterwards we decided to explore the feasibility of the synthesis of 2-azidothiophenes
and their application in the thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine system prepara-
tion by anionic domino reactions. New azides 11 and 16 were obtained by the diazotization
of amines 4 and 15 with sodium nitrite in sulfuric acid, followed by treatment with sodium
azide. In case of the compound 1b, its diazotization led to intermolecular cyclization of
diazonium salt, yielding thieno[2,3-d]-1,2,3-triazine, as described by Santer and Deinham-
mer.13 Attempts to transform it into an azide did not give a positive result. Moreover, yields

TANDEM TRANSFORMATIONS IN GEWALD THIOPHENES
2095
O
OEt
N
N
N
N
O
O
1)
MeCOCl
Et3N
dioxane
S
OEt
OEt
N
OPOCl2
Me
Me
9
NH2
O
NaN
2)
S
O
N
3
S
Me
POCl3
MeCN
C
8
S
10
Scheme 4
of azides 11 and 16 were poorer than those of ethyl 2-azido-3-thiophenecarboxylates de-
scribed in Pokhodylo et al.11 Azides 11 and 16 were allowed to react with propanedinitrile
12a and 1,3-benzothiazol-2-ylacetonitrile 12b, which were selected due to the fact that they
exhibited high reactivity in such reactions.11 Under these conditions, the cycloaddition reac-
tion proceeded smoothly to completion at room temperature, and triazoles were isolated in
good yields and high purity after simple filtration. However, domino reaction occurred sat-
isfactorily in case of the compound 13a. On the contrary, 1,3-benzothiazol-2-ylacetonitrile
12b reacted with azide 11 to form thieno[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine 13b as a
H2N
N
NCCH2CN
N
N
N
NaNO2
H2SO4
12a
N
N
N
MeONa
MeOH
S
NaN3
S
S
NH2
N3
4
11
13a
MeONa
MeOH
BthCH2CN
12b
N
NH2
N
N
N
N
N
N
+
S
N
N
S
S
S
NH2
N
18 %
73 %
14
13b
O
O
O
NaNO2
H2SO4
BthCH2CN
N
N
12b
N
N3
N
MeONa
MeOH
NaN3
NH2
S
S
S
S
NH2
16
15
17
N
S
N
N
N
N
S
18
Scheme 5

2096
N. T. POKHODYLO ET AL.
minor product at 18% yield and noncyclic aminotriazole 14 at 73% yield, respectively.
Furthermore, aminotriazole 17, instead of the expected thieno[3,2-e][1,2,3]triazolo[1,5-
a]pyrimidine 18, was isolated in the reaction of azide 16. Our attempts to cyclize the
compound 17 into pyrimidine were unsuccessful. This is possibly due to weak reactivity
and a sterically shielded carbonyl group. Moreover, low solvation of compounds 13 and 17
complicated their further transformations (Scheme 5).
As a continuation of our interest in the synthesis of novel polycyclic thienopyrimidine
systems, one-pot synthesis of the title thieno[3,2-e]pyrazolo[1,5-a]pyrimidine compounds
via reaction of hydrazonoyl halides 19 with activated acetonitriles was studied. Such an
approach has been used previously for construction of pyrazolo[1,5-a]quinazoline by Ev-
dokimoff.14 By the coupling of ethyl 2-chloro-3-oxobutanoate with the diazotized ary-
lamine 8 in NaOAc-buffered solution of EtOH, hydrazonoyl chloride 19 was synthesized
(Scheme 6). Treatment of hydrazonoyl chloride 19 with ethyl cyanoacetate, propanedini-
trile, or 1,3-benzothiazol-2-ylacetonitrile in ethanolic sodium ethoxide solution at room
temperature afforded products 20a–с, respectively. Compound 20c without isolation un-
derwent hydrolysis to form dicarboxylic acid 21 in moderate yields. The structures of the
isolated products were established by analytical and spectroscopic data.
O
H
O
O
N
O
OEt
R
OEt RCH2CN
OEt
NH2
NaNO2
H2SO4
N
12 a-c
N
N
Cl
COOEt
N
S
H
EtONa
EtOH
NaOAc
S
S
20 a-c
AcCHClCOOEt
EtOH
19
8
R=COOEt
H2O
O
H
N
COOH
COOH
12, 20a; R = CN
12, 20b; R = Bth
N
N
S
12, 20c; R = COOEt
21
Scheme 6
In conclusion, having established some chemical modifications of the Gewald 2-
aminothiophenes, we determined the scope of their synthetic application in various
thienopyrimidines preparation.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 400 instrument (400 MHz for
1H). The 1H 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. Compounds 1b, 4, 8, and 15 were
prepared according to the method of Gewald et al.15
Reaction Conditions for Preparation of Compounds 3a,b and Mixtures
6 and 7
A suspension of 5 mmol of the required thiophene 1a,b or 4, triethyl orthoformate
(3.79 mL, 0.023 mol), and sodium azide (0.39 g, 0.006 mol) in glacial acetic acid (4 mL)

TANDEM TRANSFORMATIONS IN GEWALD THIOPHENES
2097
was stirred and heated under reflux for 2 h. The reaction mixture was cooled to room
temperature, and 0.7 mL of conc. HCl was added. The solid was filtered off, the filtrate was
evaporated, and the residue was recrystallized from ethanol.
Thieno[2,3-d]pyrimidin-4(3H)-one 3a. Yield: 0.46 g (61%); white solid; mp
245–247◦С. (lit.16 246–247◦С).
5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one 3b. Yield:
1
0.75 g (73%); white crystals; mp 256–257◦С (lit.1 255–257◦С). H NMR (DMSO-d6): δ
1.73–1.93 (m, 4H, CH2), 2.75 (t, J = 5.6 Hz, 2H, CH2), 2.90 (t, J = 5.8 Hz, 2H, CH2),
7.83 (s, 1H, CH), 12.16 (br.s, 1H, NH). (In ref.17 1H NMR (300 MHz, CDCl3): 1.86 (4H,
d, J = 6 Hz, CH2 at 6 and 7), 2.86 (2H, s, CH2 at 5), 3.02 (2H, s, CH2 at 8), 7.24 (1H, s,
CH at 2), 8.07 (1H, br d, J = 6.0 Hz, NH at 3).
3-(2H-Tetrazol-5-yl)-4,5,6,7-tetrahydro-1-benzothiophen-2-amine
6.
Yield: 0.54 g (49%); white crystals; mp 171–172◦С (dec.). 1H NMR (DMSO-d6): δ 1.82
(br.s, 4H), 2.93 (br.s, 4H), 5.65 (br.s, 2H). MS (CI): m/z (%) = 222 (100%) [M+H+].
Anal. requires for C9H11N5S (221.29) calcd./found: C, 48.85/49.04; H, 5.01/5.14; N,
31.65/31.44.
N-[3-(2H-Tetrazol-5-yl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]forma-
mide 7. Yield: 0.25 g (20%); white crystals; mp 194–195◦С (dec.). 1H NMR (DMSO-d6):
δ 1.89 (br.s, 4H), 2.66 (br.s, 2H), 2.80 (br.s, 2H), 8.45 (s, 1H), 12.37 (s, 1H). MS (CI): m/z
(%) = 250 (100%) [M+H+]. Anal. requires for C10H11N5OS (249.30) calcd./found: C,
48.18/48.45; H, 4.45/4.28; N, 28.09/27.91.
Synthesis of 2-Methyl-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]-
oxazin-4-one 10
Ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate
8 (2.25 g,
0.01 mol) was dissolved in dioxane, and Et3N (0.7 mL, 0.01 mol) was added. The mixture
was cooled to 0◦C, and acetyl chloride (0.71 mL, 0.01 mol) was added while keeping the
temperature below 5◦C. The solution was left at room temperature for 1 h, and H2O (5 mL)
was then added. The obtained solid was filtered, washed with H2O, crystallized (EtOH),
and dried in vacuo.
The mixture of obtained the acetamide (0.01 mol) with NaN3 (1.3 g, 0.02 mol) and
POCl3 (7.7 g, 0.05 mol) in MeCN (50 mL) was stirred under reflux for 10 h. The solvent and
excess POCl3 were removed under reduced pressure. The residue was cooled, neutralized
with sat. NaHCO3 solution, and evaporated to dryness. Compounds 10 were extracted
and crystallized from EtOH. Yield: 0.40 g (18%); white crystals; mp 133–134◦С. (lit.18
132.0–132.5◦С).
General Procedure for the Synthesis of 2-Azidothiophenes 11 and16
The appropriate 2-aminothiophene 4 or 15 (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, the
saturated sodium nitrite (1.73 g, 0.025 mol) aqueous solution was added while keeping the
temperature below 5◦C. After 10 min, any resinous sediment that has formed should be
filtered. To the filtrate solution of the diazonium salt, sodium azide (1.3 g, 0.02 mol) in
water (5 mL) was added dropwise. The solution was left for 15 min at room temperature,
and azide was extracted by diethyl ether (3 × 10 mL). Ether was evaporated in vacuo.
Azides were used without subsequent cleaning: 11, yield 2.16 g, 53%; yellow solid, mp:

2098
N. T. POKHODYLO ET AL.
83–84◦C (dec.); MS (m/z): 205 [M+H+]; 16, yield 2.32 g, 41%; dark red oil; MS (m/z):
284 [M+H+].
General Procedure for the Synthesis of 1,2,3-Triazoles 13a,b, 14, and 17
To a solution of sodium methoxide (540 mg, 10.0 mmol) in dry methanol (20 mL),
the substituted acetonitrile 12 (10.0 mmol) was added. To this solution, 2-azidothiophene
11 or 16 (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 suspension was filtered, and the
solid product was washed with water and methanol to give the corresponding compounds
13a,b, 14, and 17.
5-Imino-4,5,6,7,8,9-hexahydro[1]benzothieno[3,2-e][1,2,3]triazolo[1,5-a]
1
pyrimidine-3-carbonitrile 13a. Yield: 1.94 g (72%); white crystals; mp >300◦С. H
NMR (DMSO-d6): δ 1.75–2.01 (m, 4H), 2.86–3.09 (m, 4H), 6.55 (br.s, 1H). MS (CI):
m/z (%) = 271 (100%) [M+H+]. Anal. requires for C12H10N6S (270.32) calcd./found: C,
53.32/53.13; H, 3.73/3.61; N, 31.09/31.28.
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)-imine 13b. Yield: 0.68 g (18%); white crystals; mp
1
>300◦С. H NMR (DMSO-d6): δ 1.89–1.94 (m, 4H), 2.79–2.84 (m, 2H), 2.95–3.01 (m,
2H), 7.60 (t, J = 7.8 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.28 (d, J
= 8.2 Hz, 1H). MS (CI): m/z (%) = 379 (100%) [M+H+]. Anal. requires for C18H14N6S2
(378.48) calcd./found: C, 57.12/57.27; H, 3.73/3.61; N, 22.20/22.28.
2-[5-Amino-4-(1,3-benzothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4,5,6,7-tetrah
ydro-1-benzothiophene-3-carbonitrile 14. Yield: 2.76 g (73%); white crystals; mp
1
>300◦С. H NMR (DMSO-d6): δ 1.81–1.89 (m, 4H), 2.70 (br.s, 2H), 3.06 (br.s, 2H),
6.88–6.96 (br.s, 1H, NH2), 7.26 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.92 (d, J =
8.6 Hz, 2H) MS (CI): m/z (%) = 379 (100%) [M+H+]. Anal. requires for C18H14N6S2
(378.48) calcd./found: C, 57.12/57.04; H, 3.73/3.56; N, 22.20/22.16.
{2-[5-Amino-4-(1,3-benzothiazol-2-yl)-1H-1,2,3-triazol-1-yl]-4,5,6,7-tetra
hydro-1-benzothien-3-yl}(phenyl)methanone 17. Yield: 3.89 g (85%); white
1
crystals; mp >300◦С. H NMR (DMSO-d6): δ 1.57–1.73 (m, 2H), 1.81–2.01 (m, 2H),
2.08–2.27 (m, 2H), 2.77–3.04 (m, 2H), 7.51–7.65 (m, 7H, NH2 + Ph), 7.68 (t, J = 7.6
Hz, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H). MS (CI): m/z (%) = 458
(100%) [M+H+]. Anal. requires for C24H19N5OS2 (457.58) calcd./found: C, 63.00/62.85;
H, 4.19/4.09; N, 15.31/15.48.
Preparation of Ethyl 2-[2-(1-Chloro-2-ethoxy-2-oxoethylidene)
hydrazino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 19
To the solution of ethyl 2-chloro-3-oxobutanoate (3.29 g, 0.02 mol) in EtOH 100 mL
sodium, acetate trihydrate (25 g) was added. The mixture was cooled to 0◦C and treated with
a cold solution of diazonium salt prepared by diazotizing an amine 8 (0.02 mol) dissolved
in concentrated sulfuric acid (5 mL) and ice (15 g) with a saturated sodium nitrite (1.73
g, 0.025 mol) aqueous solution while keeping the temperature below 5◦C. The addition of
the diazonium salt was carried out with rapid stirring over a period of 20 min. The reaction
mixture was kept basic by the addition, when necessary, of more NaOAc. When the addition
was complete, the mixture was left for 1 h. Water was added, and the resulting red solid
was removed by filtration and washed with H2O. The crude product was crystallized from

TANDEM TRANSFORMATIONS IN GEWALD THIOPHENES
2099
hexane. Yield: 5.02 g (71%); red crystals; mp 91–93◦С. 1H NMR (DMSO-d6): δ 1.36 (t, J =
7.1 Hz, 6H), 1.71–1.84 (m, 4H), 2.60 (m, 2H), 2.71 (m, 2H), 4.30 (q, J = 7.1 Hz, 4H), 11.21
(s, 1H). MS (CI): m/z (%) = 360 (100%) [M+H+]. Anal. requires for C15H19ClN2O4S
(358.85) calcd./found: C, 50.21/49.03; H, 5.34/5.21; N, 7.81/7.99.
General Procedure for the Thieno[3,2-e]pyrazolo[1,5-a]pyrimidines
20a,b,c
To a solution of sodium ethoxide (680 mg, 10.0 mmol) in dry ethanol (20 mL), the
substituted acetonitrile 12 (10.0 mmol) was added. To this solution, hydrazonoyl chloride
19 (3.58 g, 10.0 mmol) in dry methanol (2 mL) was added dropwise, and a solid started to
precipitate. The resulting suspension was filtered, and the solid product was washed with
water and methanol.
Ethyl 3-cyano-5-oxo-4,5,6,7,8,9-hexahydro[1]benzothieno[3,2-e]pyrazo
lo[1,5-a]pyrimidine-2-carboxylate 20a. Yield: 1.85 g (54%); white crystals; mp
>300◦С. 1H NMR (DMSO-d6): δ 1.40 (t, J = 7.2 Hz, 3H), 1.81–1.89 (m, 4H), 2.69–2.76
(m, 2H), 2.92–2.98 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H). MS (CI): m/z (%) = 343 (100%)
[M+H+]. Anal. requires for C16H14N4O3S (342.38) calcd./found: C, 56.13/56.32; H,
4.12/4.01; N, 16.17/16.36.
Ethyl 3-(1,3-benzothiazol-2-yl)-5-oxo-4,5,6,7,8,9-hexahydro[1]benzothie
no[3,2-e]pyrazolo[1,5-a]pyrimidine-2-carboxylate 20b. Yield: 3.10 g (69%); white
crystals; mp >300◦С. 1H NMR (DMSO-d6): δ 1.45 (t, J = 7.2 Hz, 3H), 1.79–1.87 (m, 4H),
2.72–2.78 (m, 2H), 2.90–2.96 (m, 2H), 4.46 (q, J = 7.2 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H),
7.76 (t, J = 7.6 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H). MS (CI): m/z
(%) = 452 (100%) [M+H+]. Anal. requires for C22H18N4O3S2 (450.54) calcd./found: C,
58.65/58.59; H, 4.03/4.19; N, 12.44/12.29.
5-Oxo-4,5,6,7,8,9-hexahydro[1]benzothieno[3,2-e]pyrazolo[1,5-a]
pyrimidine-2,3-dicarboxylic Acid 21
The mixture (prepared as mention above for compounds 20) was kept in an ice water
bath for 3 h and then slowly heated under reflux for 1 h. The solid precipitated. Hot water
was added to dissolve the precipitate (50 mL), and if necessary, a solution of sodium
hydroxide should be added to pH 11–12 and heated under reflux for 1 h. The hot solution
was poured to a concentrated HCl (10 mL) and left to crystallize. The obtained solid was
filtered, washed with water twice, and crystallized from ethanol. Yield: 1.36 g (41%); white
crystals; mp 274◦С (dec.). 1H NMR (DMSO-d6): δ 1.84 (m, 4H), 2.77 (m, 1H), 2.93 (m,
1H). MS (CI): m/z (%) = 334 (100%) [M+H+]. Anal. requires for C14H11N3O5S (333.32)
calcd./found: C, 50.45/50.68; H, 3.33/3.16; N, 12.61/12.41.
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