One-Pot Synthesis of Thieno[3,2- e]pyrrolo[1,2- a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors

Article abstract of DOI:10.1021/acs.joc.9b00711

A new, efficient, and versatile one-pot cascade reaction of diverse Gewald's aminothiophenes, 2-hydroxy-4-oxobut-2-enoic acid, and derivatives of cyanoacetic acid catalyzed by Et₃N is presented. It enables direct synthesis of diverse 1-(2-oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine in good to excellent yields. The reaction exhibits a broad substrate scope and also presents an opportunity for further modification of the structure. The method offers a convenient practical alternative to the known procedures. The synthesized thieno[3,2-e]pyrrolo[1,2-a]pyrimidine scaffold is an important structural motif of new poly(ADP-ribose) polymerase (PARP) inhibitors, playing a useful role in multiple pharmacological applications.

Full text of DOI:10.1021/acs.joc.9b00711

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Article
One-pot synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine
derivatives scaffold: A valuable source of PARP-1 inhibitors
Sergei A. Shipilovskikh, and Aleksandr E. Rubtsov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00711 • Publication Date (Web): 26 Nov 2019
Downloaded from pubs.acs.org on November 26, 2019
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Page 1 of 10
The Journal of Organic Chemistry
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One-pot synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine
derivatives scaffold: A valuable source of PARP-1 inhibitors
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Sergei A. Shipilovskikh,†‡ Aleksandr E. Rubtsov*†
† Department of Chemistry, Perm State University, Bukireva 15, Perm, 614990, Russia
‡ Institute of Chemical Technology, Ural Federal University, Mira 19, Yekaterinburg, 620002, Russia.
O
I)Reflux, Toluene, 1 h.
R2
O
R4
OEt
II)DCC, Reflux, 2 h.
III)NCCH2R4, Et3N,
100oC, 1h.
O
R3
R1
R3
NH2
O
S
+
NH
N
one-pot
O
S
gram scale
23 examples
up to 96% yield
OH
R2
R1
O
O
H
ABSTRACT: A new, efficient and versatile one-pot cascade reaction of diverse Gewald's aminothiophenes, 2-hydroxy-4-oxobut-2-
enoic acid and derivatives of cyanoacetic acid catalyzed by Et3N is presented. It enables direct synthesis of diverse 1-(2-
oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine in good to excellent yields. The reaction exhibits a broad substrate scope,
and also present an opportunity for further modification of the structure. The method offers a convenient practical alternative to the
known procedures.The synthesized thieno[3,2-e]pyrrolo[1,2-a]pyrimidine scaffold is an important structural motif of new PARP
inhibitors, playing a useful role in multiple pharmacological applications.
INTRODUCTION
reported.5 All the methods described in the literature involved
multistage sequences and were characterized by low overall
yields. For example, synthesis of compound 3 required 5 steps
starting from commercially available compounds.4
Poly(ADP-ribose) polymerase-1 (PARP-1) is the most
prominent member of the PARP family. This is a DNA-binding
protein activated by nicks in DNA that occur during
inflammation, ischemia, neurodegeneration or cancer therapy.1
Most of the known inhibitors of PARP mimic the structure of
nicotinamide 1.2 Conformationally constrained cyclic inhibitors
feature an anti-configuration of the amide bond. Attempts to
improve affinity of PARP inhibitors to the binding site have
been made by locking the carboxamide group which is usually
free to rotate. This locking can be realized by incorporating the
amide group into a heterocyclic unit. Recognition of the
importance of the conformational rigidity of the benzamide
pharmacophore led to the development of substituted
quinazolin-4-ones 2,3 some of which are 50-fold more potent
inhibitors. Fused heterocycles pyrrolo[1,2-a]quinazolin-
O
O
H
H
N
N
H
N
N
R
R
1
2
O
O
R2
S
H
H
S
N
N
R1
R4
O
R
N
N
5(4H)ones
and
pyrrolo[1,2-a]thieno[2,3-e]pyrimidin-
4(5H)ones 3 have been claimed to show good inhibitory activity
towards PARP-1.4 The PARP-1 pharmacophore includes one or
more of the following structural elements that contribute to the
inhibitory potency: (i) an amide moiety fused within a bicyclic
ring system (blue, Figure 1, 4); (ii) small hydrophobic
substituents on the A-ring adjacent to the amide (pink, Figure
1, 4); (iii) large groups in the southeast portion of the
pharmacophore (green, Figure 1, 4).2c
R
R
O
O
R3
4
3
Figure 1. Structures known inhibitors of PARP 1-3, and structure
of proposed scaffold 4.
RESULTS AND DISCUSSION
In our search for effective PARP inhibitors, we required a
robust, facile synthesis of derivatives of 1-(2-oxoethylidene)-2-
oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine-3-carboxylic acid 4
containing the structural elements contributing to the inhibitory
potency and also additional functional groups for further
modification. To date, only a few examples of the synthesis of
In our retrosynthetic analysis of 4, the final thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine
4
could be assembled by
intramolecular amidation of 5 (Scheme 1), which in turn can be
obtained by Lewis base mediated cyclization of the amino
group onto the nitrile in 6. Acylation of ethyl cyanoacetate with
α-aminoacid 7 should install the necessary groups in 6 for
thieno[3,2-e]pyrrolo[1,2-a]pyrimidine
analogues
were
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subsequent aminopyrrole ring formation. The oxoethylidene Synthetic protocols where several chemical bonds are formed
1
2
3
4
5
6
7
8
fragment in 7 could be introduced by reacting the appropriate
2-hydroxy-4-oxoylbut-2-enoic acids 8 with the aminothiophene
precursor. All these transformations could be through a cascade
process, since all the steps require basic condition. Modern
organic synthesis often aims to build molecular complexity and
diversity while minimizing the number of synthetic steps
required to achieve this goal.
and/or cleaved in a one-pot process have attracted much
attention. Cascade reactions are atom economical; they save
resources in both time and cost by reducing the number of
operations required to reach a specific target.6 Herein we report
a new, efficient, mild and convenient method for the preparation
of analogues of 4 by Et3N-catalyzed one-pot cascade reaction
employing Gewald's aminothiophenes, dioxobutanoic acid and
derivatives of cyanoacetic acid.
Scheme 1. Retrosynthetic Analysis of thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine.
Our investigations were initiated using the reaction of model 9
(for its synthesis, see7) with ethyl cyanoacetate under various
reaction conditions. The results are summarized in Table 1.
First, the influence of the base (0.004 M) was examined at 50
°C in the dioxane (Table 1, entries 1-5). When Et3N was used
as base, only 5 was obtained in a low yield.8 By increasing the
reaction time, 4a was obtained in a low yield (5%), the yield of
5 increased to 92%. With DMAP as a base, product 5 was
formed in 68% yield, while with pyridine as a base, the reaction
did not proceed. Additionally, the utilization of t-BuOK led
exclusively to the ring opened product 6. Based on these initial
experiments, further investigation employed Et3N. Subsequent
optimization involved screening of solvents, reaction
temperature and concentration of Et3N. Finally, entry 14
presents the optimal conditions (0.4 M TEA as a catalyst,
toluene as a solvent, T 100 °C).
9
R2
R2
O
O
OEt
R2
10
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12
13
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H
O
OEt
N
N
O
R1
O
R1
R1
NH2
R4
S
S
N
S
NH
N
R4
R4
O
O
R3
O
R3
O
R3
6
4
5
R4 CN
O
R2
OEt
O
R2
R1
OEt
(COOEt)2
S
NH2
O
R1
+
R3
S
NH
OH
O
HO
O
OH
R3 Me
O
O
R3
8
7
Table 1. Optimization of the Reaction Conditions.
O
OEt
O
O
O
NH
NH2
S
O
CN
O
S
S
OEt
S
OEt
+
N
+
KO
N
OEt
CN
N
H
OEt
N
EtO
O
O
Base
O
O
OEt
O
O
O
Ph
O
O
Ph
4a
Ph
Ph
6
4a)
(X-ray
5
9
entry
Base (c, M)a
solvent
Time (h)
T, °C
yield 4a, yield 5,%b
%
yield 6, %b
b
1
Et3N (0.004)
Et3N (0.004)
Py (0.004)
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
toluene
toluene
dioxane
DCM
3
50
n.d.
5
18
n.d.
n.d.
n.d.
98
2
24
24
0.5
24
12
2
50
92
3
50
n.d.
n.d.
n.d.
16
n.d.
n.d.
68
4
t-BuOK (0.004)
DMAP (0.004)
Et3N (0.004)
Et3N (0.004)
Et3N (0.004)
Et3N (0.3)
50
5
50
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
6
100
100
100
100
40
31
7
n.d.
14
72
8
12
6
63
9
25
45
10
11
12
13
14
15
Et3N (0.4)
1
n.d.
n.d.
n.d.
99
99
Et3N (0.4)
CHCl3
1
60
99
Et3N (0.3)
toluene
toluene
toluene
toluene
0.3
6
100
100
100
100
90
Et3N (0.3)
n.d.
n.d.
18
Et3N (0.4)
1
99
Et3N (1)
1
43
aMolar concentration (mol/L). bYields was calculated from HPLC.
Based on the collected experimental data, a plausible reaction
mechanism can be suggested (Scheme 2). Initially,
deprotonation of cyanoacetate derivatives with triethylamine
generates carbanion. Nucleophilic attacks of this carbanion into
the C2 atom of the furan ring gives intermediate A, which after
the subsequent fragmentation is converted into intermediate B
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with a negative charge on the O atom and a delocalized double
bond conjugated with the aromatic ring. This sets up attack by
1
2
3
4
5
6
7
8
Scheme 3. One-pot synthesis of thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine.
the nitrogen atom possessing excess electron density onto the
electrophilic C terminus of the nitrile group to form
intermediate C. In the next stage, the negative charged
exocyclic nitrogen attacks the ethyl ester group to generate
intermediate D, which is then tautomerized into compound 4.
O
O
OEt
NH
I) Reflux, Toluene, 1 h.
II )DCC, Reflux, 2 h.
O
S
NH2
N
S
+
10a
III) NCCH2R4, Et3N,
100oC, 1h.
OEt
O
Scheme 2. Proposed Reaction Mechanism
O
Ph
R2
R2
R2
OH
4a
O
O
R1
R1
O
O
R1
Ph
O
8a
O
N
N
H
9
Base
-H+
NCCH2COOEt, Et3N,
100oC, Toluene, 1 h.
OEt
OEt
S
OEt
S
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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42
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44
45
46
47
48
49
50
51
52
53
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59
60
Reflux, Toluene, 1 h.
O
N
R4
N
O
R4
N
N
O
O
R3
R3
R4
Ph
R3
O
O
O
OH
N
O
R4
S
OEt
N
O
HN
S
9
B
A
DCC, Reflux, 2 h.
Toluene
EtO
9
7a
Ph
O
R2
R2
R2
O
O
EtO
O
R1
R1
Initially, we carried out the reaction of 2-hydroxy-4-oxo-4-
phenylbut-2-enoic acid 8a (1 equiv) with ethyl 2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylate (1 equiv) 10a in
toluene at 111 °C for 2 h, to afford the desired product 7a. The
subsequent cyclization was performed using DCC as
dehydratation agent instead of employing the standard
conditions (heating in acetic anhydride)7 to yield furanone 9.
The solution of 9 thus obtained was treated, in succession, with
cyanoacetic ester (1 equiv) and Et3N (0.4 M). After heating the
reaction mixture at 100° C for 1 h, the respective ethyl 1-(2-
oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine-3-
carboxylate 4a was obtained.
R1
O
O
N
N
S
S
S
NH
N
N
O
-EtO-
N
R4
R4
R4
R3
O
R3
R3
O
O
O
O
C
D
4
Synthesis of 3-(thiophen-2-yl)imino-3H-furan-3-ones 9 can be
achieved in a two-step reaction starting from derivatives of 2-
hydroxy-4-oxobut-2-enoic acid 8 and Gevald’s aminothiophene
10 through the intermediate formation of 2-(2-tiennyl)amino-4-
oxobut-2-enoic acid 7.7 We now opted to combine the synthesis
of
3-(thiophen-2-yl)imino-3H-furan-3-ones 9 and their
recyclization into a one-pot method (Scheme 3).
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Table 2. Scope of the Reaction
O
N
R2
1
2
3
4
5
6
O
O
I) Reflux, Toluene, 1 h.
II) DCC, Reflux, 2 h.
NH
R1
R2
R3
OEt
NH2
OH
+
R4
S
III) NCCH2R4,
Et3N, 100oC, 1h.
R1
O
O
H
S
O
8a-f
4a-p
10a-e
O
R3
7
8
9
O
N
O
N
O
O
O
O
NH
NH
O
NH
NH
NH
NH
O
O
O
OEt
O
O
S
S
S
N
S
S
S
N
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
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60
OEt
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
MeO
O
O
O
O
O
t-Bu
4a
4e
(85%)
4b
(84%)
(84%)
4f
(70%)
NH
4c
(87%)
4d
(72%)
Me
Me
Cl
MeO
MeO
Me
O
N
O
N
O
N
O
O
O
N
Me
Me
NH
NH
NH
NH
NH
Me
Me
Me
Me
O
O
O
O
O
OEt
O
S
S
S
S
S
S
N
N
OEt
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
4i
O
O
4k
O
O
4h
(86%)
4j
(79%)
4l
(76%)
(75%)
(93%)
NH
4g
(88%)
O
Me
MeO
Cl
O
N
O
N
O
O
O
N
Ph
Me
NH
NH
NH
NH
NH
O
Me
O
S
S
S
S
S
CN
N
S
CN
N
N
CN
NH2
OEt
NH2
O
O
O
O
O
O
O
O
O
O
O
O
4m
(83%)
O
4n
4o
(96%)
(92%)
4q
(90%)
4r
(87%)
4p
(88%)
MeO
O
MeO
Me
O
N
O
N
O
N
Me
NH
NH
NH
NH
NH
Me
S
S
S
S
S
CN
N
CN
CN
CN
CN
N
O
O
O
O
O
O
O
O
O
O
4u
4v
4w
(87%)
(81%)
4t
(89%)
(85%)
4s
(89%)
MeO
Me
MeO
The substrate scope was investigated next. As shown in Table
2, the reaction tolerated well various combinations of R1, R2, R3
and R4, thus allowing generation of thieno[3,2-e]pyrrolo[1,2-
a]pyrimidines 4 with broad structural diversity.
Scheme 4. Synthetic Applications of the Product 4c
O
O
O
NH
NH
NH
O
O
O
S
S
S
N
N
N
OEt
OEt
MeO
OEt
MeOH
H+
Zn
Derivatives of ethyl 1-(2-oxoethylidene)-2-oxothieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate
O
O
O
AcOH
4
are excellent
O
O
O
precursors for accessing new biologically active compounds.
For the illustration of their synthetic utility, the activated
exocyclic alkene in 4c was further exploited for the synthesis of
compounds 11-13. Under the standard Zn/AcOH reduction
conditions, the double bond was reduced to give compound 11.
The reaction of compound 4с with methanol in the presence of
a catalytic amount of HCl led to compound 12. Furthermore,
the aroylethylidene fragment can be cleaved from the
heterocyclic core of compound 4 by the reaction with
hydroxylamine, to afford ethyl 2,5-dioxo-1,2,4,5,6,7,8,9-
octahydrobenzo[4,5]thieno[3,2-e] pyrrole[1,2-a]pyrimidine-3-
carboxylate 13. The structure of 13 was unambiguously
confirmed a single-crystal X-ray analysis(Scheme 4).
MeO
MeO
MeO
4c
12 (86%)
11 (70%)
NH2OH
O
NH
O
S
N
OEt
O
13 (83%)
(X-Ray 13)
CONCLUSION
We developed
organocascade
a
highly efficient, three-component
by employing Gewald's
aminothiophenes, dioxobutanoic acid and derivatives of
reaction
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cyanoacetic acid. The base-catalyzed multiple reaction cascade Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.94 g, 84 % yield; m.p.
258-259 °С (acetonitrile). IR (nujol) ν: 1698, 1715, 3209 cm-1.
1H NMR (DMSOd6:CCl4(4:1), 400 MHz): δH 10.27 (s, 1Н), 7.84
(m, 2Н), 7.32 (m, 2Н), 6.97 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H),
2.90 (m, 2H), 2.80 (m, 2H), 2.42 (s, 3Н), 1.85 (m, 4H), 1.23 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (DMSOd6:CCl4(4:1), 100
MHz): δC 190.8, 173.6, 170.6, 163.2, 160.6, 153.9, 143.9,
134.0, 133.9, 132.0, 129.0, 128.7, 128.5, 117.5, 115.9, 86.9,
59.4, 24.8, 23.8, 22.3, 21.4, 21.1, 14.1. MS (ESI): m/z 463.12
[М+H]+. Anal. Calcd for C25H22N2O5S: C, 64.92; H, 4.79; N,
6.06; S, 6.93. Found: C, 64.85; H, 4.83; N, 6.01; S, 6.88.
1
2
3
4
5
6
7
8
proceeded smoothly via a sequence of condensation reactions.
Further exploitation of this strategy is currently underway in our
laboratory.
EXPERIMENTAL SECTION
NMR spectra were recorded on Bruker Avance III (400
MHz) and DRX-500 (500 MHz) instruments. The chemical
shifts (δ) were measured in ppm with respect to the solvent
(CDCl3, 1Н: δ = 7.26 ppm, 13C: δ = 77.2 ppm; DMSOd6, 1Н: δ
= 2.50 ppm, 13C: δ = 39.5 ppm). IR spectra were recorded on
an FSM-1202 spectrometer from samples dispersed in mineral
oil. Mass spectra were recorded with a Kratos MS-30
instrument with 70 eV electron impact ionization at 200 ºC.
Elemental analyses were performed with Leco CHNS-932
elemental analyzer instrument. Melting points were recorded
with a Stuart SMP 40. ULPC/UV/MS analysis were performed
on a Waters UPLC-UV-MS instrument Acquity I-Class
equipped with a Xevo TQD detector in ESI+ ionization mode.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
(E)-1-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,5-
dioxo-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4c). Obtained from
10a (1.13 g, 5 mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 2.08 g, 87 % yield; m.p.
253-254 °С (acetonitrile). IR (nujol) ν: 1694, 1715, 3202 cm-1.
1H NMR (CDCl3, 500 MHz): δH 10.81 (s, 1H), 7.94 (m, 2H),
6.92 (m, 2H), 6.81 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.86 (s,
3H), 2.99 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 1.89 (m,
4H), 1.28 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 125
MHz): δC 189.7, 174.0, 164.5, 164.4, 160.8, 153.9, 143.6,
134.3, 133.4, 131.3, 129.3, 129.2, 118.1, 116.7, 114.1, 87.8,
60.7, 55.6, 25.3, 24.5, 22.8, 21.8, 14.4. MS (EI): m/z 478 [М]+.
Anal. Calcd for C25H22N2O6S: C, 62.75; H, 4.63; N, 5.85; S,
6.70. Found: C, 62.67; H, 4.69; N, 5.93; S, 6.62.
Solvents of chemically pure grade were subjected to
additional purification and drying. All other reagents were
purchased from various commercial sources and used without
additional purification.
General method for one-pot synthesis of thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine derivatives.
In a 100 mL of single-neck round-bottom flask equipped
with magnetic stirring (equipped with aluminum block) and
Dean-Stark trap, 10a-c (5 mmol) was mixed with 8a-e (5 mmol)
in 50 ml of anhydrous toluene, the resulting solution was stirred
at reflux for 1 h. Then solution was cooled to r.t. and DCC (5
mmol) was added. The mixture was stirred at 111 °C for 2 h.
Then the solution was cooled to r.t. and ethyl 2-cyanoacetate (5
mmol), 2-cyanoacetamide (5 mmol) or malononitrile (5 mmol)
was added, followed by addition of Et3N (2.02 g) to a
concentration of 0.4 mol/l. The reaction mixture was stirred at
100 °C for 1 h. Then from the hot solution the precipitated urea
was filtered off and the filtrate was cooled to -27 °C, the
precipitated product was filtered off and recrystallized from
acetonitrile.
Ethyl
(E)-1-(2-(4-chlorophenyl)-2-oxoethylidene)-2,5-
dioxo-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4d). Obtained from
10a (1.13 g, 5 mmol, 1 equiv), 8d (1.13 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.73 g, 72 % yield; m.p.
264-265 °С (acetonitrile). IR (nujol) ν: 1697, 1717, 3198 cm-1.
1H NMR (DMSOd6:PyD (2:3), 400 MHz): δH 8.17 (m, 2H), 7.56
(m, 2H), 7.17 (s, 1H), 7.08 (s, 1H), 4.26 (q, J = 7.1 Hz, 2Н),
2.96 (m, 2H), 2.70 (m, 2H), 1.76 (m, 4H), 1.22 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (DMSOd6:PyD (2:3), 100 MHz): δC 190.6,
173.8, 163.4, 160.9, 154.1, 149.5, 143.6, 138.8, 135.4, 132.2,
130.0, 128.6, 123.3, 116.4, 116.1, 87.1, 59.4, 24.8, 23.6, 22.3,
21.3, 13.8. MS (ESI): m/z 482.80 [М+H]+. Anal. Calcd for
C24H19ClN2O5S: C, 59.69; H, 3.97; N, 5.80; S, 6.64. Found: C,
59.57; H, 4.12; N, 5.92; S, 6.53.
Ethyl
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carboxylate (4a). Obtained from 10a (1.13 g, 5
mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 M). Yellow solid; 1.90 g, 85 % yield; m.p. 253-255 °С
Еthyl
(E)-1-(2-(2,4-dimethoxyphenyl)-2-oxoethylidene)-
1
(acetonitrile). IR (nujol) ν: 1664, 1711, 3211 cm-1. H NMR
2,5-dioxo-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4e). Obtained from
10a (1.13g, 5 mmol, 1 equiv), 8e (1.26 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 2.13 g, 84 % yield; m.p.
229-230 °С (acetonitrile). IR (nujol) ν: 1687, 1714, 3220 cm-1.
1H NMR (CDCl3, 400 MHz): δH 10.76 (s, 1Н), 8.05 (m, 1Н),
6.99 (s, 1H), 6.59 (m, 1Н), 6.38 (m, 1Н), 4.28 (q, J = 7.1 Hz,
2H), 3.85 (s, 3Н), 3.77 (s, 3Н), 2.98 (m, 2H), 2.76 (m, 2H), 1.86
(m, 4H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δC 187.8, 173.8, 165.0, 164.1, 160.9, 159.5, 153.5, 143.2, 132.8,
132.8, 130.6, 128.4, 122.8, 119.3, 116.0, 105.6, 97.8, 87.3, 60.0,
55.1, 55.1, 24.7, 23.9, 22.2, 21.2, 13.9. MS (ESI): m/z 531.06
[М+Na]+. Anal. Calcd for C26H24N2O7S: C, 61.41; H, 4.76; N,
5.51; S, 6.30. Found: C, 61.45; H, 4.73; N, 5.49; S, 6.28.
(CDCl3, 500 MHz): δH 10.82 (s, 1H), 7.98 (m, 2H), 7.58 (m,
1H), 7.46 (m, 2H), 6.82 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.00
(d, J = 6.0 Hz, 2H), 2.77 (d, J = 6.0 Hz, 2H), 1.90 (m, 4H), 1.30
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 125 MHz): δC 191.3,
174.0, 164.5, 161.0, 153.9, 143.6, 136.1, 134.7, 134.0, 133.5,
129.3, 128.8, 128.9 117.8, 116.7, 87.8, 60.8, 25.3, 24.5, 22.8,
21.8, 14.4. MS (EI): m/z 448 [М]+. MS (ESI): m/z 449.12
[М+H]+. Anal. Calcd for C24H20N2O5S: C, 64.27; H, 4.50; N,
6.25; S, 7.15. Found: C, 64.43; H, 4.61; N, 6.16; S, 7.10.
Ethyl
(E)-1-(2-(4-methylphenyl)-2-oxoethylidene)-2,5-
dioxo-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4b). Obtained from
10a (1.13 g, 5 mmol, 1 equiv), 8b (1.03 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
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Ethyl
(E)-1-(3,3-dimethyl-2-oxobutylidene)-2,5-dioxo-
[М+Na]+. Anal. Calcd for C23H20N2O6S: C, 61.05; H, 4.46; N,
6.19; S, 7.09. Found: C, 60.98; H, 4.52; N, 6.25; S, 7.01.
Ethyl (E)-8-(2-(4-chlorophenyl)-2-oxoethylidene)-2,3-
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1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carboxylate (4f). Obtained from 10a (1.13 g, 5
mmol, 1 equiv), 8f (0.86 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 mol/l). Yellow solid; 1.50 g, 70 % yield; m.p. 223-224 °С
(acetonitrile). IR (nujol) ν: 1705, 3201 cm-1. 1H NMR (CDCl3,
400 MHz): δH 10.81 (s, 1H), 6.69 (s, 1H), 4.37 (q, J = 7.1 Hz,
2Н), 2.98 (m, 2H), 2.77 (m, 2H), 1.91 (m, 4H), 1.37 (t, J = 7.1
Hz, 3H) 1.31 (s, 9H). 13C{1H} NMR (CDCl3, 100 MHz): δC
206.2, 173.3, 163.9, 160.0, 153.2, 142.8, 133.3, 132.9, 128.5,
117.8, 116.0, 87.3, 60.2, 44.6, 25.7, 24.6, 23.8, 22.2, 21.2, 13.9.
MS (ESI): m/z 429.17 [М+H]+. Anal. Calcd for C22H24N2O5S:
C, 61.67; H, 5.65; N, 6.54; S, 7.48. Found: C, 61.76; H, 5.71;
N, 6.43; S 7.39.
dimethyl-4,7-dioxo-4,5,7,8-tetrahydropyrrolo[1,2-
a]thieno[3,2-e]pyrimidine-6-carboxylate (4j). Obtained from
10b (0.99 g, 5 mmol, 1 equiv), 8d (1.13 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.71 g, 75 % yield; m.p.
250-251 °С (acetonitrile). IR (nujol) ν: 1697, 1718, 3188 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 10.82 (s, 1H), 7.97 (m, 2H),
7.60 (m, 2H), 7.05 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 2.40 (s,
3H), 2.39 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(DMSOd6, 100 MHz) δ (ppm): δC 190.6, 173.8, 163.1, 160.6,
154.2, 143.4, 138.5, 135.1, 134.4, 130.2, 130.0, 128.7, 125.8,
116.8, 116.6, 86.8, 59.4, 14.1, 12.2, 11.8. MS (ESI): m/z 478.84
[М+Na]+.Anal. Calcd for C22H17ClN2O5S: C, 57.83; H, 3.75; N,
6.13; S, 7.02. Found: C, 57.70; H, 3.82; N, 6.23; S, 6.91.
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Ethyl (E)-8-(2-phenyl-2-oxoethylidene)-2,3-dimethyl-4,7-
dioxo-4,5,7,8-tetrahydropyrrolo[1,2-a]thieno[3,2-
e]pyrimidine-6-carboxylate (4g). Obtained from 10b (0.99 g, 5
mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 mol/l). Yellow solid; 1.86 g, 88 % yield; m.p. 242-243 °С
Ethyl
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,7,8,9,10-octahydro-6H-cyclohepta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4k). Obtained from
10c (1.19 g, 5 mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.83 g, 79 % yield; m.p.
256-257 °С (acetonitrile). IR (nujol) ν: 1670, 1702, 3229 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 10.78 (s, 1Н), 7.96 (m, 2Н),
7.67 (m, 1Н), 7.53 (m, 2Н), 7.08 (s, 1H), 4.17 (q, J = 7.0 Hz,
2H), 3.27 (m, 2H), 2.88 (m, 2H), 1.89 (m, 2H), 1.67 (m, 4H),
1.20 (t, J = 7.0 Hz, 3H). 13C NMR (DMSOd6, 100 MHz): δC
191.5, 173.7, 163.2, 160.4, 154.5, 142.6, 137.4, 136.3, 134.2,
133.4, 132.4, 128.5, 128.4, 117.6, 116.4, 86.6, 59.4, 31.3, 28.2,
27.1, 26.5, 26.4, 14.1. MS (ESI): m/z 485.05 [М+Na]+. Anal.
Calcd for C25H22N2O5S: C, 64.92; H, 4.79; N, 6.06; S, 6.93.
Found: C, 64.88; H, 4.82; N, 6.04; S, 6.89.
(acetonitrile). IR (nujol) ν: 1662, 1718, 3230 cm-1. H NMR
1
(DMSOd6, 400 MHz): δH 10.70 (s, 1H), 7.97 (m, 2H), 7.66 (m,
1H), 7.53 (m, 2H), 7.03 (s, 1H), 4.20 (q, J = 7.0 Hz, 2H), 2.42
(s, 6H), 1.22 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (DMSOd6, 100
MHz) δ (ppm): δC 191.5, 173.7, 163.2, 160.5, 154.2, 143.4,
136.3, 134.2, 133.4, 130.0, 128.5, 128.4, 125.8, 117.4, 116.6,
86.8, 59.4, 14.1, 12.2, 11.8. MS (ESI): m/z 423.07 [М+H]+.
Anal. Calcd for C22H18N2O5S: C, 62.55; H, 4.29; N, 6.63; S,
7.59. Found: C, 62.52; H, 4.31; N, 6.67; S, 7.58.
Ethyl
(E)-8-(2-(4-methylphenyl)-2-oxoethylidene)-2,3-
dimethyl-4,7-dioxo-4,5,7,8-tetrahydropyrrolo[1,2-
a]thieno[3,2-e]pyrimidine-6-carboxylate (4h). Obtained from
10b (0.99 g, 5 mmol, 1 equiv), 8b (1.03 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.87 g, 86 % yield; m.p.
246-247 °С (acetonitrile). IR (nujol) ν: 1697, 1714, 3209 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 10.75 (s, 1H), 7.85 (m, 2H),
7.32 (m, 2H), 6.99 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.40 (m,
9H), 1.22 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (DMSOd6, 100
MHz): δC 190.9, 173.7, 163.2, 160.4, 154.2, 144.0, 143.4,
134.1, 134.0, 129.9, 129.1, 128.5, 125.7, 117.5, 116.6, 86.8,
59.4, 21.1, 14.1, 12.2, 11.8. MS (ESI): m/z 458.93 [М+Na]+.
Anal. Calcd for C23H20N2O5S: C, 63.29; H, 4.62; N, 6.42; S,
7.35. Found: C, 63.25; H, 4.68; N, 6.24; S, 7.22.
Ethyl
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,6,7,8,9,10,11-decahydrocycloocta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (4l). Obtained from
10d (1.27 g, 5 mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.81 g, 76 % yield; m.p.
243-244 °С (acetonitrile). IR (nujol) ν: 1683, 1701, 3188 cm-1.
1H NMR (CDCl3, 400 MHz): δH 10.82 (s, 1Н), 8.01 (m, 2Н),
7.60 (m, 1Н), 7.48 (m, 2Н), 6.85 (s, 1H), 4.31 (q, J = 7.1 Hz,
2H), 3.14 (m, 2H), 2.91 (m, 2H), 1.75 (m, 4H), 1.53 (m, 2H),
1.41 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (CDCl3, 100
MHz): δC 190.7, 173.3, 163.8, 160.3, 153.3, 142.5, 135.7,
135.6, 134.1, 133.3, 131.2, 128.3, 128.2, 117.2, 116.2, 87.0,
60.1, 31.4, 29.0, 25.9, 25.3, 25.1, 24.1, 13.8. MS (ESI): m/z
499.09 [М+Na]+. Anal. Calcd for C26H24N2O5S: C, 65.53; H,
5.08; N, 5.88; S, 6.73. Found: C, 65.57; H, 5.06; N, 5.91; S,
6.71.
Ethyl
(E)-8-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,3-
dimethyl-4,7-dioxo-4,5,7,8-tetrahydropyrrolo[1,2-
a]thieno[3,2-e]pyrimidine-6-carboxylate (4i). Obtained from
10b (0.99 g, 5 mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57
g, 5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 2.10 g, 93 % yield; m.p.
253-254 °С (acetonitrile). IR (nujol) ν: 1695, 1715, 3198 cm-1.
1H NMR (CDCl3, 500 MHz): δH 10.79 (s, 1H), 7.94 (m, 2H),
6.92 (m, 2H), 6.81 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.86 (s,
3H), 2.46 (s, 3H), 2.41 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (CDCl3, 125 MHz): δC 189.7, 173.9, 164.4, 164.3, 160.6,
154.1, 142.9, 134.3, 131.5, 131.2, 129.3, 125.8, 118.1, 117.4,
114.1, 87.7, 60.7, 55.6, 14.4, 12,9, 12.4. MS (ESI): m/z 475.02
Ethyl
(E)-4,7-dioxo-8-(2-oxo-2-phenylethylidene)-3-
phenyl-4,5,7,8-tetrahydropyrrolo[1,2-a]thieno[3,2-
e]pyrimidine-6-carboxylate (4m). Obtained from 10e (1.24 g, 5
mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and ethyl 2-cyanoacetate (0.57 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 mol/l). Yellow solid; 1.95 g, 83 % yield; m.p. 231-232 °С
1
(acetonitrile). IR (nujol) ν: 1698, 1721, 3199 cm-1. H NMR
(DMSOd6, 400 MHz): δH 10.82 (s, 1H), 7.99 (m, 2H), 7.68 (m,
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1H), 7.54 (m, 4H), 7.49 (s, 1H), 7.43 (m, 3H), 7.22 (s, 1H), 4.18
mol/l). Yellow solid; 1.94 g, 90 % yield; m.p. 192-194 °С
(q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(DMSOd6, 100 MHz) δ (ppm): δC 191.8, 173.9, 163.2, 160.8,
153.8, 147.5, 139.4, 136.1, 134.0, 134.0, 133.5, 129.2, 128.6,
128.5, 127.9, 127.6, 118.0, 116.9, 114.7, 86.6, 59.5, 14.2. MS
(ESI): m/z 470.89 [М+H]+. Anal. Calcd for C26H18N2O5S: C,
66.37; H, 3.86; N, 5.95; S, 6.81. Found: C, 66.25; H, 3.78; N,
5.87; S, 6.74.
(acetonitrile). IR (nujol) ν: 1653, 2196, 3328 cm-1. H NMR
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5
6
7
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(DMSOd6, 400 MHz): δH 7.89 (m, 2H), 7.04 (m, 2H), 6.79 (s,
1H), 3.86 (s, 3H), 2.86 (m, 2H), 2.74 (m, 2H), 1.80 (m, 4H).
13C{1H} NMR (DMSOd6, 100 MHz): δC 190.1, 176.2, 163.4,
160.4, 143.2, 134.2, 131.9, 130.9, 129.5, 127.0, 116.8, 115.3,
113.9, 113.8, 69.6, 55.5, 25.1, 23.7, 22.4, 21.5. MS (ESI): m/z
431.94 [М+H]+. Anal. Calcd for C23H17N3O4S: C, 64.03; H,
3.97; N, 9.74; S, 7.43. Found: C, 64.00; H, 4.08; N, 9.68; S,
7.37.
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carboxamide (4n). Obtained from 10a (1.13 g,
5 mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and 2-cyanoacetamide (0.42 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 mol/l). Yellow solid; 1.89 g, 92 % yield; m.p. 283-285 °С
9
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57
58
59
60
tolyl)ethylidene)-4,5,7,8-tetrahydropyrrolo[1,2-a]thieno[3,2-
e]pyrimidine-6-carbonitrile (4r). Obtained from 10b (0.99 g, 5
mmol, 1 equiv), 8b (1.03 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and malononitrile (0.13 g, 5 mmol, 1 equiv), in
solution anhydrous toluene (50 ml) with Et3N (2.02 g, 0.4
mol/l). Yellow solid; 1.69 g, 87 % yield; m.p. 205-206 °С
1
(acetonitrile). IR (nujol) ν: 1662, 1709, 3201 cm-1. H NMR
(DMSOd6:CCl4(4:1), 400 MHz): δH 11.38 (s, 1H), 7.98 (m, 2H),
7.66 (m, 1H), 7.53 (m, 2H), 7.06 (m, 3H), 2.91 (t, J = 5.9 Hz,
2H), 2.80 (t, J = 5.9 Hz, 2H), 1.86 (m, 4H). 13C{1H} NMR
(DMSOd6:CCl4(4:1), 100 MHz): δC 191.0, 175.6, 164.6, 160.3,
143.8, 136.2, 133.4, 132.8, 132.1, 128.5, 128.4, 128.2, 127.9,
118.1, 115.8, 89.0, 24.8, 23.8, 22.4, 21.4. MS (ESI): m/z 441.96
[М+Na]+. Anal. Calcd for C22H17N3O4S: C, 63.00; H, 4.09; N,
10.02; S, 7.64. Found: C, 62.87; H, 4.13; N, 9.87; S, 7.58.
1
(acetonitrile). IR (nujol) ν: 1668, 2201, 3332 cm-1. H NMR
(DMSOd6, 400 MHz): δH 7.82 (m, 2H), 7.31 (m, 2H), 6.70 (s,
1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR
(DMSOd6, 100 MHz): δC 191.5, 176.0, 160.6, 143.7, 142.3,
134.8, 134.2, 130.0, 129.0, 128.6, 123.4, 117.8, 114.4, 114.1,
69.4, 21.1, 12.6, 11.7. MS (ESI): m/z 411.97 [М+Na]+. Anal.
Calcd for C21H15N3O3S: C, 64.77; H, 3.88; N, 10.79; S, 8.23.
Found: C, 64.53; H, 3.96; N, 10.80; S, 8.12.
(E)-1-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,5-dioxo-
1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carboxamide (4o). Obtained from 10a (1.13 g,
5 mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and 2-cyanoacetamide (0.42 g, 5 mmol, 1
equiv), in solution anhydrous toluene (50 ml) with Et3N (2.02
g, 0.4 mol/l). Yellow solid; 2.15 g, 96 % yield; m.p. 287-288 °С
(E)-8-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,3-
dimethyl-4,7-dioxo-4,5,7,8-tetrahydropyrrolo[1,2-
a]thieno[3,2-e]pyrimidine-6-carbonitrile (4s). Obtained from
10b (0.99 g, 5 mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and malononitrile (0.13 g, 5
mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.80 g, 89 % yield; m.p.
209-210 °С (acetonitrile). IR (nujol) ν: 1630, 2200, 3327 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 7.90 (m, 2H), 7.03 (m, 2H),
6.74 (s, 1H), 3.85 (s, 3H), 2.38 (s, 3H), 2.36 (s, 3H). 13C{1H}
NMR (DMSOd6, 100 MHz): δC 190.1, 176.1, 163.4, 160.4,
142.5, 134.4, 130.8, 129.9, 129.6, 123.7, 117.6, 114.8, 113.8,
99.4, 69.5, 55.5, 12.6, 11.7. MS (ESI): m/z 405.97 [М+H]+.
Anal. Calcd for C21H15N3O4S: C, 62.21; H, 3.73; N, 10.36; S,
7.91. Found: C, 62.36; H, 3.81; N, 10.37; S, 7.82.
1
(acetonitrile). IR (nujol) ν: 1670, 1713, 3134, 3376 cm-1. H
NMR (DMSOd6:PyD (2:3), 400 MHz): δH 8.19 (m, 2H), 7.17
(br. s, 2H), 7.12 (m, 2H), 7.09 (br. s, 2H), 3.83 (s, 3H), 2.95 (t,
J = 5.6 Hz, 2H), 2.69 (t, J = 5.8 Hz, 2H), 1.76 (m, 4H). 13C{1H}
NMR (DMSOd6:PyD (2:3), 100 MHz): δC 189.3, 175.9, 164.9,
163.9, 160.1, 149.5, 143.6, 135.4, 132.3, 131.0, 129.8, 128.1,
123.4, 118.1, 113.9, 89.4, 55.2, 24.8, 23.6, 22.3, 21.3. MS
(ESI): m/z 471.95 [М+Na]+. Anal. Calcd for C23H19N3O5S: C,
61.46; H, 4.26; N, 9.35; S, 7.13. Found: C, 61.32; H, 4.33; N,
9.57; S, 7.02.
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,7,8,9,10-octahydro-6H-cyclohepta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carbonitrile (4t). Obtained from
10c (1.19 g, 5 mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and malononitrile (0.13 g, 5
mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.76 g, 85 % yield; m.p.
284-285 °С (acetonitrile). IR (nujol) ν: 1684, 2217, 3184 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 7.96 (m, 2Н), 7.67 (m, 1Н),
7.53 (m, 2Н), 7.12 (s, 1H), 3.25 (m, 2H), 2.86 (m, 2H), 1.88 (m,
2H), 1.65 (m, 4H). 13C NMR (DMSOd6, 100 MHz): δC 191.3,
176.5, 159.2, 156.4, 142.5, 137.3, 135.9, 133.6, 133.3, 132.0,
128.6, 128.5, 118.2, 116.6, 112.3, 69.2, 31.5, 28.1, 27.2, 26.4,
26.4. MS (ESI): m/z 416.05 [М+H]+. Anal. Calcd for
C23H17N3O3S: C, 66.49; H, 4.12; N, 10.11; S, 7.72. Found: C,
66.51; H, 4.12; N, 10.08; S, 7.72.
1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carbonitrile (4p). Obtained from 10a (1.13 g, 5
mmol, 1 equiv), 8a (0.96 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and malononitrile (0.13 g, 5 mmol, 1 equiv), in
solution anhydrous toluene (50 ml) with Et3N (2.02 g, 0.4
mol/l). Yellow solid; 1.76 g, 88 % yield; m.p. 186-187 °С
1
(acetonitrile). IR (nujol) ν: 1666, 2201, 3323 cm-1. H NMR
(DMSOd6, 400 MHz): δH 7.93 (m, 2H), 7.63 (m, 1H), 7.50 (m,
2H), 6.66 (s, 1H), 2.86 (m, 2H), 2.72 (m, 2H), 1.79 (m, 4H).
13C{1H} NMR (DMSOd6, 100 MHz): δC 192.2, 176.0, 161.8,
161.2, 142.8, 136.6, 135.3, 133.2, 132.1, 128.4, 126.3, 117.2,
114.8, 113.2, 69.6, 25.2, 23.7, 22.4, 21.6. MS (ESI): m/z 401.97
[М+H]+. Anal. Calcd for C22H15N3O3S: C, 65.82; H, 3.77; N,
10.47; S, 7.99. Found: C, 65.73; H, 3.86; N, 10.36; S, 7.83.
(E)-1-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,5-dioxo-
1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-
a]pyrimidine-3-carbonitrile (4q). Obtained from 10a (1.13 g, 5
mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv), DCC (1.03 g, 5
mmol, 1 equiv) and malononitrile (0.13 g, 5 mmol, 1 equiv), in
solution anhydrous toluene (50 ml) with Et3N (2.02 g, 0.4
(E)-2,5-dioxo-1-(2-oxo-2-(p-tolyl)ethylidene)-
1,2,4,5,7,8,9,10-octahydro-6H-cyclohepta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carbonitrile (4u). Obtained from
10c (1.19 g, 5 mmol, 1 equiv), 8b (1.03 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and and malononitrile (0.13 g,
5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
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The Journal of Organic Chemistry
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Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.91 g, 89 % yield; m.p. the resulting solution was stirred at reflux 2 h (magnetic stirrer
289-290 °С (acetonitrile). IR (nujol) ν: 1687, 2216, 3185 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 7.84 (m, 2Н), 7.33 (m, 2Н),
7.07 (s, 1H), 3.26 (m, 2H), 2.86 (m, 2H), 1.88 (m, 2H), 1.65 (m,
4H). 13C NMR (DMSOd6, 100 MHz): δC 190.8, 176.4, 159.1,
156.4, 144.2, 142.5, 137.3, 133.6, 133.2, 131.9, 129.1, 128.6,
118.3, 111.6, 112.3, 69.2, 31.5, 28.1, 27.2, 26.4, 26.4, 21.2. MS
(ESI): m/z 430.06 [М+H]+. Anal. Calcd for C24H19N3O3S: C,
67.12; H, 4.46; N, 9.78; S, 7.46. Found: C, 67.14; H, 4.49; N,
9.77; S, 7.43.
equipped with aluminum block). Then from the hot solution the
precipitated urea was filtered off and the filtrate was cooled to
-27 °C, the precipitated product was filtered off. Dark red solid;
1.64 g, 86 % yield; m.p. 168-170 °С (toluene). IR (nujol) ν:
1
2
3
4
5
6
7
8
1
1607, 1715, 1796 cm-1. H NMR (CDCl3, 400 MHz): δH 7.85
(m, 2Н), 7.54 (m, 3Н), 6.90 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H),
2.82 (m, 2H), 2.76 (m, 2H), 1.88 (m, 4H), 1.42 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (CDCl3, 100 MHz): δC 165.8, 163.4, 162.4,
148.5, 138.7, 135.6, 132.2, 128.6, 128.4, 128.1, 126.6, 126.0,
97.4, 60.7, 25.2, 24.5, 22.2, 21.7, 13.7.
9
(E)-1-(2-(4-methoxyphenyl)-2-oxoethylidene)-2,5-dioxo-
1,2,4,5,7,8,9,10-octahydro-6H-cyclohepta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carbonitrile (4v). Obtained from
10c (1.19 g, 5 mmol, 1 equiv), 8c (1.11 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and and malononitrile (0.13 g,
5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.8 g, 81 % yield; m.p.
278-279 °С (acetonitrile). IR (nujol) ν: 1684, 2216, 3215 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 7.91 (m, 2Н), 7.04 (m, 3Н),
3.86 (s, 3H), 3.25 (m, 2H), 2.86 (m, 2H), 1.88 (m, 2H), 1.65 (m,
4H). 13C NMR (DMSOd6, 100 MHz): δC 189.5, 176.4, 163.6,
159.0, 156.3, 142.5, 137.3, 133.0, 131.9, 130.9, 129.0, 118.4,
116.6, 113.9, 112.3, 69.2, 55.6, 31.5, 28.1, 27.2, 26.4, 26.4. MS
(ESI): m/z 446.07 [М+H]+. Anal. Calcd for C24H19N3O4S: C,
64.71; H, 4.30; N, 9.43; S, 7.20. Found: C, 64.73; H, 4.28; N,
9.41; S, 7.23.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of ethyl (E)-2-amino-1-(3-(ethoxycarbonyl)-
4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-4-oxo-5-(2-oxo-2-
phenylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylate
(5). A mixture of 9 (1.91 g, 5 mmol) and ethyl 2-cyanoacetate
(0.57 g, 5 mmol) was dissolved in 50 ml of anhydrous toluene,
and Et3N was added (0.51 g, 5 mmol). The reaction mixture was
was stirred at r.t. for 24 h. Then the solution was cooled to -27
°C, the precipitated product was filtered off and recrystallized
from dioxane. White solid; 2.22 g, 90 % yield; m.p. 216-217 °С
1
(dioxane). IR (nujol) ν: 1712, 3247 cm-1. H NMR (DMSOd6,
400 MHz): δH 8.65 (s, 1H), 8.26 (s, 1H), 7.80 (m, 2H), 7.60 (m,
1H), 7.48 (m, 2H), 5.66 (s, 1H), 4.21 (m, 2Н), 4.10 (m, 2Н),
2.82 (m, 4H), 1.80 (m, 4H), 1.16 (m, 6H). 13C{1H} NMR
(DMSOd6, 100 MHz): δC 193.2, 174.4, 166.7, 164.2, 160.9,
142.2, 137.4, 137.1, 135.4, 133.9, 132.9, 129.7, 128.3, 128.2,
108.8, 86.4, 60.4, 58.3, 25.7, 24.7, 22.2, 21.8, 14.3, 13.6. MS
(ESI): m/z 495.05 [М+H]+. Anal. Calcd for C26H26N2O6S: C,
63.14; H, 5.30; N, 5.66; S, 6.48. Found: C, 63.08; H, 5.47; N,
5.82; S, 6.36.
(E)-2,5-dioxo-1-(2-oxo-2-phenylethylidene)-
1,2,4,5,6,7,8,9,10,11-decahydrocycloocta[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carbonitrile (4w). Obtained from
10d (1.19 g, 5 mmol, 1 equiv), 8a (0.98 g, 5 mmol, 1 equiv),
DCC (1.03 g, 5 mmol, 1 equiv) and and malononitrile (0.13 g,
5 mmol, 1 equiv), in solution anhydrous toluene (50 ml) with
Et3N (2.02 g, 0.4 mol/l). Yellow solid; 1.81 g, 87 % yield; m.p.
296-297 °С (acetonitrile). IR (nujol) ν: 1684, 2218, 3259 cm-1.
1H NMR (DMSOd6, 400 MHz): δH 7.97 (m, 2Н), 7.66 (m, 1Н),
7.53 (m, 1Н), 7.10 (s, 1H), 3.08 (m, 2H), 2.91 (m, 2H), 1.68 (m,
4H), 1.48 (m, 2H), 1.36 (m, 2H). 13C NMR (DMSOd6, 100
MHz): δC 191.2, 176.4, 159.4, 155.9, 143.6, 136.1, 134.7,
133.5, 130.9, 128.5, 128.5, 118.0, 116.3, 112.2, 69.4, 31.4, 29.2,
25.5, 25.3, 25.2, 24.0. MS (ESI): m/z 430.08 [М+H]+. Anal.
Calcd for C24H19N3O3S: C, 67.12; H, 4.46; N, 9.78; S, 7.72.
Found: C, 67.14; H, 4.44; N, 9.77; S, 7.73.
Synthesis of potassium (2Z,4Z)-2-cyano-1-ethoxy-4-((3-
(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-
yl)amino)-1,6-dioxo-6-phenylhexa-2,4-dien-3-olate (6). A
mixture of 9 (0.76 g, 2 mmol) and ethyl 2-cyanoacetate (0.23 g,
2 mmol) was dissolved in 20 ml of anhydrous dioxane, and t-
BuOK (0.22 g, 2 mmol) was added, the resulting solution was
stirred at 50 °C (magnetic stirrer equipped with aluminum
block) for 30 min. Then the solution was cooled to r.t. and the
precipitated product was filtered off. Yellow solid; 0.87 g, 82
% yield; m.p. 215-216 °С (dioxane). IR (nujol) ν: 1700, 2202,
3247 cm-1. 1H NMR (CDCl3, 400 MHz): δH 13.68 (s, 1H), 7.92
(m, 2H), 7.50 (m, 3H), 5.78 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H),
3.87 (q, J = 7.0 Hz, 2H), 2.71 (m, 2H), 2.58 (m, 2H), 1.73 (m,
4H), 1.37 (t, J = 7.0 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (CDCl3, 100 MHz): δC 188.0, 182.8, 166.7, 163.1, 159.7,
148.4, 139.1, 131.9, 131.3, 128.4, 126.9, 125.9, 121.3, 112.5,
92.6, 74.9, 59.9, 57.7, 26.0, 23.9, 22.5, 22.2, 14.3, 14.3. Anal.
Calcd for C26H25KN2O6S: C, 58.63; H, 4.73; N, 5.26; S, 6.02.
Found: C, 58.75; H, 4.74; N, 5.20; S, 5.91.
Synthesis
of
2-((3-(ethoxycarbonyl)-4,5,6,7-
tetrahydrobenzo[b]thiophen-2-yl)amino)-4-oxo-4-
phenylbut-2-enoic acid (7a). In a 100 mL of single-neck
round-bottom flask equipped with magnetic stirring (equipped
with aluminum block) and Dean-Stark trap, 10a (1.13 g, 5
mmol) was mixed with 8a (0.96 g, 5 mmol) in 50 ml of
anhydrous toluene, the resulting solution was stirred at reflux 1
h. The solution was cooled to -27 °C, the precipitated product
was filtered off and recrystallized from ethanol. Red solid; 1.88
g, 95 % yield; m.p. 189-190 °С (ethanol). IR (nujol) ν: 1708,
3431 cm-1. 1H NMR (CDCl3, 500 MHz): δH 12.28 (s, 1Н), 8.05
(m, 2H), 7.64 (m, 1H), 7.54 (m, 2H), 7.16 (s, 1H), 4.41 (q, J =
7.1 Hz, 2H), 2.84 (m, 2H), 2.78 (m, 2H), 1.85 (m, 4H), 1.41 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 125 MHz): δC 189.5,
164.3, 162.2, 146.1, 144.1, 137.5, 134.7, 133.7, 129.4, 129.0,
128.6, 118.2, 96.5, 61.3, 26.4, 24.9, 22.7, 22.4, 14.2.
Synthesis of ethyl 1-(2-(4-methoxyphenyl)-2-oxoethyl)-
2,5-dioxo-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-
e]pyrrolo[1,2-a]pyrimidine-3-carboxylate (11). A mixture of
4c (0.48 g, 1 mmol) and zinc dust (0.1 g) in 5 ml of glacial acetic
acid was stirred at 100°C (magnetic stirrer equipped with
aluminum block) for 1 h. Then to reaction mixture water was
added and product was extracted with DCM (3 × 10 ml). The
combined organic layers was dried under Na2SO4, concentrated
to dryness in vacuum and recrystallized from acetonitrile.
White solid; 0.34 g, 70 % yield; m.p. 206-208 °С (acetonitrile).
IR (nujol) ν: 168, 1709, 3236 cm-1. 1H NMR (CDCl3, 500 MHz)
δ (ppm): δH 10.75 (s, 1H), 7.90 (m, 2H), 6.93 (m, 2H), 4.78 (t,
J = 4.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.86 (m, 4H), 3.74
Synthesis of ethyl (E)-2-((2-oxo-5-phenylfuran-3(2H)-
ylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-
carboxylate (9a). A mixture of 7a (2.00 g, 5 mmol) and DCC
(1.03 g, 5 mmol) was dissolved in 50 ml of anhydrous toluene,
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
The manuscript was written through contributions of all authors.
(dd, J = 18.5, 4.2 Hz, 1H), 2.90 (m, 2H), 2.61 (m, 2H), 1.79 (m,
4H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (CDCl3, 125 MHz)
δ (ppm): δC 192.6, 187.1, 164.7, 164.0, 162.5, 154.6, 147.2,
133.5, 130.5, 128.6, 128.1, 116.1, 113.9, 88.1, 62.5, 60.4, 55.5,
36.9, 25.2, 24.4, 22.7, 21.6, 14.4. MS (ESI): m/z 502.98
[М+Na]+. Anal. Calcd for C25H24N2O6S: C, 62.49; H, 5.03; N,
5.83; S, 6.67. Found: C, 62.37; H, 5.12; N, 5.99; S, 6.53.
1
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7
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ACKNOWLEDGMENT
The authors thank Russian Science Foundation for grant 18-73-
00091.
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oxoethyl)-2,5-dioxo-1,2,4,5,6,7,8,9-
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Azambuja, E.; Azim, H. A.; Piccart, M., An update on PARP
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octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidine-
3-carboxylate (12). To a solution of 4c (0.48 g, 1 mmol) in 10
ml of methanol HCl (0.1 ml, 12M) was added and the resulting
solution was stirred at reflux (magnetic stirrer equipped with
aluminum block) for 1 h. Then the solution was cooled to r.t.,
the precipitated ptroduct was filtered off. Yellow solid; 0.44 g,
9
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11
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1
86 % yield. IR (nujol) ν: 1692, 1709, 3235 cm-1. H NMR
(CDCl3, 400 MHz): δH 11.82 (s, 1H), 7.87 (m, 2H), 6.89 (m,
2H), 4.55 (d, J = 17.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.97
(d, J = 17.9 Hz, 1H), 3.86 (s, 3H), 3.31 (s, 3H), 2.89 (m, 2H),
2.70 (m, 2H), 1.83 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (CDCl3, 100 MHz): δC 193.5, 185.1, 165.2, 163.3, 162.8,
153.8, 145.4, 132.6, 129.9, 128.9, 128.8, 117.4, 113.2, 92.6,
87.4, 60.1, 54.9, 50.7, 41.3, 24.7, 24.1, 22.2, 21.3, 13.9. MS
(ESI): m/z 510.16 [М+H]+. Anal. Calcd for C26H26N2O7S: C,
61.17; H, 5.13; N, 5.49; S, 6.28. Found: C, 61.28; H, 5.16; N,
5.40; S, 6.19.
2.
(a) Purnell, M. R.; Whish, W. J., Novel inhibitors of
poly(ADP-ribose) synthetase. Biochem. J. 1980, 185, 775; (b) Banasik,
M.; Komura, H.; Shimoyama, M.; Ueda, K., Specific inhibitors of
poly(ADP-ribose) synthetase and mono(ADP-ribosyl)transferase. J.
Biol. Chem. 1992, 267, 1569; (c) Ferraris, D. V., Evolution of
poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. from concept to
clinic. J. Med. Chem. 2010, 53, 4561.
Synthesis
of
ethyl
2,5-dioxo-1,2,4,5,6,7,8,9-
octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidine-
3-carboxylate (13). A mixture of 4c (0.48 g, 1 mmol) and
NH2OH·HCl (0.07 g, 1 mmol) was dissolved in 10 ml of
anhydrous dioxane, and KOH (0.08 g) was added. The resulting
mixture was stirred at r.t. for 1 h, then to reaction mixture water
was added and desired product was extracted with DCM (3 ×
10ml). The combined organic layers was dried under Na2SO4,
concentrated to dryness in vacuum and recrystallized from
acetonitrile.White solid; 0.44 g, 83 % yield; m.p. 275-277 °С
3.
(a) Le, T. V. T.; Suh, J. H.; Kim, N.; Park, H. J., In silico
identification of poly(ADP-ribose)polymerase-1 inhibitors and their
chemosensitizing effects against cisplatin-resistant human gastric
cancer cells. Bioorg. Med. Chem. Lett. 2013, 23, 2642; (b) Hemalatha,
K.; Madhumitha, G., Inhibition of poly(adenosine diphosphate-ribose)
polymerase using quinazolinone nucleus. App. Microbiol. and
Biotechnol. 2016, 100, 7799; (c) Kulkarni, S. S.; Singh, S.; Shah, J. R.;
Low, W. K.; Talele, T. T., Synthesis and SAR optimization of
quinazolin-4(3H)-ones as poly(ADP-ribose)polymerase-1 inhibitors.
Eur. J. Med. Chem. 2012, 50, 264; (d) Hemalatha, K.; Madhumitha, G.;
Vasavi, C. S.; Munusami, P., 2,3-dihydroquinazolin-4(1H)-ones:
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activity. J. Photochem. Photobiol., B 2015, 143, 139; (e) Hattori, K.;
Kido, Y.; Yamamoto, H.; Ishida, J.; Iwashita, A.; Mihara, K., Rational
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poly(ADP-ribose)polymerase. Bioorg. Med. Chem. Lett. 2007, 17,
5577; (f) Giannini, G.; Battistuzzi, G.; Vesci, L.; Milazzo, F. M.; De
Paolis, F.; Barbarino, M.; Guglielmi, M. B.; Carollo, V.; Gallo, G.;
Artali, R.; Dallavalle, S., Novel PARP-1 inhibitors based on a 2-
propanoyl-3H-quinazolin-4-one scaffold. Bioorg. Med. Chem. Lett.
2014, 24, 462; (g) Iwashita, A.; Hattori, K.; Yamamoto, H.; Ishida, J.;
Kido, Y.; Kamijo, K.; Murano, K.; Miyake, H.; Kinoshita, T.;
Warizaya, M.; Ohkubo, M.; Matsuoka, N.; Mutoh, S., Discovery of
quinazolinone and quinoxaline derivatives as potent and selective
poly(ADP-ribose) polymerase-1/2 inhibitors. FEBS Lett. 2005, 579,
1389; (h) Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.;
Murano, K.; Ohkubo, M.; Kinoshita, T.; Iwashita, A.; Mihara, K.;
Yamazaki, S.; Matsuoka, N.; Teramura, Y.; Miyake, H., Rational
approaches to discovery of orally active and brain-penetrable
quinazolinone inhibitors of poly(ADP-ribose)polymerase. J. Med.
Chem. 2004, 47, 4151 - 4154; (i) Ishida, J.; Yamamoto, H.; Kido, Y.;
Kamijo, K.; Murano, K.; Miyake, H.; Ohkubo, M.; Kinoshita, T.;
Warizaya, M.; Iwashita, A.; Mihara, K.; Matsuoka, N.; Hattori, K.,
Discovery of potent and selective PARP-1 and PARP-2 inhibitors:
SBDD analysis via a combination of X-ray structural study and
homology modeling. Bioorg. Med. Chem. 2006, 14, 1378.
1
(acetonitrile). H NMR (CDCl3, 400 MHz): δH 10.60 (s, 1H),
4.39 (q, J = 7.1 Hz, 2H), 4.23 (s, 2H), 2.96 (m, 2H), 2.74 (m,
2H), 1.88 (m, 4H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(CDCl3, 100 MHz): δC 183.7, 164.0, 162.3, 154.1, 147.7, 133.4,
127.9, 115.1, 88.6, 60.0, 54.7, 24.8, 24.1, 22.3, 21.2, 14.0. MS
(ESI): m/z 332.90 [М+H]+. Anal. Calcd for C16H16N2O4S: C,
57.82; H, 4.85; N, 8.43; S, 9.65. Found: C, 57.87; H, 4.61; N,
8.32; S, 9.51.%:
ASSOCIATED CONTENT
Supporting Information

X-ray crystallographic for compound 4a and 13 and
copies of 1H and 13C NMR spectra for all products (PDF)

Crystallographic data for compound 4a (CIF) and 13
(CIF)
The Supporting Information is available free of charge on the ACS
Publications website.
AUTHOR INFORMATION
Corresponding Author
4.
Honda, T. E., H.; Kawashima, K.; Takaoka, S.; Fujioka, Y.;
*E-mail: rubtsov@psu.ru
Matsuda, M.; Ohashi, K.; Fujita, Y.; Hirai, S.; Kurashima, H. Novel
Author Contributions
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The Journal of Organic Chemistry
Page 10 of 10
compound having PARP inhibitory activity. WO Patent 2013008872,
January 17, 2013.
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benzothieno[3,2-e]pyrrolo[1,2-a]pyrimidinones
pyrrolo[1,2-a]thieno[3,2-e]pyrimidinones,
and 6H-
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