Synthesis of new thienopyridine derivatives by a reaction of 4-(Methylsulfanyl)-6,7-dihydrothieno[3,2-c]pyridine with amino acids

Article abstract of DOI:10.1002/hc.21073

New thienopyridine derivatives were synthesized by the reaction of 4-(methylsulfanyl)-6,7-dihydrothieno[3,2-c]pyridine (5) with amino acids. The use of β-amino acids led to thienopyridopyrimidone derivatives (9a-g). Using α-amino acids, such as glycine and racemic alanine under the same reaction conditions, compounds with two thienopyridine units were obtained. The structure of the novel compounds was confirmed by IR, ¹³C, and ¹H NMR spectroscopy, as well as mass spectrometry, along with single crystal X-ray analysis. 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:124-130, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21073

Full text of DOI:10.1002/hc.21073

Heteroatom Chemistry
Volume 24, Number 2, 2013
Synthesis of New Thienopyridine Derivatives
by a Reaction of 4-(Methylsulfanyl)-6,7-
dihydrothieno[3,2-c]pyridine with Amino
Acids
1
2
Ma´tya´s Milen,1,2 Pe´ter Abra´nyi-Balogh, Andra´s Dancso´,
´
La´szlo´ Drahos,3 and Gyo¨rgy Keglevich1
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary
2EGIS Pharmaceuticals PLC, Division for Chemical Research, H-1475 Budapest, P.O.B. 100,
Hungary
3Hungarian Academy of Sciences, Chemical Research Center, H-1525 Budapest, Hungary
Received 17 September 2012; revised 3 December 2012
and pharmacological activities. For example, ticlo-
ABSTRACT: New thienopyridine derivatives were
pidine (1), (S)-clopidogrel (2), and prasugrel (3)
synthesized by the reaction of 4-(methylsulfanyl)-6,7-
are adenosine diphosphate receptor antagonist (see
dihydrothieno[3,2-c]pyridine (5) with amino acids.
Fig. 1). These compounds block the P2Y12 receptors
The use of β-amino acids led to thienopyridopyrim-
and thus inhibit platelet activation and aggregation
idone derivatives (9a–g). Using α-amino acids, such
[1–4]. Antiplatelet agents are useful in the preven-
as glycine and racemic alanine under the same reac-
tion of stroke, myocardial infarction, and thrombo-
tion conditions, compounds with two thienopyridine
sis [5–7]. Ticlopidine (1) and clopidogrel (2) have
units were obtained. The structure of the novel com-
similar pharmacological activity, but they have dif-
pounds was confirmed by IR, 13C, and 1H NMR spec-
ferent pharmacokinetics; clopidogrel (2) has fewer
troscopy, as well as mass spectrometry, along with
side effects than ticlopidine (1) [8]. (S)-Clopidogrel
ꢀC
single crystal X-ray analysis.
2013 Wiley Periodi-
(Plavix) (2) was the worldꢁs second highest selling
pharmaceutical in the mid-2000s, and the synthesis
of this antiplatelet agent has been extensively inves-
tigated [9,10].
cals, Inc. Heteroatom Chem 24:124–130, 2013; View
this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21073
In our earlier study, the [3+2] cycloaddi-
tions and Staudinger reaction were investigated
to synthesize novel fused tricyclic, conformation-
ally constrained thienopyridines [11]. As a con-
tinuation of our work, we now describe fused
thienopyridine derivatives of other types. The
starting material (4) was prepared by a sim-
ple procedure from commercially available 4,5,6,7-
tetrahydrothieno[3,2-c]pyridine in a reaction with
elemental sulfur [12].
INTRODUCTION
The thienopyridine scaffold can be found in a few
synthetic compounds having important biological
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@mail
.bme.hu.
ꢀC
2013 Wiley Periodicals, Inc.
124

Synthesis of Thienopyridine Derivatives 125
FIGURE 1 Ticlopidine (1), (S)-clopidogrel (2), and prasugrel (3).
SCHEME 1 The thienopyridine scaffold in synthetic drugs.
RESULTS AND DISCUSSION
The reaction sequence is shown in Scheme 1/(1).
In accordance with earlier experiences [14], the
alkylthio group in the iminothioether function could
be substituted easily by amino compounds.
The key intermediate, 4-(methylsulfanyl)-6,7-
dihydrothieno[3,2-c]pyridine (5), was obtained in
a yield of 91% by S-methylation of the starting
material (4) with 1.1 equiv of methyl iodide in
acetonitrile/dichloromethane at 26◦C for 24 h
(Scheme 1). The alkylation was carried out in the
presence of Cs2CO3 that is in most cases more
favorable in the solid–liquid phase alkylations than
the other alkali carbonates [13].
Next, the reaction was investigated under
the same conditions, but with more special β-
amino acids, such as substituted anthranilic acids
(6b–g) (Scheme 1 (2)). The reaction of start-
ing material 5 with 4-chloro-, 5-chloro-, 6-chloro-,
and 4-fluoroanthranilic acids (6b–e) resulted in
the formation of the appropriate tetracycles (9b–
e) in moderate to reasonable yields (42–64%).
When the reaction was carried out with 2-
amino-5-methoxybenzoic acid (6f) and 2-amino-
5-hydroxybenzoic acid (6g), the fused tetracyclic
products 9f and 9g were obtained in a 76% and
82% yield, respectively. No reaction took place
with reagents containing less nucleophilic amino
groups, such as 2-amino-3,5-dichlorobenzoic acid,
2-amino-4-nitrobenzoic acid, and 4-amino-nicotinic
acid.
The Reaction of 4-(Methylsulfanyl)-6,7-dihydro-
thieno[3,2-c]pyridine (5) with β-Amino Acids
(6a–g)
First, the 4-(methylsulfanyl)-6,7-dihydrothieno[3,2-
c]pyridine (5) was treated with β-alanine (6a) in
glacial acetic acid at reflux temperature. The tri-
heterocyclic product (9a) was obtained only in a
33% yield after purification by chromatography.
Heteroatom Chemistry DOI 10.1002/hc

126 Milen et al.
et al. observed the analogous transformation
of 1-(ethylsulfanyl)-3,4-dihydroisoquinoline with
glycine in boiling aqueous ethanol in the presence
of equimolar sodium bicarbonate and prepared
isoquinoline analogues of 11 [16].
When racemic alanine (6i) was used instead of
glycine, 6,7-dihydro-5H-thieno[3,2-c]pyridine-4-one
(12) was obtained in a yield of 56% as the main
product. Compound 12 is known from the literature
[17]. A smaller amount of thienopyridinone (12) was
detected by LC-MS in all reactions. As another com-
ponent, a “dimer” compound (13) was also observed
in the reaction of 5 with alanine. The by-product
(13) was obtained in a 24% yield, and it can be
formed from intermediate 14 in a radical reaction
(Scheme 3).
The reaction of starting material 5 and 2-amino-
2-methylpropionic acid (2,2-dimethyl-glycine) gave
only 12 as the product in a conversion of 96% after
a 6 h reflux.
The structure of the new compounds (11 and 13)
was proved by NMR spectroscopy and single crys-
tal X-ray analysis. Perspective views of 11 and 13
are shown in Figs. 3 and 4, respectively. It is noted
that heterocycle 13 has two stereogenic centers com-
bined with a constitutional symmetry, and actually
it is the SR-configuration that is the meso form.
In summary, novel fused thienopyridine
derivatives (9a–g) were synthesized by the re-
FIGURE 2 Perspective view of thienopyridoquinazolone
derivative (9f) (the crystal contained 1 mol of water).
In the reaction of iminothioethers with β-amino
acids or β-amino acid esters, a one-pot cycloconden-
sation took place after substitution [15].
The structure of products 9a–g was proved by
1
IR, 13C, and H NMR spectroscopy, as well as mass
spectrometry. The new ring system was also justified
by single crystal X-ray analysis. A perspective view
of compound 9f is shown in Fig. 2.
The Reaction of 4-(Methylsulfanyl)-6,7-dihydro-
thieno[3,2-c]pyridine (5) with α-Amino Acids
(6h–j)
action
of
4-(methylsulfanyl)-6,7-dihydrothieno
[3,2-c]pyridine (5) and β-amino acids (6a–g). The
reaction of compound 5 with glycine (6h) and
alanine (6i) under the same conditions afforded
products containing two thienopyridine units.
These products (11 and 13) may be formed via
active intermediates 10 and 14, respectively.
Then, the reaction of 4-(methylsulfanyl)-6,7-
dihydrothieno[3,2-c]pyridine (5) was studied
with glycine, racemic alanine, and 2-amino-2-
methylpropionic acid using glacial acetic acid as
the solvent. The condensation reaction of starting
material 5 with glycine (6h) afforded (2E)-2-(6,-
7-dihydrothieno[3,2-c]pyridine-4(5H)-ylidene)-5,6-
dihydroimidazo[1,2-a]thieno[3,2-c]pyridine-3(2H)-
one 11 in a yield of 77%. Presumably, this reaction
takes place via intermediate 10, which contains
an active methylene group between the imine and
the amide functions (Scheme 2). Gomez-Parra
EXPERIMENTAL
General
All melting points were measured with a Kofler–
Boe¨tius micro apparatus and were not corrected.
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Thienopyridine Derivatives 127
SCHEME 3
FIGURE 3 Perspective view of dihydroimidazothienopyri-
done derivative (11).
1H and 13C NMR spectra were recorded with a Var-
ian Unity Inova 500 (500 and 125 MHz for H and
FIGURE 4 Perspective view of bisimidazothienopyridone
derivative (13) (one of the two conformers).
1
13C NMR spectra, respectively; Agilent Technologies
Inc., Santa Clara, CA) or with a Bruker Avance III
(400 and 100 MHz for 1H and 13C NMR spectra,
respectively) spectrometer (Bruker BioSpin GmbH,
Rheinstetten, Germany). Deuterated dimethyl sul-
foxide ([D6]DMSO) or CDCl3 was used as the sol-
vent, and tetramethylsilane was used as the internal
standard. Chemical shifts (δ) and coupling constants
(J) are given in ppm and in Hz, respectively.
III analyzer. The reactions were followed by analyti-
cal thin layer chromatography on silica gel 60 PF254
and LC-MS chromatography. Analytical samples of
new compounds were obtained by recrystallization
from the solvents given below.
The numbering of the basic ring systems is
shown in Fig. 5.
The FT-IR spectra were recorded with a Bruker
Alpha spectrometer using KBr pellets or neat. Single
crystal X-ray measurements were carried out on a
Rigaku R-Axis Spider instrument (Rigaku Americas,
The Woodlands, TX). A sealed copper X-ray tube
Preparation of 4-methylsulfanyl)-6,7-
dihydrothieno[3,2-c]pyridine(5)
To
a
solution of 5.4
g
(32.0 mmol) 6,7-
˚
was used at 1.6 kW, λ = 1.541870 A. Data collec-
dihydrothieno[3,2-c]pyridine-4(5H)-thione (4) and
12.4 g (38.0 mmol) Cs2CO3 in the solvents of 130 mL
acetonitrile and 60 mL dichloromethane, 2.2 mL
(35.0 mmol, 5.0 g) methyl iodide was added. The
reaction mixture was stirred at 26◦C for 24 h. After
tion was made at room temperature; all the calcula-
tions and the structure solutions were made by the
Rigaku CrystalStructure and CrystalClear softwares.
Elemental analyses were performed with a Vario EL
Heteroatom Chemistry DOI 10.1002/hc

128 Milen et al.
by flash-chromatography on silica (PF254) using
hexane-dichloromethane as the eluent.
The following products were thus prepared.
2,3,6,7-Tetrahydro-4H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[1,2-a]pyrimidin-4-one (9a)*. Yield 0.11 g (33%);
white crystals; mp 155–157◦C (EtOH); IR (KBr):
ν = 1686, 1645, 1416, 1380, 1320, 692 cm−1
;
1H
NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 5.3 Hz,
1H), 7.14 (d, J = 5.3 Hz, 1H), 4.18 (t, J = 6.1 Hz,
2H), 3.75 (t, J = 7.3 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H),
2.56 (t, J = 7.3 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ = 169.3 (CO-4), 147.9 (C-10b), 142.6 (C-10a), 131.4
(C-7a), 125.3 (C-9), 123.9 (C-10), 43.0 (C-2), 39.3
(C-6), 30.6 (C-3), 24.2 (C-7); C10H10N2OS (206.27):
calcd: C, 58.23; H, 4.89; N, 13.58, S, 15.54; found: C,
57.90; H, 4.83; N, 13.48; S, 15.35. HRMS calcd. for
C10H11N2O2 [M + H]+ 207.0592; found 207.0591.
FIGURE 5 Numbering of the basic 2,3,6,7-tetrahydro-
4H-thieno[3ꢁ,2ꢁ:3,4]pyrido[1,2-a]pyrimidin-4-one (*) and 4,5-
dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido[2,1-b]quinazolin-7-one ($)
scaffolds.
that the inorganic salts were filtered off, and the fil-
trate was concentrated. Then the residue was taken
up in dichloromethane (50 mL) and the mixture was
washed with water twice (2×30 mL). Finally, the or-
ganic phase was dried (MgSO4), filtered, and concen-
trated under reduced pressure. The crude product
was purified by bulb-to-bulb distillation.
10-Chloro-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9b)$. Yield 0.30 g (64%);
white crystals; mp 193–195◦C (CH3CN); IR (KBr):
ν = 1671, 1590, 1416, 1314, 690 cm−1; 1H NMR (400
MHz, CDCl3): δ = 8.19 (d, J = 8.6 Hz, 1H), 7.69 (d,
J = 4.8 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.36 (dd,
J1 = 2.0 Hz, J2 = 8.5 Hz, 1H), 7.24 (d, J = 5.2 Hz,
1H), 4.51 (t, J = 6.7 Hz, 2H), 3.22 (t, J = 6.7 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ = 161.1 (CO-7),
148.8 (C-11a), 147.9 (C-12a), 143.5 (C-12b), 140.4
(CCl-10), 132.0 (C-3a), 128.4 (C-8), 126.8 (two signs
C-9 and C-11), 125.9 (C-2), 124.5 (C-1), 119.2 (C-7a),
40.6 (C-5), 23.2 (C-4). C14H9ClN2OS (288.76): calcd:
C, 58.23; H, 3.14; Cl, 12.28; N, 9.70, S, 11.10; found:
C, 58.05; H, 3.19; Cl, 12.17; N, 9.66; S, 11.02. HRMS
calcd. for C14H10ClN2OS [M + H]+ 289.0202; found
289.0206.
Yield 5.4 g (91%); light yellow liquid; bp
80◦C/0.41 mbar; IR (film): ν = 1581, 1236, 1166,
1
864 cm−1; H NMR (500 MHz, CDCl3): δ = 7.15 (d,
J = 4.9 Hz, 1H), 7.06 (d, J = 5.1 Hz, 1H), 3.85 (t,
J = 7.9 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.44 (s, 3H)
{lit [18] τ (CDCl3) 2.88 (1H, d, J 5.0 Hz, 2-H), 3.03
(1H, d, J 5.0 Hz, 3-H), 6.18 (2H, t, J 7.5 Hz, 6-H2),
7.20 (2H, t, J 7.5 Hz, 7-H2), and 7.58 (3H, s, Me)}; 13
C
NMR (125 MHz, CDCl3): δ = 160.2 (C-4), 141.8 (C-
3a), 131.1 (C-7a), 123.3 (C-2), 122.2 (C-3), 49.0 (C-6),
22.8 (C-7), 11.7 (S-CH3).
9-Chloro-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9c)$. Yield 0.26 g (54%);
white crystals; mp 198–200◦C (EtOH); IR (KBr):
General Procedure for the Preparation of the
Thienopyridine Derivatives
ν = 1658, 1579, 1558, 1472 cm−1
;
1H NMR (400
The suspension of an equimolar amount of
4-(methylsulfanyl)-6,7-dihydrothieno[3,2-c]pyridine
(5) (0.30 g, 1.6 mmol) and amino acids [0.15 g
of β-alanine (6a), 0.28 g of 4-chloroanthranilic
MHz, CDCl3): δ = 8.25–8.23 (m, 1H), 7.69 (d, J = 5.2
Hz, 1H), 7.65–7.63 (m, 2H), 7.24 (d, J = 5.2 Hz, 1H),
4.52 (t, J = 6.7 Hz, 2H), 3.22 (t, J = 6.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ = 160.7 (CO-7), 147.0
(C-12a), 146.4 (C-11a), 143.2 (C-12b), 134.6 (C-10),
132.0 (CCl-9), 131.9 (C-3a), 128.9 (C-8), 126.3 (C-11),
125.8 (C-2), 124.5 (C-1), 121.8 (C-7a), 40.7 (C-5),
23.2 (C-4). C14H9ClN2OS (288.76): calcd: C, 58.23;
H, 3.14; Cl, 12.28; N, 9.70, S, 11.10; found: C, 58.05;
H, 3.23; Cl, 12.05; N, 9.69; S, 11.02. HRMS calcd. for
C14H10ClN2OS [M + H]+ 289.0202; found 289.0208.
acid (6b), 0.28
g of 5-chloroanthranilic acid
(6c), 0.28 of 6-chloroanthranilic acid (6d),
g
0.25 g of 4-fluoroanthranilic acid (6e), 0.27 g of
2-amino-5-methoxybenzoic acid (6f), 0.25 g of 2-
amino-5-hydroxybenzoic acid (6g), 0.12 g of glycine
(6h), 0.15 g of racemic alanine (6i), and 0.17 g of
2-amino-2-methylpropionic acid] was refluxed in
glacial acetic acid (20 mL) until the starting material
disappeared (2–8 h). After cooling, evaporation of
the solvent gave a crude product, which was purified
8-Chloro-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9d)$. Yield 0.26 g (54%);
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Thienopyridine Derivatives 129
white crystals; mp 225–226◦C (EtOH); IR (KBr):
285.0698; found 285.0697. X-ray structure: CCDC
900934.
ν = 1679, 1670, 1455, 808, 687 cm−1
;
1H NMR
(500 MHz, CDCl3): δ = 7.69 (d, J = 5.3 Hz, 1H),
7.59 dd (J1 = 1.5 Hz, J2 = 8.2 Hz, 1H), 7.57–7.53 (m,
1H), 7.41 (dd, J1 = 1.5 Hz, J2 = 7.7 Hz, 1H), 7.23
(d, J = 5.1 Hz, 1H), 4.48 (t, J = 6.7 Hz, 2H), 3.20
(t, J = 6.8 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ = 159.8 (CO-7), 150.3 (C-11a), 147.4 (C-12a), 143.6
(C-12b), 134.2 (CCl-8), 133.5 (C-10), 131.9 (C-3a),
129.0 (C-9), 126.7 (C-11), 125.8 (C-2), 124.5 (C-1),
118.0 (C-7a), 40.6 (C-5), 23.3 (C-4). C14H9ClN2OS
(288.76): calcd: C, 58.23; H, 3.14; Cl, 12.28; N, 9.70,
S, 11.10; found: C, 58.28; H, 3.23; Cl, 12.16; N, 9.72;
S, 11.06. HRMS calcd. for C14H10ClN2OS [M + H]+
289.0202; found 289.0207.
9-Hydroxy-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9g)$. Yield 0.36 g (82%);
white crystals; mp 274–276◦C (EtOH); IR (KBr):
ν = 3261, 1636, 1585, 1308, 835 cm−1; 1H NMR (500
MHz, DMSO): δ = 10.03 (bs, 1H), 7.57 (d, J = 5.1
Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 5.1
Hz, 1H), 7.45 (d, J = 2.9 Hz, 1H), 7.26 (dd, J1 = 2.9
Hz, J2 = 8.8 Hz, 1H), 4.39 (t, J = 6.7 Hz, 2H), 3.22
(t, J = 6.7 Hz, 2H); 13C NMR (125 MHz, DMSO):
δ = 160.4 (CO-7), 156.0 (C-9), 144.4 (C-12a), 142.8
(C-12b), 140.6 (C-11a), 131.9 (C-3a), 128.8 (C-11),
125.2 (two signs C-2 and C-10), 124.0 (C-1), 121.6 (C-
7a), 109.5 (C-8), 40.2 (C-5), 22.6 (C-4); C14H10N2O2S
(270.31): calcd: C, 62.21; H, 3.73; N, 10.36; S, 11.86;
found: C, 62.05; H, 3.79; N, 10.25; S, 11.73. HRMS
calcd. for C14H11N2O2S [M + H]+ 271.0541; found
271.0546.
10-Fluoro-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9e)$. Yield 0.19 g (42%);
white crystals; mp 177–178◦C (CH3CN); IR (KBr):
ν = 1661, 1587, 1484, 1135, 695 cm−1
;
1H NMR
(400 MHz, CDCl3): δ = 8.28 (dd, J1 = 6.0 Hz,
J2 = 8.8 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.33
(dd, J1 = 2.6 Hz, J2 = 9.7 Hz, 1H), 7.24 (d, J = 5.3
Hz, 1H), 7.15–7.11 (m, 1H), 4.52 (t, J = 6.8 Hz,
2H), 3.22 (t, J = 6.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ = 166.5 (d, J = 253.9 Hz, CF-10), 161.0
(CO-7), 150.0 (d, J = 13.2, C-11a), 147.9 (C-12a),
143.5 (C-12b), 132.1 (C-3a), 129.6 (d, J = 10.7 Hz,
C-8), 126.0 (C-2), 124.5 (C-1), 117.6 (d, J = 2.1 Hz,
C-7a), 115.0 (d, J = 23.4 Hz, C-9), 112.5 (d, J = 22.0
Hz, C-11), 40.5 (C-5), 23.3 (C-4). C14H9FN2OS
(272.30): calcd: C, 61.75; H, 3.33; N, 10.29, S, 11.78;
found: C, 61.81; H, 3.34; N, 10.33; S, 11.68. HRMS
calcd. for C14H10FN2OS [M + H]+ 273.0498; found
273.0500.
(2E)-2-(6,7-Dihydrothieno[3,2-c]pyridine-4(5H)-
ylidene)-5,6-dihydroimidazo[1,2-a]thieno[3,2-c]
pyridine-3(2H)-one (11). Yield 0.41 g (77%); yellow
crystals; mp 249–250◦C (CHCl3-EtOH); IR (KBr):
ν = 1616, 1479, 1310, 1293, 1216, 689 cm−1
;
1H
NMR (400 MHz, DMSO): δ = 9.20 (bs, 1H), 8.44
(d, J = 5.3 Hz, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.49
(d, J = 5.3 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 3.87
(t, J = 6.8 Hz, 2H), 3.67–3.63 (m, 2H), 3.18 (t,
J = 6.7 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H); 13C NMR
(100 MHz, DMSO): δ = 166.8 (CO-3), 145.8 (C-4ꢁ),
144.2 (C-9b), 140.4 (C-9a), 138.8 (C-3aꢁ), 129.2
(C-2ꢁ), 128.6 (C-6a)a, 128.3 (C-7aꢁ)b, 125.5 (C-8),
123.4 (C-9), 122.8 (C-2ꢁ), 113.9 (C-2), 39.6 (C-6ꢁ),
a-b c-d
37.3 (C-5), 23.7 (C-6)c, 23.3 (C-7ꢁ)d,
,
may be
reversed; C16H13N3OS2 (327.43): calcd: C, 58.69; H,
4.00; N, 12.83; S, 19.59; found: C, 58.54; H, 4.02;
N, 12.73; S, 19.41. HRMS calcd. for C16H14N3OS2
[MH+] 328.0578; found 328.0583. X-ray structure:
CCDC 900932.
9-Methoxy-4,5-dihydro-7H-thieno[3ꢁ,2ꢁ:3,4]pyrido
[2,1-b]quinazole-7-one (9f)$. Yield 0.35 g (76%);
white crystals; mp 164–165◦C (CH3CN); IR (KBr):
ν = 1656, 1488, 1361, 1025, 831, 720 cm−1; 1H NMR
(500 MHz, CDCl3): δ = 7.69 (d, J = 5.1 Hz, 1H), 7.66
(d, J = 2.9 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.32
(dd, J1 = 3.1 Hz, J2 = 9.0 Hz, 1H), 7.22 (d, J = 5.3
Hz, 1H), 4.54 (t, J = 6.7 Hz, 2H), 3.92 (s, 3H), 3.20
(t, J = 6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ = 161.5 (CO-7), 158.1 (C-9), 145.0 (C-12a), 142.4
(C-12b), 141.9 (11-a), 132.4 (C-3a), 128.9 (C-11),
125.7 (C-2), 124.5 (C-10), 124.2 (C-1), 121.5 (C-7a),
106.5 (C-8), 55.8 (OCH3), 40.7 (C-5), 23.3 (C-4).
C15H12N2O2S (284.34): calcd: C, 63.36; H, 4.25; N,
9.85; S, 11.28; found: C, 63.17; H, 4.22; N, 9.83; S,
11.19. HRMS calcd. for C14H13N2O2S [M + H]+
6,7-Dihydrothieno[3,2-c]pyridine-4(5H)-one (12).
Yield 0.14 g (56%); white crystals; mp 89–91◦C
(EtOAc-Et2O); IR (KBr): ν = 3289, 1659, 1633, 1484,
1314 cm−1
;
1H NMR (500 MHz, CDCl3): δ = 7.43
(d, J = 5.3 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 6.64
(b, 1H), 3.66–3.63 (m, 2H), 3.06 (t, J = 6.9 Hz, 2H)
{lit [17] (300 MHz, CDCl3) δ = 7.45 (d, 1H), 7.13 (d,
1H), 5.9–5.7 (br s, 1H), 3.7–3.6 (m, 2H), 3.1 (t, 2H)};
13C NMR (125 MHz, CDCl3): δ = 164.0 (CO-4), 146.1
(C-3a), 132.1 (C-7a), 125.9 (C-2), 123.0 (C-3), 41.2 (C-
6), 24.4 (C-7). HRMS calcd. for C7H8NOS [M + H]+
154.0327; found 154.0329.
Heteroatom Chemistry DOI 10.1002/hc

130 Milen et al.
2,2ꢁ-Dimethyl-5,5ꢁ,6,6ꢁ-tetrahydro-2,2ꢁ-bisimidazo
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menthala, P. R.; Padi, P. R. Org Process Res Dev 2012,
16, 240–243.
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J Clinic Invest 2012, 42, 384–392.
[1,2-a]thieno[3,2-c]pyridine-3,3ꢁ (2H,2ꢁH)-dione (13).
Yield 0.08 g (24%); light brown crystals; mp 200–
202◦C (decomp.), (MeOH); IR (KBr): ν = 1726,
1637, 1473, 1342, 1308, 967, 708 cm−1 1H NMR
;
[5] Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin,
W. L.; Meekes, H.; Enckevort, W. J. P.; Kaptein, B.;
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1667–1672.
(500 MHz, CDCl3): δ = 7.48 (d, J = 5.3 Hz, 2H), 7.20
(d, J = 5.3 Hz, 2H), 3.91–3.86 (m, 2H), 3.71–3.65
(m, 2H), 3.13 (t, J = 6.2 Hz, 4H), 1.69 (s, 6H); 13C
NMR (125 MHz, CDCl3): δ = 181.7 (CO-3, CO-3ꢁ),
153.9 (C-9b, C-9bꢁ), 144.6 (C-9a, C-9aꢁ), 127.4 (C-6a,
C-6aꢁ), 124.7 (C-8, C-8ꢁ), 124.3 (C-9, C-9ꢁ), 75.2 (C-2,
C-2ꢁ), 37.7 (C-5, C-5ꢁ), 23.6 (C-6, C-6ꢁ), 17.9 (2×CH3);
HRMS calcd. for C20H19N4O2S2 [M + H]+ 411.0949;
found 411.0952. X-ray structure: CCDC 900933.
[9] Kalinski, C.; Lemonie, H.; Schmidt. J.; Burdack, C.;
Kolb, J.; Umkehrer, M.; Ross, G. Synthesis 2008, 24,
4007–4011.
[10] Aillaud, I.; Haurena, C.; Gall, E. L.; Martens, T.; Ricci,
G. Molecules 2010, 15, 8144–8155.
[11] Milen, M.; Abra´nyi-Balogh P.; Dancso´, A.; Keglevich,
SUPPORTING INFORMATION
´
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[12] Milen, M.; Abra´nyi-Balogh P.; Dancso´, A.; Keglevich,
Deposited X-ray structures can be found at
the Cambridge Crystallographic Data Centre,
http://www.ccdc.cam.ac.uk.
´
G. y. J Sulfur Chem 2012, 33, 33–41.
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ACKNOWLEDGEMENT
The authors are grateful to Re´ka Puska´s for the mi-
croanalyses.
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Heteroatom Chemistry DOI 10.1002/hc