Synthesis of new thienopyridine derivatives by [3+2]- and [2+2]-cycloaddition reactions

Article abstract of DOI:10.1055/s-0032-1316794

The reaction of 6,7-dihydrothieno[3,2-c]pyridine derivatives with 1,3-dipoles, such as a nitrile oxides or nitrile imines, gave novel fused heterocycles. The Staudinger reaction of the starting material was also studied. This reaction was stereoselective

Full text of DOI:10.1055/s-0032-1316794

PAPER
▌3447
paper
Synthesis of New Thienopyridine Derivatives by [3+2]- and [2+2]-Cycloaddition
Reactions
New Thienopyridine Derivatives
Mátyás Milen,*a,b Péter Ábrányi-Balogh,a András Dancsó,b György Keglevich*a
a
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
b
EGIS Pharmaceuticals PLC, Division for Chemical Research, P.O.B. 100, 1475 Budapest, Hungary
Fax +36(1)4633648; E-mail: gkeglevich@mail.bme.hu
Received: 16.07.2012; Accepted after revision: 17.09.2012
the presence of a base.6 They can also be prepared by de-
Abstract: The reaction of 6,7-dihydrothieno[3,2-c]pyridine deriva-
hydration of nitroalkanes with phenyl isocyanate or N,N′
tives with 1,3-dipoles, such as a nitrile oxides or nitrile imines, gave
-dicyclohexylcarbodiimide,7 by treatment of oximes with
novel fused heterocycles. The Staudinger reaction of the starting
material was also studied. This reaction was stereoselective and ex-
tert-butyl hypoiodite,8 or by dehydration of O-silylated
clusively gave racemic cis-cycloadducts in which the thienopyri- hydroxamic acids.9 Nitrile imines can be generated as
dine core was fused with a β-lactam ring.
transient intermediates in solution by treatment of hydra-
zonyl halides with triethylamine.10
Key words: heterocycles, cycloadditions, nitrile oxides, nitrile
imines, Staudinger reactions
Another type of cycloaddition is the Staudinger reaction
between imines and ketenes or appropriate acyl chlo-
rides.11 This reaction is one of the most commonly used
Although thienopyridines have not been found in nature,
a few representative compounds of this type possess sig-
nificant biological activities. For instance, ticlopidine (1),
(S)-clopidogrel (2), and prasugrel (3) inhibit platelet acti-
vation and aggregation by binding irreversibly to the
P2Y12 component of the adenosine diphosphate receptor.1
These compounds are used, inter alia, for treatment of
ischemic strokes, heart attacks, and atherosclerosis, and
for the prevention of thrombosis.2 (S)-Clopidogrel
(Plavix; 2) was the world’s second-highest-selling phar-
maceutical in the mid-2000s.3
methods for the synthesis of the β-lactam scaffold. The β-
lactam ring is an important structural element in a large
number of antibiotics. Current interest in these species has
been expressed in the form of several recent publica-
tions.12
In our previous study, we examined cycloaddition reac-
tions of 3,4-dihydro-β-carbolines to give new tetracyclic
alkaloids.13 As a continuation of our work, we now de-
scribe the cycloaddition of 4-substituted 6,7-dihydrothie-
no[3,2-c]pyridines 4a–c with 1,3-dipoles, such as nitrile
oxides or nitrile imines, generated in situ. We also exam-
ined the Staudinger reaction of model compound 4b.
The starting materials 4a–c were prepared according to
literature procedures from commercially available [2-(2-
thienyl)ethyl]amine. The amine was acylated with suit-
able acyl chlorides and subjected to ring closure under the
standard conditions for the Bischler–Napieralski reac-
tion.14
Cl
Cl
MeO2C
N
O
F
N
N
O
O
S
S
S
1
2
3
Figure 1 Ticlopidine (1), (S)-clopidogrel (2), and prasugrel (3)
First, we investigated the reaction of 4-substituted 6,7-di-
hydrothieno[3,2-c]pyridines 4a–c with nitrile imines. The
appropriate nitrile imines, which served as active 1,3-di-
poles, were prepared in situ from N-phenylbenzenecarbo-
hydrazonyl chloride (5a) or its 4-nitro derivative 5b. The
reaction was carried out by using 1.5 equivalents of
reactant 5a or 5b in the presence of triethylamine in di-
chloromethane and gave the expected tetrahydrothienotri-
azolopyridine derivatives 6a–f (Scheme 1 and Table 1).
Substrate 5b, bearing an electron-withdrawing nitro group
on the phenyl ring, required shorter reaction times (20
minutes) than the unsubstituted substrate 5a (24 hours).
The products 6a–f were obtained in good-to-excellent
yields (76–99%). The methyl-substituted products 6a and
6d were isolated in somewhat lower yields (76% and
88%, respectively) than those with cyclohexyl or phenyl
substituents, possibly because in the methylated reactant
4a, small amounts of the enamine form may be present
We aimed to synthesize novel, fused, conformationally
constrained, tricyclic thienopyridines by means of cyclo-
addition reactions.
Cycloaddition reactions play an important role in synthet-
ic heterocyclic chemistry and they have been applied in
syntheses of many natural products, pharmaceuticals, and
agrochemicals.4 Nitrile oxides and nitrile imines are fre-
quently used in 1,3-dipolar cycloadditions. Both nitrile
oxides and nitrile imines can react with various types of
unsaturated systems, so it is possible to prepare a range of
heterocyclic systems.5 Nitrile oxides can be generated in
situ from the corresponding hydroximinoyl chlorides in
SYNTHESIS 2012, 44, 3447–3452
Advanced online publication: 02.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316794; Art ID: SS-2012-T0593-OP
© Georg Thieme Verlag Stuttgart · New York

3448
M. Milen et al.
PAPER
N
O
and could react with reactant 5a or 5b. Analogous reac-
tions of enamines with nitrile imines have been reported
in the literature.15 However, the C=C double bond is less
reactive than the polarized C=N double bond and, as a
consequence, byproducts may have been formed only in
small quantities. In the cases of the cyclohexyl-substituted
substrates 4b and 4e, the corresponding enamines cannot
react with the nitrile imine as a result of steric hindrance,
whereas the phenyl-substituted substrate 4c cannot under-
go enamine formation. This provides a convincing expla-
nation as to why products 6b, 6c, 6e, and 6f were obtained
in excellent yields.
R
Ar
R
N
N
CH2Cl2
+
Ar
C N O
26 °C, 20–90 min
S
S
Et3N
– HCl
OH
9a–c
4a–c
R = Me (a), Cy (b), Ph (c)
Ar = 4-ClC6H4
N
Ar
Cl
8
Scheme 2
Ar
R
N
N
R
N
Table 2 Reaction Times and Yields for the Transformation of 4a–c
into 9a–c
Ph
CH2Cl2
26 °C
N
N
+
N
Ar
Ph
Product
R
Time (min)
Yield (%)
S
S
4a–c
Et3N
Cl
– HCl
6a–f
9a
9b
9c
Me
Cy
Ph
20
90
90
89
84
86
H
N
Ar
Ph
N
5a,b
Scheme 1
Finally, we studied the Staudinger reaction of 4-cyclohex-
yl-6,7-dihydrothieno[3,2-c]pyridine (4b). Compound 4b
was treated with (aryloxy)ketenes generated from the cor-
responding (aryloxy)acetyl chloride precursors (10a–c) in
the presence of triethylamine in dichloromethane. Prod-
ucts 11a–c were obtained in yields of 61, 86, and 61%, re-
spectively (Scheme 3 and Table 3). The higher yield
obtained in the case of the 4-chloro-2-nitrophenyl substit-
uent is due to the greater ease with which reactant 10b un-
dergoes deprotonation at the methylene group. Two new
stereocenters were formed in the reaction, providing the
cis-cycloadducts exclusively.
Table 1 Reaction Times and Yields for the Transformation of 4a–c
into 6a–f
Product
R
Ar
Time
Yield (%)
6a
6b
6c
6d
6e
6f
Me
Cy
Ph
Ph
24 h
76
82
87
88
96
99
Ph
24 h
Ph
24 h
Me
Cy
Ph
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
20 min
20 min
20 min
Table 3 Reaction Times and Yields for the Transformation of 4b
into 11a–c
The second model reaction was that of 4-substituted 6,7-
dihydrothieno[3,2-c]pyridines 4a–c with nitrile oxides.
An oxadiazolo ring was obtained by reaction with the ni-
trile oxide generated from 4-chloro-N-hydroxybenzene-
carboximidoyl chloride (8) at 26 °C in dichloromethane in
the presence of triethylamine (Scheme 2 and Table 2).
When the R group was a bulky substituent such as cyclo-
hexyl or phenyl, the reaction required a longer time of 90
minutes. Products 9a–c were all obtained in similar yields
of 84–89%. The harder oxygen atom of the nitrile oxide
attacks the more-polarized C=N function of 4a or 4b rath-
er than the C=C double bond of the corresponding en-
amine.
Product
Ar
Time (min)
Yield (%)
11a
11b
11c
4-ClC6H4
20
90
90
61
86
61
2-O2N-4-ClC6H3
2-naphthyl
A similar stereospecificity has been observed in an analo-
gous reaction that we previously investigated by means of
high-level quantum chemical calculations. In the stereo-
specific Staudinger reaction investigated, two possible
pathways have been suggested.16 One route involves acyl-
ation of the imine nitrogen by the acyl chloride, and the
other involves formation of an unstable ketene from the
reagent by dehydrohalogenation by triethylamine, with
subsequent formation of a cumulene that might act as the
acylating agent.
Comparison of the two types of reaction discussed above
shows that the nitrile oxide was more reactive than the ni-
trile imines. This difference in reactivity of 1,3-dipoles
has been previously observed.13 We found that the reac-
tions under discussion do not occur by a concerted mech-
anism but instead occur in a stepwise manner.13
These new thienopyridine derivatives with a β-lactam ring
might show antibacterial activities, because β-lactams
Synthesis 2012, 44, 3447–3452
© Georg Thieme Verlag Stuttgart · New York

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New Thienopyridine Derivatives
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Ar
O
O
O
Ar
C
C
O
H
ArO
R
R
O
0 → 26 °C
N
N
20 min
R
NEt3
– HCl
O
+
N
CH2Cl2
S
S
S
4b
INT
O
Ar
Cl
11a–c
10a–c
R = Cy
Ar = 4-ClC6H4 (a), 2-O2N-4-Cl-C6H3 (b), 2-naphthyl (c)
Scheme 3
fused with sulfur-containing heterocycles form a well-
known group of antibiotics that includes penicillins, ceph-
alosporins, and penems.
Figure 4 Perspective view of 11a
In summary, we prepared twelve representative examples
of three novel tricyclic thienopyridine ring systems, which
are biologically important fused scaffolds. The heterocy-
clic rings were constructed by 1,3-dipolar cycloaddition
reactions, whereas the β-lactam ring was prepared by a
Staudinger reaction. The latter protocol gave products in
a diastereospecific manner, providing the cis-cycloadduct
exclusively.
The structures of products 6a–f, 9a–c, and 11a–c were
1
confirmed by 13C and H NMR spectroscopy and by IR
spectroscopy. The presence of the new ring systems were
also confirmed by single-crystal X-ray analyses. Perspec-
tive views of compounds 6f, 9c, and 11a are shown in Fig-
ures 2–4 (C, gray; H, black; N, blue; O, red; S, orange; Cl,
yellow).
Commercially available reagents were purchased from Sigma-
Aldrich and used without further purification. All melting points
were measured with a Kofler–Boëtius microapparatus and are un-
1
corrected. H and 13C NMR spectra were recorded with a Varian
1
Unity Inova 500 spectrometer (500 and 125 MHz for H and 13C
NMR spectra, respectively) or with a Bruker Avance III spectro-
meter (400 and 100 MHz for 1H and 13C NMR spectra, respective-
ly). DMSO-d6 or CDCl3 was used as the solvent, and TMS was used
as the internal standard.
The FT-IR spectra of KBr pellets or neat samples were recorded
with a Bruker Vector 22 spectrometer. Single-crystal X-ray mea-
surements were carried out on a Rigaku R-Axis Spider instrument.
Elemental analyses were performed with a Vario EL III analyzer.
The reactions were monitored by analytical TLC on silica gel 60
PF254. Analytical samples of new compounds were obtained by
crystallization.
Figure 2 Perspective view of 6f co-crystallized with one molecule
All reactions were carried out in anhyd solvents under argon. Re-
agents 5a and 5b were prepared from N-phenylbenzohydrazide or
N-(4-nitrophenyl)benzohydrazide, respectively, by treatment with
Ph3P and CCl4 according to the procedure described in the litera-
ture.17 4-Chloro-N-hydroxybenzenecarboximidoyl chloride (8) was
prepared from 4-chlorobenzaldehyde according to the procedure
described in the literature.18 Aryloxyacetyl chlorides (10a–c) were
synthesized from the appropriate aryloxyacetic acids by a procedure
described in the literature.19
of chloroform
1,5,6,9b-Tetrahydrothieno[3,2-c][1,2,4]triazolo[4,3-a]pyri-
dines 6a–f; General Procedure
N-Arylbenzenecarbohydrazonoyl chloride 5a (1.95 mmol, 0.45 g)
or 5b (1.95 mmol, 0.54 g) was added in one portion to a stirred so-
lution of the appropriate 6,7-dihydrothienopyridine derivative 4a–c
(1.3 mmol) and Et3N (2.0 mmol, 0.28 mL) in CH2Cl2 (20 mL). The
mixture was stirred at 26 °C until the starting material disappeared
(TLC: 20 min with 5b; 24 h with 5a). The mixture was then washed
with H2O (2 × 10 mL), and the organic layer was dried (MgSO4) and
concentrated in vacuo. The residue was purified by flash chroma-
tography [silica gel (PF254), hexane–CH2Cl2].
Figure 3 Perspective view of 9c
© Georg Thieme Verlag Stuttgart · New York
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M. Milen et al.
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9b-Methyl-1,3-diphenyl-1,5,6,9b-tetrahydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine (6a)
Yield: 0.34 g (76%); white crystals; mp 149–151 °C (MeCN).
9b-Cyclohexyl-3-(4-nitrophenyl)-1-phenyl-1,5,6,9b-tetrahy-
drothieno[3,2-c][1,2,4]triazolo[4,3-a]pyridine (6e)
Yield: 0.57 g (96%); orange crystals; mp 236–237 °C (EtOH).
IR (KBr): 1596, 1491, 1300, 752 cm–1.
IR (KBr): 2930, 1593, 1491, 1300, 1115, 766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.63 (m, 2 H), 7.45–7.41 (m,
3 H), 7.32–7.25 (m, 4 H), 7.11–7.07 (m, 1 H), 6.81 (d, J = 5.3 Hz, 1
H), 6.11 (d, J = 5.3 Hz, 1 H), 3.94–3.89 (m, 1 H), 3.31–3.24 (m, 1
H), 2.74–2.65 (m, 1 H), 2.52–2.46 (m, 1 H), 2.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6 (C=N), 145.5 (C=), 136.2
(C=), 135.2 (C=), 129.5 (HC=), 129.2 (C=), 128.6 (HC=), 128.5
(HC=), 127.8 (HC=), 125.8 (HC=), 123.9 (HC=), 122.9 (HC=),
121.2 (HC=), 86.6 (C), 41.7 (CH2), 28.3 (CH3), 24.2 (CH2).
1H NMR (500 MHz, CDCl3): δ = 8.07–8.02 (m, 2 H), 7.77–7.74 (m,
2 H), 7.51–7.48 (m, 3 H), 7.38–7.34 (m, 2 H), 7.32 (d, J = 5.5 Hz, 1
H), 7.17–7.16 (m, 1 H), 4.01–3.96 (m, 1 H), 3.10–3.04 (m, 1 H),
2.74–2.66 (m, 2 H), 2.64–2.59 (m, 1 H), 1.82–1.68 (m, 4 H), 1.55–
1.51 (m, 1 H), 1.38–1.16 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 154.4 (C=N), 148.9 (=C–NO2),
141.4 (C=), 138.8 (C=), 131.7 (C=), 130.4 (HC=), 129.0 (HC=),
128.4 (C=), 128.1 (HC=), 126.9 (HC=), 125.4 (HC=), 121.9 (HC=),
113.5 (HC=), 88.9 (C), 46.6 (CH2), 46.3 (CH), 26.5 (CH2), 26.3
(two signals: 26.33, 26.28) (2 × CH2), 26.0 (CH2), 25.6 (CH2), 25.1
(CH2).
Anal. Calcd for C21H19N3S (345.47): C, 73.01; H, 5.54; N, 12.16; S,
9.28. Found: C, 72.65; H, 5.49; N, 12.05; S, 9.25.
9b-Cyclohexyl-1,3-diphenyl-1,5,6,9b-tetrahydrothieno[3,2-
c][1,2,4]triazolo[4,3-a]pyridine (6b)
Yield: 0.44 g (82%); pale-yellow crystals; mp 173–174 °C (MeCN).
Anal. Calcd for C26H26N4O2S (458.59): C, 68.10; H, 5.71; N, 12.22;
S, 6.99. Found: C, 67.76; H, 5.66; N, 12.14; S, 6.90.
IR (KBr): 2927, 1595, 1489, 1296, 1227, 701 cm–1.
3-(4-Nitrophenyl)-1,9b-diphenyl-1,5,6,9b-tetrahydrothie-
no[3,2-c][1,2,4]triazolo[4,3-a]pyridine (6f)
1H NMR (500 MHz, CDCl3): δ = 7.73–7.71 (m, 2 H), 7.46–7.39 (m,
3 H), 7.18–7.14 (m, 4 H), 6.96–6.92 (m, 1 H), 6.80 (d, J = 5.3 Hz, 1
H), 6.55 (d, J = 5.3 Hz, 1 H), 3.98–3.96 (m, 1 H), 3.18–3.12 (m, 1
H), 2.72–2.66 (m, 1 H), 2.50–2.46 (m, 1 H), 2.34–2.26 (m, 2 H),
1.90–1.86 (m, 1 H), 1.78–1.74 (m, 2 H), 1.52–1.20 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 152.3 (C=N), 145.5 (C=), 138.6
(C=), 133.4 (C=), 129.6 (C=), 129.2 (HC=), 128.6 (HC=), 128.2
(HC=), 127.9 (HC=), 126.3 (HC=), 122.8 (HC=), 122.1 (HC=),
120.4 (HC=), 49.1 (CH), 45.1 (CH2), 27.6 (CH2), 26.9 (CH2), 26.8
(CH2), 26.6 (CH2), 26.4 (CH2), 24.4 (CH2).
Yield: 0.58 g (99%); brick-red crystals; mp 249–251 °C (MeCN).
IR (KBr): 1591, 1490, 1303, 1109 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.95–7.92 (m, 2 H), 2.62–2.60 (m,
2 H), 7.51–7.47 (m, 4 H), 7.46–7.43 (m, 4 H), 7.14 (d, J = 5.3 Hz, 1
H), 7.07 (d, J = 5.3 Hz, 1 H), 6.06–6.03 (m, 2 H), 3.84–3.79 (m, 1
H), 3.22–3.15 (m, 1 H), 2.81–2.73 (m, 1 H), 2.64–2.59 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 153.3 (C=N), 147.6 (=C–NO2),
140.4 (C=), 138.3 (C=), 137.8 (C=), 133.1 (C=), 130.4 (HC=),
129.5 (HC=), 128.9 (HC=), 128.3 (HC=), 127.9 (HC=), 127.3 (C=),
126.0 (HC=), 125.2 (HC=), 123.5 (HC=), 113.4 (HC=), 87.6 (C),
39.1 (CH2), 24.3 (CH2).
Anal. Calcd for C26H27N3S (413.59): C, 75.51; H, 6.58; N, 10.16; S,
7.75. Found: C, 75.52; H, 6.67; N, 10.14; S, 7.66.
Anal. Calcd for C26H20N4O2S (452.54): C, 69.01; H, 4.45; N, 12.38;
S, 7.09. Found: C, 68.72; H, 4.47; N, 12.30; S, 7.02.
1,3,9b-Triphenyl-1,5,6,9b-tetrahydrothieno[3,2-c][1,2,4]triazo-
lo[4,3-a]pyridine (6c)
Yield: 0.46 g (87%); white crystals; mp 225–227 °C (MeCN).
9b-Substituted 3-(4-Chlorophenyl)-6,9b-dihydro-5H-
[1,2,4]oxadiazolo[4,5-a]thieno[3,2-c]pyridines 9a–c; General
Procedure
IR (KBr): 1592, 1492, 1322, 849, 749 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.64 (m, 2 H), 7.63–7.60 (m,
2 H), 7.44–7.40 (m, 6 H), 7.09–7.05 (m, 2 H), 7.00–6.97 (m, 2 H),
6.89 (d, J = 5.3 Hz, 1 H), 6.84–6.80 (m, 1 H), 6.48 (d, J = 5.3, 1 H),
3.78–3.73 (m, 1 H), 3.14–3.07 (m, 1 H), 2.77–2.70 (m, 1 H), 2.54–
2.49 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 150.8 (C=N), 144.5 (C=), 143.3
(C=), 137.9 (C=), 132.7 (C=), 129.4 (HC=), 129.0 (HC=), 128.8
(HC=), 128.7 (HC=), 128.6 (HC=), 128.3 (HC=), 128.2 (HC=),
127.8 (HC=), 127.0 (HC=), 121.5 (HC=), 120.8 (HC=), 118.4
(HC=), 89.7 (C), 39.3 (CH2), 24.1 (CH2).
Carboximidoyl chloride 8 (0.25 g, 1.3 mmol for 4a; 0.30 g, 1.56
mmol for 4b or 4c) was added in one portion to a stirred soln of the
appropriate 6,7-dihydrothienopyridine 4a–c (1.3 mmol) in CH2Cl2
(20 mL). The mixture was stirred at 26 °C until the starting material
disappeared (20–90 min) then washed with H2O (2 × 10 mL). The
organic layer was dried (MgSO4), and concentrated in vacuo to give
a residue that was purified by flash chromatography [silica gel
(PF254), hexane–CH2Cl2].
3-(4-Chlorophenyl)-9b-methyl-6,9b-dihydro-5H-[1,2,4]oxa-
diazolo[4,5-a]thieno[3,2-c]pyridine (9a)
Yield: 0.35 g (89%); off-white crystals; mp 172–175 °C (MeCN).
IR (KBr): 1583, 1492, 1391, 1352, 835, 822 cm–1.
Anal. Calcd for C26H21N3S (407.54): C, 76.63; H, 5.19; N, 10.31; S,
7.87. Found: C, 76.58; H, 5.34; N, 10.32; S, 7.74.
1H NMR (400 MHz, CDCl3): δ = 7.53–7.50 (m, 2 H), 7.44–7.42 (m,
2 H), 7.15 (d, J = 5.2 Hz, 1 H), 7.04 (d, J = 5.3 Hz, 1 H), 3.75–3.70
(m, 1 H), 3.42–3.35 (m, 1 H), 2.62–2.53 (m, 2 H), 1.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 157.3 (C=N), 136.7 (C=), 136.2
(C=), 135.1 (ClC=), 129.3 (HC=), 129.2 (HC=), 124.9 (HC=), 124.5
(C=), 123.7 (HC=), 97.3 (C), 42.1 (CH2), 26.3 (CH3), 23.9 (CH2).
9b-Methyl-3-(4-nitrophenyl)-1-phenyl-1,5,6,9b-tetrahydrothie-
no[3,2-c][1,2,4]triazolo[4,3-a]pyridine (6d)
Yield: 0.45 g (88%); red crystals; mp 212–213 °C (MeCN).
IR (KBr): 1592, 1474, 1293, 1113, 830 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.13–8.10 (m, 2 H), 7.67–7.64 (m,
2 H), 7.50–7.46 (m, 3 H), 7.43–7.39 (m, 2 H), 7.09 (d, J = 5.3 Hz, 1
H), 7.07 (d, J = 5.3 Hz, 1 H), 3.97–3.92 (m, 1 H), 3.38–3.32 (m, 1
H), 2.74–2.67 (m, 1 H), 2.61–2.57 (m, 1 H), 2.20 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.4 (C=N), 149.0 (=C–NO2),
139.4 (C=), 137.3 (C=), 135.2 (C=), 130.4 (HC=), 128.8 (HC=),
128.0 (HC=), 125.4 (two signals: 125.43, 125.39) (2 × HC=), 123.2
(HC=), 114.6 (HC=), 84.4 (C), 42.1 (CH2), 27.8 (CH3), 24.6 (CH2).
Anal. Calcd for C15H15ClN2OS (304.80): C, 59.11; H, 4.30; Cl,
11.63; N, 9.19; S, 10.52. Found: C, 59.10; H, 4.19; Cl, 11.77; N,
9.23; S, 10.44.
3-(4-Chlorophenyl)-9b-cyclohexyl-6,9b-dihydro-5H-[1,2,4]oxa-
diazolo[4,5-a]thieno[3,2-c]pyridine (9b)
Yield: 0.41 g (84%); white crystals; mp 159–161 °C (MeCN).
IR (KBr): 1593, 1409, 1228, 1091, 829 cm–1.
Anal. Calcd for C21H18N4O2S (390.47): C, 64.60; H, 4.65; N, 14.35;
S, 8.21. Found: C, 64.40; H, 4.62; N, 14.30; S, 8.16.
Synthesis 2012, 44, 3447–3452
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New Thienopyridine Derivatives
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1H NMR (500 MHz, CDCl3): δ = 7.57–7.54 (m, 2 H), 7.45–7.42 (m,
2 H), 7.16 (dd, J1 = 0.6 Hz, J2 = 5.1 Hz, 1 H), 7.03 (d, J = 5.3 Hz, 1
H), 3.73–3.68 (m, 1 H), 3.44–3.38 (m, 1 H), 2.72–2.65 (m, 1 H),
2.62–2.58 (m, 1 H), 2.19–2.09 (m, 2 H), 1.86–1.82 (m, 1 H), 1.78–
1.74 (m, 1 H), 1.74–1.69 (m, 1 H), 1.50–1.46 (m, 1 H), 1.37–1.30
(m, 2 H), 1.22–1.16 (m, 3 H).
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 2.6 Hz, 1 H), 7.56 (d,
J = 9.0 Hz, 1 H), 7.49 (dd, J1 = 2.6 Hz, J2 = 9.0 Hz, 1 H), 7.19 (d,
J = 5.3 Hz, 1 H), 6.97 (d, J = 5.3 Hz, 1 H), 4.98 (s, 1 H), 4.20–4.14
(m, 1 H), 3.38–3.31 (m, 1 H), 3.14–3.07 (m, 1 H), 2.96–2.90 (m, 1
H), 2.34–2.28 (m, 1 H), 2.03–1.98 (m, 1 H), 1.81–1.72 (m, 3 H),
1.71–1.66 (m, 1 H), 1.47–1.34 (m, 2 H), 1.15–1.02 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.2 (C=N), 136.6 (C=), 136.5
(C=), 134.6 (ClC=), 129.5 (HC=), 129.2 (HC=), 124.7 (HC=), 124.6
(C=), 123.4 (HC=), 100.9 (C), 47.5 (CH), 43.9 (CH2), 27.5 (CH2),
26.6 (CH2), 26.5 (CH2), 26.0 (CH2), 25.8 (CH2), 24.0 (CH2).
13C NMR (125 MHz, CDCl3): δ = 165.7 (C=O), 149.4 (=C–O),
139.9 (=C–NO2), 134.9 (C=), 134.3 (HC=), 134.2 (C=), 127.2
(ClC=), 125.3 (HC=), 125.1 (HC=), 123.4 (HC=), 119.2 (HC=),
87.6 (CH–O), 66.4 (C), 42.9 (CH2), 37.0 (CH), 29.9 (CH2), 28.8
(CH2), 26.4 (CH2), 26.2 (CH2), 26.1 (CH2), 23.1 (CH2).
Anal. Calcd for C20H21ClN2OS (372.92): C, 64.42; H, 5.68; Cl,
9.51; N, 7.51; S, 8.60. Found: C, 64.28; H, 5.66; Cl, 9.64; N, 7.51;
S, 8.50.
Anal. Calcd for C21H21ClN2O4S (432.93): C, 58.26; H, 4.89; Cl,
8.19; N, 6.47; S, 7.41. Found: C, 58.31; H, 4.89; Cl, 8.29; N, 6.46;
S, 7.41.
3-(4-Chlorophenyl)-9b-phenyl-6,9b-dihydro-5H-[1,2,4]oxa-
diazolo[4,5-a]thieno[3,2-c]pyridine (9c)
Yield: 0.41 g (86%); white crystals; mp 161–162 °C (MeCN).
IR (KBr): 1589, 1450, 1405, 824, 765, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.58–7.56 (m, 2 H), 7.53–7.51 (m,
2 H), 7.44–7.41 (m, 2 H), 7.40–7.37 (m, 3 H), 7.17 (d, J = 5.3 Hz, 1
H), 6.87 (d, J = 5.3 Hz, 1 H), 3.71–3.66 (m, 1 H), 3.42–3.35 (m, 1
H), 2.78–2.67 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 156.7 (C=N), 141.8 (C=), 136.8
(C=), 136.7 (C=), 134.3 (ClC=), 129.4 (HC=), 129.2 (HC=), 128.9
(HC=), 128.2 (HC=), 127.2 (HC=), 126.3 (HC=), 124.1 (C=), 123.6
(HC=), 99.0 (C), 41.5 (CH2), 24.0 (CH2).
(8R*,8aR*)-8a-Cyclohexyl-8-(2-naphthyloxy)-4,5,8,8a-tetra-
hydro-7H-azeto[1,2-a]thieno[3,2-c]pyridin-7-one (11c)
Yield: 0.32 g (61%); white foam.
IR (KBr): 2929, 1760, 1630, 1600, 1254, 1217 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.80–7.77 (m, 2 H), 7.74–7.71 (m,
1 H), 7.47–7.43 (m, 1 H), 7.39–7.35 (m, 2 H), 7.27 (dd, J1 = 2.6 Hz,
J2 = 8.8 Hz, 1 H), 7.24 (d, J = 5.3 Hz, 1 H), 6.98 (d, J = 5.3 Hz, 1
H), 5.18 (s, 1 H), 4.27–4.21 (m, 1 H), 3.30–3.24 (m, 1 H), 3.17–3.08
(m, 1 H), 2.93–2.88 (m, 1 H), 2.19–2.88 (m, 1 H), 2.19–2.11 (m, 2
H), 1.83–1.77 (m, 1 H), 1.71–1.61 (m, 3 H), 1.34–1.23 (m, 1 H),
1.22–1.14 (m, 1 H), 1.14–1.06 (m, 1 H), 1.05–0.98 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 166.9 (C=O), 155.5 (=C–O),
134.9 (C=), 134.7 (C=), 134.3 (C=), 129.8 (HC=), 129.6 (C=),
127.7 (HC=), 127.0 (HC=), 126.6 (HC=), 125.0 (HC=), 124.2
(HC=), 123.4 (HC=), 118.5 (HC=), 108.9 (HC=), 86.7 (CH–O),
67.2 (C), 42.9 (CH2), 37.0 (CH), 30.1 (CH2), 29.0 (CH2), 26.7
(CH2), 26.30 (two signals: 26.304, 26.296) (2 × CH2), 23.7 (CH2).
Anal. Calcd for C20H15ClN2OS (366.87): C, 65.48; H, 4.12; Cl,
9.66; N, 7.64; S, 8.74. Found: C, 65.28; H, 4.07; Cl, 9.69; N, 7.64;
S, 8.65.
8-Aryl-8a-cyclohexyl-4,5,8,8a-tetrahydro-7H-azeto[1,2-a]thie-
no[3,2-c]pyridin-7-one 11a–c; General Procedure
A soln of the appropriate aryloxyacetyl chloride 10a–c (2.60 mmol)
in CH2Cl2 (5 mL) was added a stirred solution of dihydrothienopyr-
idine 4b (1.3 mmol, 0.29 g) and Et3N (2.60 mmol, 0.36 mL) in
CH2Cl2 (20 mL) at 0 °C, and the mixture was stirred at 26 °C until
the starting material disappeared (20 min). The mixture was then
washed with H2O (2 × 10 mL), and the organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography [silica gel (PF254), hexane–CH2Cl2].
Anal. Calcd for C25H25NO2S (403.55): C, 74.41; H, 6.24; N, 3.47;
S, 7.95. Found: C, 74.58; H, 6.31; N, 3.28; S, 7.71.
Crystallographic data for compounds 6f, 9c, and 11a have been de-
posited with the accession numbers CCDC 885578, CCDC 885577,
and CCDC 885579, respectively, and can be obtained free of charge
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: depos-
it@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/conts/retriev-
ing.html.
(8R*,8aR*)-8-(4-Chlorophenoxy)-8a-cyclohexyl-4,5,8,8a-tetra-
hydro-7H-azeto[1,2-a]thieno[3,2-c]pyridin-7-one (11a)
Yield: 0.31 g (61%); white crystals; mp 160–161 °C (MeCN).
Acknowledgment
IR (KBr): 1753, 1491, 1245, 828 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.27–7.24 (m, 2 H), 7.20 (d,
J = 5.3 Hz, 1 H), 7.03–7.00 (m, 2 H), 6.91 (d, J = 5.3 Hz, 1 H), 4.94
(s, 1 H), 4.22–4.17 (m, 1 H), 3.30–3.23 (m, 1 H), 3.12–3.05 (m, 1
H), 2.92–2.86 (m, 1 H), 2.16–2.10 (m, 1 H), 2.10–2.05 (m, 1 H),
1.81–1.77 (m, 1 H), 1.73–1.63 (m, 3 H), 1.37–1.19 (m, 2 H), 1.14–
1.00 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.7 (C=O), 156.3 (=C–O),
134.9 (C=), 134.5 (C=), 129.5 (HC=), 127.2 (ClC=), 124.9 (HC=),
123.4 (HC=), 117.0 (HC=), 87.0 (CH–O), 66.9 (C), 43.0 (CH2),
36.9 (CH), 30.0 (CH2), 28.9 (CH2), 26.7 (CH2), 26.3 (2 × CH2), 23.5
(CH2).
The authors are grateful to Réka Puskás for the microanalyses.
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Synthesis 2012, 44, 3447–3452
© Georg Thieme Verlag Stuttgart · New York