Three-step synthesis of 3-aryl-2-sulfanylthieno[2,3-b]-, -[2,3-c]-, or -[3,2-c]pyridines from the corresponding aryl(halopyridinyl)methanones

Article abstract of DOI:10.1002/hlca.201200123

A convenient three-step procedure for the synthesis of three types of 3-aryl-2-sulfanylthienopyridines 4, 8, and 12 has been developed. The first step of the synthesis of thieno[2,3-b]pyridine derivatives 4 is the replacement of the halo with a (sulfanylmethyl)sulfanyl group in aryl(2-halopyridin-3-yl) methanones 1 by successive treatment with Na₂S×9 H₂O and chloromethyl sulfides to give aryl{2-[(sulfanylmethyl)sulfanyl]pyridin-3- yl}methanones 2. In the second step, these were treated with LDA (LiN ⁱPr₂) to give 3-aryl-2,3-dihydro-2-sulfanylthieno[2,3-b] pyridin-3-ols 3, which were dehydrated in the last step with SOCl₂ in the presence of pyridine to give the desired products. Similarly, thieno[2,3-c]pyridine and thieno[3,2-c]pyridine derivatives, 8 and 12, respectively, can be prepared from aryl(3-chloropyridin-4-yl)methanones 5 and aryl(4-chloropyridin-3-yl)methanones 9, respectively. Copyright

Full text of DOI:10.1002/hlca.201200123

Helvetica Chimica Acta – Vol. 96 (2013)
69
Three-Step Synthesis of 3-Aryl-2-sulfanylthieno[2,3-b]-, -[2,3-c]-, or -[3,2-
c]pyridines from the Corresponding Aryl(halopyridinyl)methanones
by Kazuhiro Kobayashi*, Teruhiko Suzuki, and Yuko Egara
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4 – 101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81(857)315263; e-mail: kkoba@chem.tottori-u.ac.jp)
A convenient three-step procedure for the synthesis of three types of 3-aryl-2-sulfanylthienopyr-
idines 4, 8, and 12 has been developed. The first step of the synthesis of thieno[2,3-b]pyridine derivatives
4 is the replacement of the halo with a (sulfanylmethyl)sulfanyl group in aryl(2-halopyridin-3-
yl)methanones 1 by successive treatment with Na2S · 9 H2O and chloromethyl sulfides to give aryl{2-
[(sulfanylmethyl)sulfanyl]pyridin-3-yl}methanones 2. In the second step, these were treated with LDA
(LiNiPr2) to give 3-aryl-2,3-dihydro-2-sulfanylthieno[2,3-b]pyridin-3-ols 3, which were dehydrated in the
last step with SOCl2 in the presence of pyridine to give the desired products. Similarly, thieno[2,3-
c]pyridine and thieno[3,2-c]pyridine derivatives, 8 and 12, respectively, can be prepared from aryl(3-
chloropyridin-4-yl)methanones 5 and aryl(4-chloropyridin-3-yl)methanones 9, respectively.
Introduction. – Recently, thienopyridine derivatives have attracted intense interest
from synthetic and medicinal chemists due to their biological properties1). Although
the syntheses of thieno[2,3-b]pyridine2), thieno[2,3-c]pyridine3), and thieno[3,2-
c]pyridine derivatives4) have been reported by a number of groups, there have been
few reports on methods for preparing the corresponding 2-sulfanylated derivatives5),
which may also be of potential importance from a biological point of view [9].
Therefore, we became interested in developing a synthetic approach applicable to all of
these three 2-sulfanylated thieno-pyridine derivatives as an extension of our previous
work, in which 2-sulfanylated 3-arylbenzo[b]thiophenes were synthesized by intra-
molecular cyclization of aryl{2-[(sulfanylmethyl)sulfanyl]phenyl}methanones using 2
mol-equiv. of LiNiPr2 (LDA) and subsequent dehydration of the resulting 3-aryl-2,3-
dihydro-2-sulfanylbenzo[b]thiophen-3-ols [10]. We herein describe the results of our
1
)
For recent reports on the biological activity of compounds having the thieno[2,3-b]pyridine moiety,
see [1] and also pertinent references cited in [2] and [3]. For recent reports on the biological activity
of compounds having the thieno[2,3-c]pyridine moiety, see [4] and also pertinent references cited in
[3]. For recent reports on the biological activity of compounds having the thieno[3,2-c]pyridine
moiety, see [5] and [4a], as well as pertinent references cited in [3].
2
3
4
5
)
)
)
)
For recent reports on the synthesis of thieno[2,3-b]pyridine derivatives, see [6], and also [2] and [3]
and pertinent references cited therein.
For recent reports on the synthesis of thieno[2,3-c]pyridine derivatives, see [7] and [3] and pertinent
references cited therein.
For recent reports on the synthesis of thieno[3,2-c]pyridine derivatives, see [3] and pertinent
references cited therein.
2-(Methylsulfanyl)thienopyridine-3-carboxylic acid derivatives were synthesized previously [8].
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

70
Helvetica Chimica Acta – Vol. 96 (2013)
study, which provide a convenient synthetic route to 3-aryl-2-sulfanylthieno[2,3-b]-,
-[2,3-c]-, or -[3,2-c]pyridines starting from the respective aryl(halopyridinyl)metha-
nones, employing this 2-sulfanylated-thiophene ring-forming methodology.
Results and Discussion. – Our syntheses of 3-aryl-2-sulfanylthienopyridines 4, 8,
and 12 were conducted following the procedure outlined in the Scheme and the results
obtained are compiled in the Table. First, preparation of 3-aryl-2-sulfanylthieno[2,3-
b]pyridines 3 from aryl(2-halopyridin-3-yl)methanones 1, which could be easily
prepared from 2-chloropyridine or 2-bromopyridine according to the methods
described in [2][3][11], was carried out. The reaction of 1 with Na2S · 9 H2O in DMF
at 708, followed by sulfanylmethylation with chloromethyl sulfides at room temper-
ature, furnished aryl{2-[(sulfanylmethyl)sulfanyl]pyridin-3-yl}methanones 2 in moder-
ate yields. Cyclization via the addition of the carbanions between the two S-atoms
(dithioacetal anions6)), generated by treatment of 2 with 3 mol-equiv. of LDA7) in
DME at ꢀ 788, to the C¼O group proceeded relatively cleanly by raising the reaction
temperature to 08 to give, after aqueous workup, the corresponding 2,3-dihydrothi-
eno[2,3-b]pyridin-3-ols 3 as mixtures of diastereisomers, as judged by TLC analyses
(SiO2). These crude alcohols, without any purification, were subjected to the dehydra-
tion with SOCl2 in THF in the presence of pyridine (08 – room temperature) to afford
the desired products 4 in acceptable overall yields from 2 (Table, Entries 1 – 5).
Scheme
Next, the synthesis of 3-aryl-2-sulfanylthieno[2,3-c]pyridines 8 from aryl(3-
chloropyridin-4-yl)methanones 5 was carried out. The preparation of 5 has also been
6
)
)
For recent relevant reports on the synthesis utilizing dithioacetal anions (CoreyꢀSeebach reaction),
see [12].
7
The use of 3 equiv. of LDA was essential for satisfactory formation of the desired products. When
2 equiv. of LDA were used for the preparation of benzo[b]thiophenes [10], mixtures containing only
lower yields of the alcohols and considerable amounts of recovered 2 were obtained, from which the
desired products were isolated in yields which never exceeded 20%, though the reason for this is not
clear yet.

Helvetica Chimica Acta – Vol. 96 (2013)
71
Table. Preparation of 3-Aryl-2-sulfanylthienopyridines 4, 8, and 12
Entry
1
R
Temp. 2, 6, 10 Yielda) [%] 4, 8, 12 Yielda) [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
1a (N ¼ a, Ar¼ Ph, X ¼ Br)
Ph 708
Me 708
tBu 708
Ph 708
2a
2b
2c
2d
2e
6a
6b
6c
6d
10a
10b
10c
10d
51
55
51
52
48
74
73
71
77
79
74
78
75
4a
4b
4c
4d
4e
8a
8b
8c
8d
12a
12b
12c
12d
54
50
48
47
52
59
57
55
56
51
52
52
49
1a
1a
1b (N ¼ a, Ar¼ 3-ClꢀC6H4, X ¼ Br)
1c (N ¼ a, Ar¼ 3,4-(OCH2O)ꢀC6H3, X ¼ Cl) Ph 708
5a (N ¼ b, Ar¼ Ph, X ¼ Cl)
Ph 808
Me 808
Ph 808
tBu 808
Ph 608
tBu 608
Ph 608
Me 608
5a
5b (N ¼ b, Ar¼ thiophen-2-yl, X ¼ Cl)
5b
9a (N ¼ g, Ar¼ Ph, X ¼ Cl)
9a
9b (N ¼ g, Ar¼ 4-MeOꢀC6H4, X ¼ Cl)
9b
a) Yields of isolated products.
achieved by the method described in [3][11]. The reaction of 5 with Na2S · 9 H2O
proceeded more smoothly and cleanly than that of 1 but at somewhat higher
temperature to give, after treatment with chloromethyl sulfides, aryl{[3-(sulfanylme-
thyl)sulfanyl]pyridin-4-yl}methanones 6 in fair-to-good yields. These ketones were
treated with LDA, and the resulting 2,3-dihydrothieno[2,3-c]pyridin-3-ols 7 were
dehydrated in a manner similar to that described for the preparation of 4 to give the
desired products 8 in reasonable overall yields from 6 (Table, Entries 6 – 9).
Subsequently, attempts were made at obtaining 3-aryl-2-sulfanylthieno[3,2-c]pyr-
idines 12 from aryl(4-chloropyridin-3-yl)methanones 9 employing a sequence similar to
those for the preparation of 4 and 8. As can be seen from the Table, it was found that
the reaction of 9 with Na2S · 9 H2O proceeded smoothly at the lowest temperature of
the present three sequences to give the corresponding aryl{[4-(sulfanylmethyl)sulfan-
yl]pyridin-3-yl}methanones 10 in yields comparable to 6. Similarly, treatment of these
ketones 10 with 3 mol-equiv. of LDA, followed by aqueous workup and subsequent
dehydration of the resulting alcohol derivatives 11, gave the desired products 12 in
satisfactory overall yields from 10 (Table, Entries 10 – 13).
In conclusion, we have demonstrated that three types of 3-aryl-2-sulfanylthieno-
pyridines can be obtained in reasonable overall yields from the respective aryl(halo-
pyridinyl)methanones employing the essentially same three-step sequence. The present
approach has the advantage that the operations are very simple, and the starting
materials are readily available.
Experimental Part
General. All of the org. solvents used in this study were dried over appropriate drying agents and
distilled prior to use. TLC: Merck silica gel 60 PF254. Column chromatography (CC): Wako Gel C-
200E. M.p.: Laboratory Devices MEL-TEMP II melting point apparatus; uncorrected. IR Spectra:
Shimadzu FTIR-8300 spectrophotometer. 1H-NMR Spectra: in CDCl3 with TMS as an internal reference
with a JEOL ECP500 FT NMR spectrometer, at 500 MHz, or a JEOL LA400 FT NMR spectrometer, at

72
Helvetica Chimica Acta – Vol. 96 (2013)
400 MHz. 13C-NMR Spectra: in CDCl3 with TMS as an internal reference with a JEOL ECP500 FT
NMR spectrometer, at 125 MHz. LR-MS (EI, 70 eV): with JEOL JMS AX505 HA spectrometer.
Aryl(halopyridinyl)methanones 1, 5, and 9. These compounds, excluding 5a, were prepared by the
appropriate procedures reported previously by us (1a and 1b: [2], 1c, 5b, and 9b: [3]; 9a: [11]). BuLi was
supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially
available.
(3-Chloropyridin-4-yl)(phenyl)methanone (5a) [13]. This compound was prepared from 3-chloro-4-
lithiopyridine [14] with N,N-dimethylbenzamide under conditions as described for the preparation of 9a
and 9b [3][11]. Yield: 61%. Colorless crystals. M.p. 48 – 498 (hexane). IR (KBr): 1669. 1H-NMR
(500 MHz): 7.29 (d, J ¼ 5.0, 1 H); 7.51 (dd, J ¼ 8.2, 7.3, 2 H); 7.60 (tt, J ¼ 7.3, 1.4, 1 H); 7.80 (d, J ¼ 8.2, 1.4,
2 H); 8.64 (d, J ¼ 5.0, 1 H); 8.73 (s, 1 H).
Aryl[(sulfanylmethylsulfanyl)pyridinyl]methanones 2, 6, and 10. General Procedure. A mixture of 1,
5, or 9 (3.0 mmol) and Na2S · 9 H2O (0.79 g, 3.3 mmol) in DMF (7 ml) was heated at the temp. indicated
in the Table, under stirring until complete consumption of the starting material was confirmed by TLC
(SiO2) analysis. After cooling to r.t., the appropriate chloromethyl sulfide (3.3 mmol) was added, and the
resulting mixture was stirred for 1 h at the same temp., before H2O (20 ml) was added. The org. materials
were extracted with AcOEt (3 ꢁ 10 ml), and the combined extracts were washed with H2O (3 ꢁ 10 ml)
and then brine (10 ml), dried (Na2SO4), and concentrated by evaporation. The residue was purified by
CC (SiO2; THF/hexane 1:5) to afford the desired product.
Phenyl(2-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (2a). Yellow solid. M.p. 105 –
1
1098 (hexane/CH2Cl2). IR (KBr): 1661, 1626. H-NMR (500 MHz): 4.73 (s, 2 H); 7.12 (dd, J ¼ 7.3, 4.6,
1 H); 7.19 (tt, J ¼ 7.3, 1.4, 1 H); 7.25 (dd, J ¼ 7.8, 7.3, 2 H); 7.41 (dd, J ¼ 7.8, 1.4, 2 H); 7.47 (dd, J ¼ 7.8, 7.3,
2 H); 7.58 (t, J ¼ 7.3, 1 H); 7.71 – 7.74 (m, 3 H); 8.62 (dd, J ¼ 4.6, 1.3, 1 H). Anal. calc. for C19H15NOS2
(337.46): C 67.62, H 4.48, N 4.15; found: C 67.57, H 4.62, N 4.12.
(2-{[(Methylsulfanyl)methyl]sulfanyl}pyridin-3-yl)(phenyl)methanone (2b). Yellow oil. Rf (THF/
hexane 1:4) 0.30. IR (neat): 1659. 1H-NMR (500 MHz): 2.18 (s, 3 H); 4.37 (s, 3 H); 7.12 (dd, J ¼ 7.3, 4.6,
1 H); 7.49 (dd, J ¼ 8.2, 7.3, 1 H); 7.59 (tt, J ¼ 7.3, 1.4, 1 H); 7.70 (dd, J ¼ 7.3, 1.8, 1 H); 7.76 (dd, J ¼ 8.2, 1.4,
2 H); 8.62 (dd, J ¼ 4.6, 1.8, 1 H). Anal. calc. for C14H13NOS2 (275.39): C 61.06, H 4.76, N 5.09; found: C
60.84, H 4.76, N 5.01.
(2-{[(tert-Butylsulfanyl)methyl]sulfanyl}pyridin-3-yl)(phenyl)methanone (2c). Yellow oil. Rf (THF/
hexane 1:5) 0.42. IR (neat): 1659. 1H-NMR (500 MHz): 1.36 (s, 9 H); 4.40 (s, 2 H); 7.10 (dd, J ¼ 7.3, 4.6,
1 H); 7.48 (dd, J ¼ 7.8, 7.3, 2 H); 7.60 (tt, J ¼ 7.3, 1.4, 1 H); 7.69 (dd, J ¼ 7.3, 1.8, 1 H); 7.75 (dd, J ¼ 8.2, 1.4,
2 H); 8.61 (dd, J ¼ 4.6, 1.8, 1 H). Anal. calc. for C17H19NOS2 (317.47): C 64.32, H 6.03, N 4.41; found: C
64.07, H 6.07, N 4.39.
(3-Chlorophenyl)(2-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (2d). Yellow solid.
1
M.p. 110 – 1118 (hexane/CH2Cl2). IR (KBr): 1655. H-NMR (500 MHz): 4.73 (s, 2 H); 7.14 (dd, J ¼ 7.8,
5.0, 1 H); 7.20 (tt, J ¼ 7.3, 1.4, 1 H); 7.26 (dd, J ¼ 7.8, 7.3, 2 H); 7.39 – 7.43 (m, 3 H); 7.55 – 7.60 (m, 2 H);
7.69 – 7.71 (m, 2 H); 8.64 (dd, J ¼ 5.0, 1.8, 1 H). Anal. calc. for C19H14ClNOS2 (371.90): C 61.36, H 3.79, N
3.77; found: C 61.26, H 3.81, N 3.60.
(1,3-Benzodioxol-5-yl)(2-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (2e). Yellow
1
oil. Rf (THF/hexane 1:2) 0.42. IR (neat): 1651, 1603. H-NMR (500 MHz): 4.72 (s, 2 H); 6.07 (s, 2 H);
6.82 (d, J ¼ 8.2, 1 H); 7.12 (dd, J ¼ 7.3, 5.0, 1 H); 7.19 (t, J ¼ 7.3, 1 H); 7.23 – 7.27 (m, 3 H); 7.32 (d, J ¼ 1.8,
1 H); 7.40 (dd, J ¼ 7.8, 1.4, 2 H); 7.64 (dd, J ¼ 7.3, 1.8, 1 H); 8.60 (dd, J ¼ 5.0, 1.8, 1 H). Anal. calc. for
C20H15NO3S2 (381.47): C 62.97, H 3.96, N 3.67; found: C 63.02, H 4.03, N 3.64.
Phenyl(3-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-4-yl)methanone (6a). Yellow oil. Rf (THF/
hexane 2 :3) 0.28. IR (neat): 1668. 1H-NMR (400 MHz): 4.26 (s, 2 H); 7.22 – 7.33 (m, 6 H); 7.47 (t, J ¼ 7.8,
2 H); 7.63 (t, J ¼ 7.8, 1 H); 7.75 (d, J ¼ 7.8, 2 H); 8.65 (d, J ¼ 4.9, 1 H); 8.83 (s, 1 H). Anal. calc. for
C19H15NOS2 (337.46): C 67.62, H 4.48, N 4.15; found: C 67.53, H 4.48, N 4.03.
(3-{[(Methylsulfanyl)methyl]sulfanyl}pyridin-4-yl)(phenyl)methanone (6b). Yellow oil. Rf (THF/
hexane 1:4) 0.25. IR (neat): 1668. 1H-NMR (400 MHz): 2.07 (s, 3 H); 3.91 (s, 2 H); 7.26 (d, J ¼ 4.9, 1 H);
7.49 (t, J ¼ 7.8, 2 H); 7.64 (t, J ¼ 7.8, 1 H); 7.79 (d, J ¼ 7.8, 2 H); 8.65 (d, J ¼ 4.9, 1 H); 8.85 (s, 1 H). Anal.
calc. for C14H13NOS2 (275.39): C 61.06, H 4.76, N 5.09; found: C 61.04, H 4.77, N 5.02.

Helvetica Chimica Acta – Vol. 96 (2013)
73
(3-{[(Phenylsulfanyl)methyl]sulfanyl}pyridin-4-yl)(thiophen-2-yl)methanone (6c). Yellow oil. Rf
(THF/hexane 1:2) 0.26. IR (neat): 1645. 1H-NMR (400 MHz): 4.32 (s, 2 H); 7.12 (dd, J ¼ 4.9, 3.9,
1 H); 7.22 – 7.29 (m, 4 H); 7.33 – 7.36 (m, 3 H); 7.80 (dd, J ¼ 3.9, 1.4, 1 H); 8.65 (d, J ¼ 4.9, 1 H); 8.83 (s,
1 H). Anal. calc. for C17H13NOS3 (343.49): C 59.44, H 3.81, N 4.08; found: C 59.44, H 3.81, N 4.11.
[3-({[(tert-Butyl)sulfanyl]methyl}sulfanyl)pyridin-4-yl](thiophen-2-yl)methanone (6d). Yellow oil.
Rf (THF/hexane 1:2) 0.24. IR (neat): 1649. 1H-NMR (400 MHz): 1.30 (s, 9 H); 4.03 (s, 2 H); 7.15 (dd, J ¼
4.9, 3.9, 1 H); 7.34 (d, J ¼ 4.9, 1 H); 7.40 (d, J ¼ 3.9, 1 H); 7.81 (d, J ¼ 4.9, 1 H); 8.64 (d, J ¼ 4.9, 1 H); 8.88
(s, 1 H). Anal. calc. for C15H17NOS3 (323.50): C 55.69, H 5.30, N 4.33; found: C 55.60, H 5.37, N 4.28.
Phenyl(4-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (10a). Pale-yellow oil. Rf
(THF/hexane 1:3) 0.23. IR (neat): 1651. 1H-NMR (500 MHz): 4.37 (s, 2 H); 7.25 – 7.31 (m, 3 H);
7.41 – 7.51 (m, 5 H); 7.61 (tt, J ¼ 7.3, 1.4, 1 H); 7.78 (dd, J ¼ 7.8, 1.4, 2 H); 8.58 (d, J ¼ 5.2, 1 H); 8.62 (s, 1 H).
Anal. calc. for C19H15NOS2 (337.46): C 67.62, H 4.48, N 4.15; found: C 67.56, H 4.50, N 4.12.
[4-({[(tert-Butyl)sulfanyl]methyl}sulfanyl)pyridin-3-yl](phenyl)methanone (10b). Yellow oil. Rf
1
(THF/hexane 1:3) 0.24. IR (neat): 1655. H-NMR (400 MHz): 1.38 (s, 9 H), 4.07 (s, 2 H), 7.46 (d, J ¼
5.9, 1 H), 7.50 (t, J ¼ 7.8, 2 H); 7.63 (t, J ¼ 7.8, 1 H); 7.79 (d, J ¼ 7.8, 2 H); 8.57 (d, J ¼ 5.9, 1 H); 8.60 (s,
1 H). Anal. calc. for C17H19NOS2 (317.47): C 64.32, H 6.03, N 4.41; found: C 64.18, H 6.13, N 4.36.
(4-Methoxyphenyl)(4-{[(phenylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (10c). Pale-yellow
oil. Rf (THF/hexane 1:3) 0.31. IR (neat): 1651. 1H-NMR (400 MHz): 3.89 (s, 3 H); 4.36 (s, 2 H); 6.96 (d,
J ¼ 8.8, 2 H); 7.23 – 7.30 (m, 3 H); 7.40 – 7.44 (m, 3 H); 7.79 (d, J ¼ 8.8, 2 H); 8.567 (d, J ¼ 5.2, 1 H); 8.572
(s, 1 H). Anal. calc. for C20H17NO2S2 (367.48): C 65.37, H 4.66, N 3.81; found: C 65.21, H 4.89, N 3.58.
(4-Methoxyphenyl)(4-{[(methylsulfanyl)methyl]sulfanyl}pyridin-3-yl)methanone (10d). Pale-yellow
oil. Rf (THF/hexane 1:3) 0.31. IR (neat): 1649. 1H-NMR (400 MHz): 2.19 (s, 3 H); 3.90 (s, 3 H); 4.04 (s,
2 H); 6.97 (d, J ¼ 8.8, 2 H); 7.42 (d, J ¼ 5.9, 1 H); 7.81 (d, J ¼ 8.8, 2 H); 8.565 (s, 1 H); 8.571 (d, J ¼ 5.9,
1 H). Anal. calc. for C15H15NO2S2 (305.42): C 58.99, H 4.95, N 4.59; found: C 58.97, H 5.00, N 4.43.
3-Phenyl-2-(phenylsulfanyl)thieno[2,3-b]pyridine (4a; Representative Procedure). To a stirred soln.
of LDA (1.8 mmol), generated from BuLi and iPr2NH by the standard method, in DME (4 ml) at ꢀ 788
was added a soln. of 2a (0.20 g, 0.59 mmol) dropwise. After 30 min, the temp. was raised gradually to 08,
and then the reaction was quenched by adding sat. aq. NH4Cl (10 ml). The mixture was extracted with
Et2O (3 ꢁ 10 ml). The combined extracts were washed with brine (10 ml), dried (Na2SO4), and
concentrated by evaporation. The residue (crude 3a) was dissolved in THF (4 ml) and pyridine (0.47 g,
5.9 mmol), the soln. was cooled to 08, and then SOCl2 (0.14 g, 1.2 mmol) was added. After stirring the
mixture at r.t. for 1 h, sat. aq. NaHCO3 (10 ml) was added. The mixture was worked up as described
above to give a residue, which was purified by PLC (SiO2) to afford 4a (0.10 g, 54%). Yellow oil. Rf
(Et2O/hexane 1:3) 0.27. IR (neat): 1371. 1H-NMR (500 MHz): 7.24 – 7.30 (m, 4 H); 7.34 (dd, J ¼ 7.8, 1.4,
2 H); 7.42 – 7.46 (m, 3 H); 7.50 (dd, J ¼ 7.8, 7.3, 2 H); 7.85 (dd, J ¼ 7.8, 1.4, 1 H); 8.55 (dd, J ¼ 5.5, 1.4, 1 H).
13C-NMR: 119.9; 127.4; 128.3; 128.6 (two overlapped Cs); 129.2; 129.9; 130.0; 130.7; 132.5; 133.4; 135.7;
138.6; 147.1; 162.3. MS: 319 (100, Mþ). Anal. calc. for C19H13NS2 (319.44): C 71.44, H 4.10, N 4.38; found:
C 71.29, H 4.15, N 4.21.
2-(Methylsulfanyl)-3-phenylthieno[2,3-b]pyridine (4b). Pale-yellow solid. M.p. 102 – 1038 (hexane/
CH2Cl2). IR (KBr): 1374. 1H-NMR (500 MHz): 2.55 (s, 3 H); 7.24 (dd, J ¼ 8.2, 4.6, 1 H); 7.43 – 7.47 (m,
3 H); 7.52 (dd, J ¼ 7.8, 7.3, 2 H); 7.79 (dd, J ¼ 8.2, 1.4, 1 H); 8.50 (dd, J ¼ 4.6, 1.4, 1 H). 13C-NMR: 19.4;
119.9; 128.0; 128.6; 129.6; 129.8; 133.7; 133.7; 133.8; 136.5; 145.9; 161.2. MS: 257 (100, Mþ). Anal. calc. for
C14H11NS2 (257.37): C 65.33, H 4.31, N 5.44; found: C 65.08, H 4.49, N 5.49.
2-[(tert-Butyl)sulfanyl]-3-phenylthieno[2,3-b]pyridine (4c). White solid. M.p. 74 – 758 (hexane/
Et2O). IR (KBr): 1368. 1H-NMR (400 MHz): 1.24 (s, 9 H); 7.27 (dd, J ¼ 7.8, 4.9, 1 H); 7.41 – 7.44 (m, 3 H);
7.50 (dd, J ¼ 7.8, 7.3, 2 H); 7.85 (dd, J ¼ 7.8, 1.5, 1 H); 8.60 (dd, J ¼ 4.9, 1.5, 1 H). 13C-NMR: 31.1; 49.5;
119.7; 127.8; 128.2; 130.7; 131.1; 131.2; 133.3; 134.0; 141.8; 147.4; 162.4. MS: 299 (13, Mþ), 243 (100). Anal.
calc. for C17H17NS2 (299.45): C 68.18, H 5.72, N 4.68; found: C 68.04, H 5.82, N 4.52.
3-(3-Chlorophenyl)-2-(phenylsulfanyl)thieno[2,3-b]pyridine (4d). Yellow crystal. M.p. 106 – 1078
1
(hexane/CH2Cl2). IR (KBr): 1373. H-NMR (500 MHz): 7.27 – 7.36 (m, 7 H); 7.42 – 7.43 (m, 3 H); 7.82
(dd, J ¼ 8.2, 1.4, 1 H); 8.56 (dd, J ¼ 4.6, 1.4, 1 H). 13C-NMR: 120.0; 127.8; 128.1; 128.4; 129.3 (two
overlapped Cs); 129.9; 130.3; 130.5; 133.1; 133.9; 134.5; 135.1; 135.2; 136.4; 147.2; 162.1. MS: 353 (100,
Mþ). Anal. calc. for C19H12ClNS2 (353.89): C 64.48, H 3.42, N 3.96; found: C 64.40, H 3.45, N 3.92.

74
Helvetica Chimica Acta – Vol. 96 (2013)
3-(1,3-Benzodioxol-5-yl)-2-(phenylsulfanyl)thieno[2,3-b]pyridine (4e). Pale-yellow oil. Rf (Et2O/
hexane 1:2) 0.32. IR (neat): 1371, 1234. 1H-NMR (500 MHz): 6.04 (s, 2 H); 6.90 – 6.94 (m, 3 H); 7.23 –
7.31 (m, 4 H); 7.34 (d, J ¼ 7.3, 2 H); 7.86 (dd, J ¼ 7.8, 1.4, 1 H); 8.55 (dd, J ¼ 4.6, 1.4, 1 H). 13C-NMR: 101.3;
108.5; 110.2; 119.8; 123.7; 126.9; 127.5; 129.2; 130.0; 130.6; 132.3; 133.4; 135.6; 138.0; 147.1; 147.6; 147.8;
162.2. MS: 363 (100, Mþ). Anal. calc. for C20H13NO2S2 (363.45): C 66.09, H 3.61, N 3.85; found: C 66.12, H
3.43, N 4.04.
3-Phenyl-2-(phenylsulfanyl)thieno[2,3-c]pyridine (8a). Pale-yellow oil. Rf (AcOEt/hexane 1:3) 0.25.
1
IR (neat): 1573, 1439. H-NMR (400 MHz): 7.31 – 7.34 (m, 3 H); 7.42 – 7.58 (m, 8 H); 8.44 (d, J ¼ 4.9,
1 H); 8.96 (s, 1 H). 13C-NMR: 116.8; 128.3; 128.4; 128.7; 129.4; 129.8; 131.8; 133.0; 134.2; 136.6; 137.2;
143.3; 143.7; 145.0; 145.2. MS: 319 (100, Mþ). Anal. calc. for C19H13NS2 (319.44): C 71.44, H 4.10, N 4.38;
found: C 71.19, H 4.16, N 4.25.
2-(Methylsulfanyl)-3-phenylthieno[2,3-c]pyridine (8b). Pale-yellow oil. Rf (AcOEt/hexane 1:2)
0.33. IR (neat): 1601, 1576, 1433. 1H-NMR (400 MHz): 2.59 (s, 3 H); 7.42 (d, J ¼ 5.9, 1 H); 7.43 – 7.48 (m,
3 H); 7.53 (dd, J ¼ 7.8, 7.3, 2 H); 8.43 (d, J ¼ 5.9, 1 H); 9.03 (s, 1 H). 13C-NMR: 18.9; 116.1; 128.2; 128.8;
129.7 (two overlapped Cs); 133.2; 133.9; 135.6; 143.4; 143.8; 145.3. MS: 257 (100, Mþ). Anal. calc. for
C14H11NS2 (257.37): C 65.33, H 4.31, N 5.44; found: C 65.10, H 4.29, N 5.45.
2-(Phenylsulfanyl)-3-(thiophen-2-yl)thieno[2,3-c]pyridine (8c). Yellow oil. Rf (AcOEt/hexane 1:2)
0.41. IR (neat): 1576, 1440. 1H-NMR (400 MHz): 7.22 (dd, J ¼ 4.9, 3.9, 1 H); 7.30 (d, J ¼ 2.9, 1 H); 7.33 –
7.41 (m, 3 H); 7.47 – 7.51 (m, 3 H); 7.70 (d, J ¼ 5.9, 1 H); 8.48 (d, J ¼ 5.9, 1 H); 8.92 (s, 1 H). 13C-NMR:
116.7; 126.8; 127.4; 127.8; 128.5; 128.8; 129.0; 129.6; 132.3; 133.1; 133.5; 136.0; 143.6; 144.0; 144.9. MS: 325
(100, Mþ). Anal. calc. for C17H11NS3 (325.47): C 62.73, H 3.41, N 4.30; found: C 62.71, H 3.42, N 4.30.
2-[(tert-Butyl)sulfanyl]-3-(thiophen-2-yl)thieno[2,3-c]pyridine (8d). Pale-yellow oil. Rf (AcOEt/
1
hexane 1:4) 0.29. IR (neat): 1573, 1454, 1161. H-NMR (400 MHz): 1.32 (s, 9 H); 7.20 (dd, J ¼ 4.9, 2.9,
1 H); 7.27 (d, J ¼ 2.9, 1 H); 7.49 (d, J ¼ 4.9, 1 H); 7.74 (d, J ¼ 5.9, 1 H); 8.51 (d, J ¼ 5.9, 1 H); 9.07 (s, 1 H).
13C-NMR: 31.1; 50.3; 117.5; 126.8; 127.0; 128.9; 133.7; 135.1; 137.3; 138.5; 143.6; 143.7; 144.4. MS: 305 (35,
Mþ), 249 (100). Anal. calc. for C15H15NS3 (305.48): C 58.98, H 4.95, N 4.59; found: C 58.72, H 5.01, N 4.42.
3-Phenyl-2-(phenylsulfanyl)thieno[3,2-c]pyridine (12a). Pale-yellow solid. M.p. 131 – 1338 (hexane/
CH2Cl2). IR (neat): 1566, 1437. 1H-NMR (500 MHz): 7.26 – 7.33 (m, 5 H); 7.45 – 7.54 (m, 5 H); 7.68 (dd,
J ¼ 5.2, 1.1, 1 H); 8.47 (d, J ¼ 5.2, 1 H); 8.87 (d, J ¼ 1.1, 1 H). 13C-NMR: 116.6; 127.5; 128.5; 128.6; 129.2;
129.9; 130.0; 132.8; 133.2; 135.6; 135.7; 139.8; 143.4; 145.7; 148.2. MS: 319 (100, Mþ). Anal. calc. for
C19H13NS2 (319.44): C 71.44, H 4.10, N 4.38; found: C 71.36, H 4.13, N 4.56.
2-[(tert-Butyl)sulfanyl]-3-phenylthieno[3,2-c]pyridine (12b). Yellow oil. Rf (AcOEt/hexane 1:3)
0.44. IR (neat): 1570, 1427, 1163. 1H-NMR (400 MHz): 1.22 (s, 9 H); 7.42 – 7.55 (m, 5 H); 7.73 (d, J ¼ 5.9,
1 H); 8.48 (d, J ¼ 5.9, 1 H); 8.86 (s, 1 H). 13C-NMR: 31.0; 49.6; 116.3; 128.1; 128.3; 130.8; 131.9 (two
overlapped Cs); 133.4; 143.2; 143.4; 146.3; 148.5. MS: 299 (13, Mþ), 243 (100). Anal. calc. for C17H17NS2
(299.45): C 68.18, H 5.72, N 4.68; found: C 68.14, H 5.73, N 4.52.
3-(4-Methoxyphenyl)-2-(phenylsulfanyl)thieno[3,2-c]pyridine (12c). White solid. M.p. 123 – 1258
(hexane/CH2Cl2). IR (KBr): 1611, 1573, 1523, 1438, 1249. 1H-NMR (500 MHz): 3.88 (s, 3 H); 7.04 (d, J ¼
8.6, 2 H); 7.25 – 7.32 (m, 5 H); 7.43 (dd, J ¼ 8.6, 2 H); 7.67 (d, J ¼ 5.7, 1 H); 8.46 (d, J ¼ 5.7, 1 H); 8.88 (s,
1 H). 13C-NMR: 55.3; 114.1; 116.6; 125.0; 127.4; 129.2; 129.8; 131.1; 132.3; 135.8; 135.8; 139.8; 143.4;
145.8; 148.3; 159.7. MS: 349 (100, Mþ). Anal. calc. for C20H15NOS2 (349.47): C 68.74, H 4.33, N 4.01;
found: C 68.70, H 4.35, N 3.87.
3-(4-Methoxyphenyl)-2-(methylsulfanyl)thieno[3,2-c]pyridine (12d). White solid. M.p. 82 – 848
1
(hexane/CH2Cl2). IR (KBr): 1610, 1523, 1433, 1249. H-NMR (400 MHz): 2.51 (s, 3 H); 3.90 (s, 3 H);
7.07 (d, J ¼ 8.8, 2 H); 7.43 (d, J ¼ 8.8, 2 H); 7.70 (d, J ¼ 5.9, 1 H); 8.43 (d, J ¼ 5.9, 1 H); 8.82 (s, 1 H).
13C-NMR: 19.8; 55.3; 114.1; 116.4; 125.3; 131.1 (two overlapped Cs); 135.6; 136.1; 142.6; 144.9; 146.9;
159.5. MS: 287 (100, Mþ). Anal. calc. for C15H13NOS2 (287.40): C 62.69, H 4.56, N 4.87; found: C 62.62, H
4.58, N 5.01.
The authors are grateful to Mrs. Miyuki Tanmatsu of our University for recording mass spectra and
performing combustion analyses.

Helvetica Chimica Acta – Vol. 96 (2013)
75
REFERENCES
[1] Y.-Z. Xu, R.-L. Zheng, Y. Zhou, F. Peng, H.-J. Lin, Q. Bu, Y.-Q. Mao, L.-T. Yu, L. Yang, S.-Y. Yang,
Y.-L. Zhao, Cancer Lett. 2011, 313, 44; M. A. M. Gad-Elkareem, A. M. Abdel-Fattah, M. A. A.
Elneairy, J. Sulfur Chem. 2011, 32, 273; K. Okuda, H. Takeuchi, T. Hirota, K. Sasaki, Heterocycles
2011, 83, 1315; P. B. McKay, M. B. Peters, G. Carta, C. T. Flood, E. Dempsey, A. Bell, C. Berry, D. G.
Lloyd, D. Fayne, Bioorg. Med. Chem. Lett. 2011, 21, 3335.
[2] K. Kobayashi, D. Nakamura, Y. Shiroyama, S. Fukamachi, H. Konishi, Synthesis 2009, 2179.
[3] K. Kobayashi, T. Suzuki, M. Horiuchi, Y. Shiroyama, H. Konishi, Synthesis 2011, 2897.
[4] a) Y. R. Hong, M. J. Lee, J. M. Kim, S. Park, W. Lee, J.-R. Choi, S. Ro, S. J. M. Joong, H. Masamune,
G. T. Elliott, PCT Int. Appl. 2011, WO 2011056725; Chem. Abstr. 2011, 154, 580291; b) J. Ohshita, Y.
Harima, T. Sugioaka, K. Kanehira, PCT Int. Appl. 2011, WO 2011115071; Chem. Abstr. 2011, 155,
457678; c) Y. Nakamura, Y. Matsuo, S. Hisada, F. Ahmed, R. Huntley, Z. Sajjadi-Hashemi, D. M.
Jenkins, R. B. Kargbo, W. Cui, P. J. F. Gauuan, J. R. Walker, H. Decornez, M. Gurram, PCT Int.
Appl. 2011, WO 2011123419; Chem. Abstr. 2011, 155, 536126.
[5] G. Gentile, G. Bernasconi, A. Pozzan, G. Merlo, P. Marzorati, P. Bamborough, B. Bax, A. Bridges, C.
Brough, P. Carter, G. Cutler, M. Neu, M. Takada, Bioorg. Med. Chem. Lett. 2011, 21, 4823.
[6] N. M. Rateb, J. Sulfur Chem. 2011, 32, 611; S. L.-F. Chan, K.-H. Low, C. Yang, S. H.-F. Cheung, C.-M.
Che, Chem. – Eur. J. 2011, 17, 4709.
[7] P. C. Too, S. H. Chua, S. H. Wong, S. Chiba, J. Org. Chem. 2011, 76, 6159.
[8] D. H. Bremner, A. D. Dunn, K. A. Wilson, Synthesis 1992, 528; D. H. Bremner, A. D. Dunn, K. A.
Wilson, K. R. Sturrock, G. Wishart, Synthesis 1997, 949.
[9] E. D. Turtle, L. A. Flippin, M. P. Arend, H. Cheng, H. US Pat. 2006, 0199836; Chem. Abstr. 2006,
145, 314973.
[10] K. Kobayashi, Y. Egara, S. Fukamachi, H. Konishi, Tetrahedron 2009, 65, 9633.
[11] K. Kobayashi, T. Kozuki, H. Konishi, Heterocycles 2009, 78, 2993.
[12] M. Oikawa, T. Uehara, T. Iwayama, M. Sasaki, Org. Lett. 2006, 8, 3943; Y.-L. Chen, H. Redlich, K.
Bergander, R. Frçhlich, Org. Biomol. Chem. 2007, 5, 3330; C. F. Morrison, C. T. M. Stamp, D. J.
Burnell, Tetrahedron Lett. 2009, 50, 7021.
[13] E. Maerten, M. Sauthier, A. Mortreux, Y. Castanet, Tetrahedron 2007, 63, 682.
[14] G. W. Gribble, M. G. Saulnier, Tetrahedron Lett. 1980, 21, 4137.
Received March 12, 2012