A simple method for the synthesis of 3-arylthieno[2,3-b]pyridines via iodine-mediated cyclization of 3-(1-arylalkenyl)-2-[(1-phenylethyl)sulfanyl] pyridines

Article abstract of DOI:10.1055/s-0029-1216857

3-Arylthieno[2,3-b]pyridines are synthesized in a short four-step sequence from readily available 2-bromopyridines. The final and key step of the reported method involves an iodine-mediated 5-endo cyclization of 3-(1-arylalkenyl)-2- [(1-phenylethyl)sulfan

Full text of DOI:10.1055/s-0029-1216857

PAPER
2179
A Simple Method for the Synthesis of 3-Arylthieno[2,3-b]pyridines via
Iodine-Mediated Cyclization of 3-(1-Arylalkenyl)-2-[(1-phenylethyl)sul-
fanyl]pyridines
A
Simple Method
afor the Syn
z
thesis of 3-A
u
rylthieno[
2
h
,3-
b
]pyridine
i
s
ro Kobayashi,* Daizo Nakamura, Yasuhiko Shiroyama, Shuhei Fukamachi, Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 20 January 2009; revised 10 March 2009
Table 1 Preparation of 2-[(1-Phenylethyl)sulfanyl]pyridin-3-yl
Ketones 3a–f
Abstract: 3-Arylthieno[2,3-b]pyridines are synthesized in a short
four-step sequence from readily available 2-bromopyridines. The
final and key step of the reported method involves an iodine-medi-
ated 5-endo cyclization of 3-(1-arylalkenyl)-2-[(1-phenylethyl)sul-
fanyl]pyridines.
Ar
1. LDA, THF, –78 °C
O
2. ArCONMe2
R
N
Br
Key words: thieno[2,3-b]pyridines, iodine, 2-bromopyridines, cy-
R
Br
N
clization, heterocycles
1a R = H
1b R = Ph
2a–f
Ar
PhCH(Me)SH, NaH
DMF, r.t.
We have recently reported the synthesis of 3-substituted
benzo[b]thiophenes,1 the key step in our procedure being
the iodine-mediated 5-endo cyclization of 2-[(1-phenyl-
ethyl)sulfanyl]styrenes. As an extension of this study we
now describe a new and simple approach for the synthesis
of 3-arylthieno[2,3-b]pyridines 5 from readily available
2-bromopyridines, which is based on the reaction of 3-(1-
arylalkenyl)-2-[(1-phenylethyl)sulfanyl]pyridines 4 with
iodine. Several methods have been reported for the prep-
aration of thieno[2,3-b]pyridines,2 as many derivatives
possessing this skeleton have been reported to exhibit var-
ied biological activity.3 Hence, we have investigated sim-
ple and general methods for the synthesis of this class of
heterocycles.
O
CH(Me)Ph
R
N
S
3a–f
Entry
R
Ar
Yield (%) Yield (%)
of 2
54
56
58
52
63
61
of 3
87
79
81
78
76
86
a
b
c
d
e
f
H
H
H
H
H
Ph
Ph
3-MeC6H4
4-MeC6H4
3-ClC6H4
4-ClC6H4
4-MeOC6H4
As starting materials, 2-bromopyridine (1a) was commer-
cially available whilst 2-bromo-6-phenylpyridine (1b)
was prepared from commercially available 2-phenylpyri-
dine according to the reported procedure.4 2-Bromopy-
ridines 1a and 1b were first lithiated using lithium
diisopropylamide (LDA) in tetrahydrofuran at –78 °C, via
the reported procedure,5 to afford the corresponding 2-
bromo-3-lithiopyridines. These were then reacted with
various N,N-dimethylbenzamides to give 3-aroyl-2-bro-
mopyridines 2a–f in moderate yields. Next, the 2-bromo
group was substituted with a (1-phenylethyl)sulfanyl
group by reaction with 1-phenylethanethiol6 and sodium
hydride in N,N-dimethylformamide at room temperature
to afford aryl 2-[(1-phenylethyl)sulfanyl]pyridin-3-yl ke-
tones 3a–f in good yields, as illustrated in Table 1.
The transformation of 2-[(1-phenylethyl)sulfanyl]pyri-
din-3-yl ketones 3 into 3-arylthieno[2,3-b]pyridines 5 was
carried out according to the procedure shown in
Scheme 1. Thus, compounds 3 were converted into the
corresponding 3-(1-arylalkenyl)-2-[(1-phenylethyl)sulfa-
nyl]pyridines 4 in good yields on treatment with methyl-
ene(triphenyl)phosphorane or ethylidene(triphenyl)phos-
phorane (Table 2). The subsequent iodine-mediated cy-
clization of 4 was initially conducted under conditions
previously reported for the preparation of ben-
zo[b]thiophenes.1 Unfortunately, we did not obtain the de-
sired products 5 in satisfactory yields; a considerable
amount of the starting material was recovered in each
case. Further investigation allowed optimization of the re-
action conditions for the conversion of 4 into thieno[2,3-
b]pyridines 5. Thus, treatment of 4 with three portions
each of two molar equivalents of iodine and sodium bicar-
bonate, at six hour intervals, in acetonitrile at room tem-
perature, and subsequent stirring overnight at the same
temperature gave the desired products 5. Preparative thin-
SYNTHESIS 2009, No. 13, pp 2179–2183
x
x.
x
x
.
2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1216857; Art ID: F01909SS
© Georg Thieme Verlag Stuttgart · New York

2180
K. Kobayashi et al.
PAPER
with a Shimadzu FTIR-8300 spectrophotometer. The H and 13C
NMR spectra were recorded in CDCl3 with TMS as an internal ref-
erence using a Jeol ECP500 FT NMR spectrometer operating at 500
MHz and 125 MHz, respectively. Low-resolution mass spectra (EI,
70 eV) were recorded using a Jeol JMS AX505 HA spectrometer.
TLC was carried out on Merck Kieselgel 60 PF254. Column chroma-
tography was performed using Merck Kieselgel 60 (0.063–0.200
mm). The organic solvents used in this study were dried over appro-
priate drying agents and distilled prior to use. N,N-Dimethylbenza-
mides were prepared from the respective benzoyl chlorides and
dimethylamine. 2-Bromo-6-phenylpyridine (1b)4 and 1-phenyl-
ethanethiol6 were prepared according to reported procedures. All
other reagents used in this study are commercially available.
1
layer chromatography afforded pure thieno[2,3-b]py-
ridines 5 in satisfactory yields (Table 2). However, lower
yields of thieno[2,3-b]pyridines 5a¢ and 5e¢ were obtained
on cyclization of compounds 4a¢ and 4e¢ which possess a
methyl substituent at the b-position of the alkenyl moiety
(entries 2 and 7); these reactions proceeded more slug-
gishly and gave complex mixtures containing unreacted
starting material. The presence of the b-methyl substituent
may restrict product formation due to steric hindrance in
the cyclization intermediate.
Ar
R2
(2-Bromopyridin-3-yl)(aryl)methanones 2; General Procedure
Compounds 2 were prepared by reaction of the 2-bromo-3-lithiopy-
ridines, generated by treatment of 2-bromopyridines 1a and 1b with
LDA according to the previously reported procedure,5 with the re-
spective N,N-dimethylbenzamides in THF at –78 °C. Aqueous
workup (sat. aq NH4Cl, Et2O) followed by column chromatography
on silica gel (THF–hexane) gave 2.
Ph3P=CHR2, THF, 0 °C
3
CH(Me)Ph
R1
N
S
4
Ar
I2, NaHCO3, MeCN, r.t.
(2-Bromopyridin-3-yl)(phenyl)methanone (2a)7
R2
Yellow oil; Rf = 0.33 (EtOAc–hexane, 1:4).
R1
N
S
IR (neat): 1672 cm–1.
5
1H NMR: d = 7.42 (dd, J = 7.8, 4.6 Hz, 1 H), 7.50 (dd, J = 7.8, 7.3
Hz, 2 H), 7.63–7.68 (m, 2 H), 7.82 (d, J = 7.8 Hz, 2 H), 8.53 (dd,
J = 4.6, 1.8 Hz, 1 H).
Scheme 1 Synthesis of thieno[2,3-b]pyridines 5
Table 2 Preparation of 3-Arylthieno[2,3-b]pyridines 5
(2-Bromopyridin-3-yl)(3-methylphenyl)methanone (2b)
Yellow oil; Rf = 0.26 (THF–hexane, 1:4).
Entry
Substrate R2
Yield (%)a of 4 Yield (%)a of 5
IR (neat): 1668 cm–1.
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3e
3f
H
4a (89)
4a¢ (75)
4b (87)
4c (93)
4d (86)
4e (91)
4e¢ (84)
4f (86)
5a (72)
5a¢ (40)
5b (75)
5c (70)
5d (76)
5e (67)
5e¢ (33)
5f (72)
1H NMR: d = 2.42 (s, 3 H), 7.38 (dd, J = 7.8, 7.3 Hz, 1 H), 7.42 (dd,
J = 7.3, 4.6 Hz, 1 H), 7.46 (d, J = 7.3 Hz, 1 H), 7.57 (d, J = 7.8 Hz,
1 H), 7.65 (s, 1 H), 7.66 (dd, J = 7.3, 1.8 Hz, 1 H), 8.53 (dd, J = 4.6,
1.8 Hz, 1 H).
Me
H
H
Anal. Calcd for C13H10BrNO: C, 56.55; H, 3.65; N, 5.07. Found: C,
56.52; H, 3.71; N, 5.08.
H
(2-Bromopyridin-3-yl)(4-methylphenyl)methanone (2c)
Yellow oil; Rf = 0.44 (THF–hexane, 1:3).
IR (neat): 1668 cm–1.
1H NMR: d = 2.44 (s, 3 H), 7.29 (d, J = 7.8 Hz, 2 H), 7.41 (dd, J =
7.3, 4.6 Hz, 1 H), 7.65 (dd, J = 7.3, 1.8 Hz, 1 H), 7.71 (d, J = 7.8 Hz,
2 H), 8.51 (dd, J = 4.6, 1.8 Hz, 1 H).
H
Me
H
a Yield of isolated product.
Anal. Calcd for C13H10BrNO: C, 56.55; H, 3.65; N, 5.07. Found: C,
56.31; H, 3.82; N, 5.00.
Attempts to obtain 3-alkylthieno[2,3-b]pyridines failed,
because, for example, the precursor (equivalent to 3) for
the synthesis of 3-ethylthieno[2,3-b]pyridine could not be
prepared using the present method. The reaction of 2-bro-
mopyridin-3-yl ethyl ketone with 1-phenylethanethiol un-
der the conditions described above resulted in the
formation of an intractable mixture of products.
(2-Bromopyridin-3-yl)(3-chlorophenyl)methanone (2d)
Yellow oil; Rf = 0.19 (THF–hexane, 1:5).
IR (neat): 1682 cm–1.
1H NMR: d = 7.43–7.46 (m, 2 H), 7.62 (dd, J = 7.3, 1.8 Hz, 1 H),
7.65–7.69 (m, 2 H), 7.81 (t, J = 1.8 Hz, 1 H), 8.55 (dd, J = 4.6, 1.8
Hz, 1 H).
In summary, the methodology described in this work al-
lows very easy access to 3-arylthieno[2,3-b]pyridines.
This method has advantages over previous syntheses of
thieno[2,3-b]pyridines because of its simplicity as well as
the ready availability of the starting materials.
Anal. Calcd for C12H7BrClNO: C, 48.60; H, 2.38; N, 4.72. Found:
C, 48.48; H, 2.49; N, 4.89.
(2-Bromopyridin-3-yl)(4-chlorophenyl)methanone (2e)7
Yellow solid; mp 54–56 °C (hexane–CH2Cl2).
IR (KBr): 1668 cm–1.
All melting points were obtained using a Laboratory Devices MEL-
TEMP II apparatus and are uncorrected. IR spectra were determined
Synthesis 2009, No. 13, 2179–2183 © Thieme Stuttgart · New York

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A Simple Method for the Synthesis of 3-Arylthieno[2,3-b]pyridines
2181
1H NMR: d = 7.34 (dd, J = 7.8, 4.6 Hz, 1 H), 7.43 (dd, J = 7.8, 1.8
Hz, 1 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.75 (d, J = 8.7 Hz, 2 H), 8.54
(dd, J = 4.6, 1.8 Hz, 1 H).
1H NMR: d = 1.71 (d, J = 6.9 Hz, 3 H), 5.26 (q, J = 6.9 Hz, 1 H),
7.08 (dd, J = 7.3, 4.6 Hz, 1 H), 7.20 (t, J = 7.3 Hz, 1 H), 7.26 (dd,
J = 7.8, 7.3 Hz, 2 H), 7.36–7.40 (m, 3 H), 7.53–7.56 (m, 2 H), 7.59
(dd, J = 7.3, 1.8 Hz, 1 H), 7.68 (t, J = 1.8 Hz, 1 H), 8.60 (dd, J = 4.6,
1.8 Hz, 1 H).
(2-Bromo-6-phenylpyridin-3-yl)(4-methoxyphenyl)methanone
(2f)
Anal. Calcd for C20H16ClNOS: C, 67.88; H, 4.56; N, 3.96. Found:
C, 67.79; H, 4.65; N, 3.84.
White solid; mp 105–107 °C (hexane–CH2Cl2).
IR (KBr): 1661 cm–1.
(4-Chlorophenyl){2-[(1-phenylethyl)sulfanyl]pyridin-3-
yl}methanone (3e)
Yellow solid; mp 112–114 °C (hexane–CH2Cl2).
IR (KBr): 1655 cm–1.
1H NMR: d = 1.69 (d, J = 7.3 Hz, 3 H), 5.26 (q, J = 7.3 Hz, 1 H),
7.19 (t, J = 7.3 Hz, 1 H), 7.25 (dd, J = 7.8, 7.3 Hz, 2 H), 7.37 (dd,
J = 7.8, 1.4 Hz, 2 H), 7.38 (dd, J = 7.8, 4.6 Hz, 1 H), 7.39 (d, J = 8.2
Hz, 2 H), 7.56 (dd, J = 7.8, 1.8 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 2 H),
8.59 (dd, J = 4.6, 1.8 Hz, 1 H).
1H NMR: d = 3.90 (s, 3 H), 6.97 (d, J = 9.2 Hz, 2 H), 7.46–7.52 (m,
3 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.84 (d,
J = 9.2 Hz, 2 H), 8.06 (dd, J = 8.2, 1.4 Hz, 2 H).
Anal. Calcd for C19H14BrNO2: C, 61.97; H, 3.83; N, 3.80. Found: C,
61.80; H, 4.02; N, 3.82.
Aryl{2-[(1-phenylethyl)sulfanyl]pyridin-3-yl]}methanones 3;
General Procedure
Compounds 3 were prepared by treatment of (2-bromopyridin-3-
yl)(aryl)methanones 2 with 1-phenylethanethiol6 in DMF at r.t. in
the presence of NaH. Aqueous workup (sat. aq NH4Cl, Et2O) fol-
lowed by column chromatography on silica gel (THF–hexane) gave
3.
Anal. Calcd for C20H16ClNOS: C, 67.88; H, 4.56; N, 3.96. Found:
C, 67.85; H, 4.50; N, 3.91.
(4-Methoxyphenyl){6-phenyl-[2-(1-phenylethyl)sulfanyl]pyri-
din-3-yl}methanone (3f)
White solid; mp 94–96 °C (hexane–Et2O).
IR (KBr): 1651 cm–1.
Phenyl{2-[(1-phenylethyl)sulfanyl]pyridin-3-yl}methanone
(3a)
Yellow oil; Rf = 0.43 (THF–hexane, 1:4).
1H NMR: d = 1.77 (d, J = 6.9 Hz, 3 H), 3.89 (s, 3 H), 5.39 (q, J =
6.9 Hz, 1 H), 6.93 (d, J = 8.7 Hz, 2 H), 7.19 (t, J = 7.3 Hz, 1 H), 7.25
(dd, J = 7.8, 7.3 Hz, 2 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.47–7.53 (m,
6 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.76 (d, J = 8.7 Hz, 2 H), 8.06 (dd,
J = 7.8, 1.4 Hz, 1 H).
IR (neat): 1661 cm–1.
1H NMR: d = 1.70 (d, J = 6.9 Hz, 3 H), 5.26 (q, J = 6.9 Hz, 1 H),
7.06 (dd, J = 7.3, 4.6 Hz, 1 H), 7.18 (tt, J = 7.3, 1.4 Hz, 1 H), 7.25
(t, J = 7.3 Hz, 2 H), 7.39 (d, J = 7.3 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 2
H), 7.58 (t, J = 7.8 Hz, 1 H), 7.59 (dd, J = 7.3, 1.8 Hz, 1 H), 7.69
(dd, J = 7.8, 1.4 Hz, 2 H), 8.58 (dd, J = 4.6, 1.8 Hz, 1 H).
Anal. Calcd for C27H23NO2S: C, 76.21; H, 5.45; N, 3.29. Found: C,
75.97; H, 5.64; N, 2.99.
Anal. Calcd for C20H17NOS: C, 75.20; H, 5.36; N, 4.39. Found: C,
74.95; H, 5.44; N, 4.38.
3-Alkenyl-2-[(1-phenylethyl)sulfanyl]pyridines 4; General Pro-
cedure
Compounds 4 were prepared by reaction of ketones 3 with methyl-
ene(triphenyl)phosphorane or ethylidene(triphenyl)phosphorane in
THF at 0 °C. Aqueous workup (H2O, Et2O) followed by column
chromatography on silica gel (THF–hexane) gave 4.
(3-Methylphenyl){2-[(1-phenylethyl)sulfanyl]pyridin-3-
yl}methanone (3b)
Yellow oil; Rf = 0.31 (THF–hexane, 1:10).
IR (neat): 1661 cm–1.
1H NMR: d = 1.70 (d, J = 6.9 Hz, 3 H), 2.38 (s, 3 H), 5.26 (q, J =
6.9 Hz, 1 H), 7.06 (dd, J = 7.3, 4.6 Hz, 1 H), 7.18 (td, J = 7.3, 0.9
Hz, 1 H), 7.25 (dd, J = 7.8, 7.3 Hz, 2 H), 7.31 (dd, J = 7.8, 7.3 Hz,
1 H), 7.39–7.40 (m, 3 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.54 (s, 1 H),
7.58 (dd, J = 7.3, 1.8 Hz, 1 H), 8.58 (dd, J = 4.6, 1.8 Hz, 1 H).
2-[(1-phenylethyl)sulfanyl]-3-(1-phenylethenyl)pyridine (4a)
Pale-yellow oil; Rf = 0.29 (THF–hexane, 1:10).
IR (neat): 1614, 1601, 1385 cm–1.
1H NMR: d = 1.63 (d, J = 6.9 Hz, 3 H), 5.17 (q, J = 6.9 Hz, 1 H),
5.27 (d, J = 0.9 Hz, 1 H), 5.83 (d, J = 0.9 Hz, 1 H), 7.00 (dd, J = 7.3,
4.6 Hz, 1 H), 7.15–7.27 (m, 8 H), 7.31–7.35 (m, 3 H), 8.45 (dd, J =
4.6, 1.8 Hz, 1 H).
Anal. Calcd for C21H19NOS: C, 75.64; H, 5.74; N, 4.20. Found: C,
75.40; H, 5.92; N, 4.11.
(4-Methylphenyl){2-[(1-phenylethyl)sulfanyl]pyridin-3-
yl}methanone (3c)
Pale-yellow solid; mp 111–113 °C (hexane–CH2Cl2).
Anal. Calcd for C21H19NS: C, 79.45; H, 6.03; N, 4.41. Found: C,
79.28; H, 6.11; N, 4.20.
IR (KBr): 1647 cm–1.
2-[(1-phenylethyl)sulfanyl]-3-[(1E/Z)-1-phenylprop-1-en-1-
yl]pyridine (4a¢)
Pale-yellow oil as a mixture of stereoisomers (E/Z = ca. 1:1); Rf =
0.56 (THF–hexane, 1:10).
1H NMR: d = 1.69 (d, J = 6.9 Hz, 3 H), 2.42 (s, 3 H), 5.25 (q, J =
6.9 Hz, 1 H), 7.01 (dd, J = 7.3, 4.6 Hz, 1 H), 7.18 (t, J = 7.3 Hz, 1
H), 7.22 (d, J = 7.8 Hz, 2 H), 7.24 (dd, J = 7.8, 7.3 Hz, 2 H), 7.38
(d, J = 7.8 Hz, 2 H), 7.55 (dd, J = 7.3, 1.8 Hz, 1 H), 7.60 (d, J = 7.8
Hz, 2 H), 8.57 (dd, J = 4.6, 1.8 Hz, 1 H).
IR (neat): 1599, 1387 cm–1.
1H NMR: d = 1.65 (d, J = 6.9 Hz, 4.5 H), 1.86 (d, J = 6.9 Hz, 1.5 H),
5.15 (q, J = 6.9 Hz, 0.5 H), 5.20 (q, J = 6.9 Hz, 0.5 H), 5.84 (q, J =
6.9 Hz, 0.5 H), 6.32 (br s, 0.5 H), 6.92 (dd, J = 7.8, 4.6 Hz, 0.5 H),
7.02–7.38 (m, 11.5 H), 8.35 (dd, J = 4.6, 1.8 Hz, 0.5 H), 8.45 (br s,
0.5 H).
Anal. Calcd for C21H19NOS: C, 75.64; H, 5.74; N, 4.20. Found: C,
75.50; H, 5.92; N, 4.16.
(3-Chlorophenyl){2-[(1-phenylethyl)sulfanyl]pyridin-3-
yl}methanone (3d)
Yellow oil; Rf = 0.25 (THF–hexane, 1:10).
IR (neat): 1650 cm–1.
Anal. Calcd for C22H21NS: C, 79.72; H, 6.39; N, 4.23. Found: C,
79.62; H, 6.50; N, 4.19.
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2182
K. Kobayashi et al.
PAPER
3-[1-(4-Methoxyphenyl)ethenyl]-6-phenyl-2-[(1-phenyleth-
3-[1-(3-Methylphenyl)ethenyl]-2-[(1-phenylethyl)sulfanyl]pyri-
dine (4b)
yl)sulfanyl]pyridine (4f)
Pale-yellow oil; Rf = 0.31 (THF–hexane, 1:20).
White solid; mp 118–120 °C (hexane–Et2O).
IR (neat): 1601, 1384 cm–1.
IR (KBr): 1605, 1348 cm–1.
1H NMR: d = 1.64 (d, J = 6.9 Hz, 3 H), 2.29 (s, 3 H), 5.18 (q, J =
6.9 Hz, 1 H), 5.25 (s, 1 H), 5.83 (s, 1 H), 6.97–7.02 (m, 3 H), 7.08
(d, J = 7.8 Hz, 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 7.17 (t, J = 7.3 Hz, 1
H), 7.23 (dd, J = 7.8, 7.3 Hz, 2 H), 7.31 (dd, J = 7.3, 1.8 Hz, 1 H),
7.35 (s, 1 H), 7.36 (d, J = 7.8 Hz, 1 H), 8.45 (dd, J = 5.0, 1.8 Hz, 1
H).
1H NMR: d = 1.72 (d, J = 6.9 Hz, 3 H), 3.81 (s, 3 H), 5.24 (s, 1 H),
5.32 (q, J = 7.3 Hz, 1 H), 5.76 (d, J = 0.9 Hz, 1 H), 6.81 (d, J = 9.2
Hz, 2 H), 7.18 (d, J = 9.2 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 1 H), 7.38–
7.50 (m, 9 H), 8.05 (dd, J = 7.3, 1.4 Hz, 2 H).
Anal. Calcd for C28H25NOS: C, 79.40; H, 5.95; N, 3.31. Found: C,
79.38; H, 6.00; N, 3.10.
Anal. Calcd for C22H21NS: C, 79.72; H, 6.39; N, 4.23. Found: C,
79.63; H, 6.44; N, 4.12.
3-Phenylthieno[2,3-b]pyridine (5a); Typical Procedure
To a stirred solution of 4a (0.19 g, 0.58 mmol) in MeCN (4 mL) at
r.t. was added three portions each of NaHCO3 (0.10 g, 1.2 mmol)
and I2 (0.29 g, 1.2 mmol) at 6 h intervals. The resulting mixture was
stirred overnight at r.t., after which 10% aq Na2S2O3 was added until
the color due to iodine had disappeared. MeCN was evaporated and
the remaining aq layer was extracted with Et2O (2 × 15 mL). The
combined extract was washed with sat. aq NaHCO3 (10 mL) and
brine (10 mL) and then dried over anhyd K2CO3. After evaporation
of the solvent, the residue was purified by preparative TLC on silica
gel to afford 5a as a pale-yellow viscous oil; yield: 88 mg (72%);
Rf = 0.38 (THF–hexane, 1:10).
3-[1-(4-Methylphenyl)ethenyl]-2-[(1-phenylethyl)sulfanyl]pyri-
dine (4c)
Pale-yellow oil; Rf = 0.46 (THF–hexane, 1:10).
IR (neat): 1609, 1385 cm–1.
1H NMR: d = 1.64 (d, J = 6.9 Hz, 3 H), 2.33 (s, 3 H), 5.17 (q, J =
6.9 Hz, 1 H), 5.21 (s, 1 H), 5.80 (s, 1 H), 6.99 (dd, J = 7.3, 5.0 Hz,
1 H), 7.06 (d, J = 9.2 Hz, 2 H), 7.08 (d, J = 9.2 Hz, 2 H), 7.16 (tt,
J = 7.3, 1.4 Hz, 1 H), 7.23 (dd, J = 7.8, 7.3 Hz, 2 H), 7.31 (dd, J =
7.3, 1.8 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 2 H), 8.44 (dd, J = 5.0, 1.8 Hz,
1 H).
IR (neat): 1601, 1371, 1082 cm–1.
Anal. Calcd for C22H21NS: C, 79.72; H, 6.39; N, 4.23. Found: C,
79.65; H, 6.47; N, 4.04.
1H NMR: d = 7.34 (dd, J = 8.2, 4.6 Hz, 1 H), 7.43 (tt, J = 7.3, 1.4
Hz, 1 H), 7.51 (dd, J = 7.8, 7.3 Hz, 2 H), 7.52 (s, 1 H), 7.56 (dd, J =
7.8, 1.4 Hz, 2 H), 8.20 (dd, J = 8.2, 1.8 Hz, 1 H), 8.62 (dd, J = 4.6,
1.8 Hz, 1 H).
3-[1-(3-Chlorophenyl)ethenyl]-2-[(1-phenylethyl)sulfanyl]pyri-
dine (4d)
Pale-yellow oil; Rf = 0.32 (THF–hexane, 1:10).
13C NMR: d = 119.43, 123.36, 127.89, 128.38, 128.95, 130.50,
131.27, 135.36, 135.72, 146.75, 162.58.
MS (EI, 70 eV): m/z (%) = 211 (100) [M+].
IR (neat): 1610, 1389 cm–1.
1H NMR: d = 1.63 (d, J = 6.9 Hz, 3 H), 5.17 (q, J = 6.9 Hz, 1 H),
5.32 (s, 1 H), 5.83 (s, 1 H), 7.02 (dd, J = 7.3, 4.6 Hz, 1 H), 7.04 (d,
J = 7.8 Hz, 1 H), 7.16–7.20 (m, 3 H), 7.23–7.26 (m, 3 H), 7.31–7.34
(m, 3 H), 8.46 (dd, J = 4.6, 1.8 Hz, 1 H).
Anal. Calcd for C13H9NS: C, 73.90; H, 4.29; N, 6.63. Found: C,
73.80; H, 4.22; N, 6.61.
2-Methyl-3-phenylthieno[2,3-b]pyridine (5a¢)
Beige solid; mp 84–86 °C (hexane–Et2O).
IR (KBr): 1601, 1387 cm–1.
Anal. Calcd for C21H18ClNS: C, 71.68; H, 5.16; N, 3.98. Found: C,
71.63; H, 5.21; N, 4.11.
3-[1-(4-Chlorophenyl)ethenyl]-2-[(1-phenylethyl)sulfanyl]pyri-
dine (4e)
Pale-yellow oil; Rf = 0.40 (THF–hexane, 1:5).
IR (neat): 1610, 1387 cm–1.
1H NMR: d = 2.54 (s, 3 H), 7.22 (dd, J = 7.8, 4.6 Hz, 1 H), 7.37 (dd,
J = 7.8, 1.4 Hz, 2 H), 7.42 (tt, J = 7.3, 1.4 Hz, 1 H), 7.50 (dd, J =
7.8, 7.3 Hz, 2 H), 7.76 (dd, J = 7.8, 1.4 Hz, 1 H), 8.50 (dd, J = 4.6,
1.4 Hz, 1 H).
1H NMR: d = 1.63 (d, J = 6.9 Hz, 3 H), 5.17 (q, J = 6.9 Hz, 1 H),
5.28 (s, 1 H), 5.80 (s, 1 H), 7.02 (dd, J = 7.8, 4.6 Hz, 1 H), 7.09 (d,
J = 8.7 Hz, 2 H), 7.18 (tt, J = 7.3, 1.4 Hz, 1 H), 7.20–7.25 (m, 4 H),
7.30–7.33 (m, 3 H), 8.46 (dd, J = 4.6, 1.8 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 225 (100) [M+].
Anal. Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found: C,
74.54; H, 4.95; N, 6.35.
Anal. Calcd for C21H18ClNS: C, 71.68; H, 5.16; N, 3.98. Found: C,
71.57; H, 5.28; N, 3.91.
3-(3-Methylphenyl)thieno[2,3-b]pyridine (5b)
Pale-yellow solid; mp 49–51 °C (hexane).
IR (KBr): 1607, 1371 cm–1.
3-[(1E/Z)-1-(4-chlorophenyl)prop-1-en-1-yl]-2-[(1-phenyleth-
yl)sulfanyl]pyridine (4e¢)
Pale-yellow oil as a mixture of stereoisomers (E/Z = ca. 6:4); Rf =
0.58 (THF–hexane, 1:5).
1H NMR: d = 2.45 (s, 3 H), 7.24 (d, J = 7.3 Hz, 1 H), 7.34 (dd, J =
7.8, 4.6 Hz, 1 H), 7.37–7.41 (m, 3 H), 7.49 (s, 1 H), 8.20 (dd, J =
7.8, 1.8 Hz, 1 H), 8.61 (dd, J = 4.6, 1.8 Hz, 1 H).
13C NMR: d = 31.48, 119.36, 123.15, 125.40, 128.62, 128.79,
129.03, 130.55, 131.27, 135.23, 135.77, 138.64, 146.67, 162.50.
IR (neat): 1601, 1387 cm–1.
1H NMR: d = 1.64 (d, J = 6.9 Hz, 4.2 H), 1.85 (d, J = 6.9 Hz, 1.8 H),
5.14 (q, J = 6.9 Hz, 0.6 H), 5.19 (q, J = 6.9 Hz, 0.4 H), 5.85 (q, J =
6.9 Hz, 0.6 H), 6.30 (br s, 0.4 H), 6.91–6.95 (m, 1 H), 7.05 (d, J =
8.7 Hz, 1.2 H), 7.17–7.27 (m, 7.6 H), 7.34 (dd, J = 7.8, 1.4 Hz, 1.2
H), 8.37 (dd, J = 4.6, 1.8 Hz, 0.6 H), 8.46 (br s, 0.4 H).
MS (EI, 70 eV): m/z (%) = 225 (100) [M+].
Anal. Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found: C,
74.46; H, 5.07; N, 6.19.
3-(4-Methylphenyl)thieno[2,3-b]pyridine (5c)
Pale-yellow solid; mp 59–62 °C (hexane).
IR (KBr): 1371, 1080 cm–1.
Anal. Calcd for C22H20ClNS: C, 72.21; H, 5.51; N, 3.83. Found: C,
72.02; H, 5.53; N, 3.93.
Synthesis 2009, No. 13, 2179–2183 © Thieme Stuttgart · New York

PAPER
A Simple Method for the Synthesis of 3-Arylthieno[2,3-b]pyridines
2183
1H NMR: d = 2.44 (s, 3 H), 7.31 (d, J = 7.8 Hz, 2 H), 7.33 (dd, J =
7.8, 4.6 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 2 H), 7.47 (s, 1 H), 8.18 (dd,
J = 7.8, 1.8 Hz, 1 H), 8.61 (dd, J = 4.6, 1.8 Hz, 1 H).
References
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Delgado, M. Heterocycles 2004, 63, 2199. (c) Abdelhamid,
A.; Al-Atoom, A. Synth. Commun. 2006, 36, 97.
MS (EI, 70 eV): m/z (%) = 225 (100) [M+].
Anal. Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found: C,
74.58; H, 5.17; N, 6.27.
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3-(3-Chlorophenyl)thieno[2,3-b]pyridine (5d)
Pale-yellow solid; mp 100–101 °C (hexane).
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R.; Mao, C.; Marshall, D.; McNeil, D.; Prokopowicz, A. III;
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IR (KBr): 1371, 1086 cm–1.
1H NMR: d = 7.37 (dd, J = 7.8, 4.6 Hz, 1 H), 7.40–7.42 (m, 1 H),
7.44–7.45 (m, 2 H), 7.55 (s, 1 H), 7.56 (t, J = 1.4 Hz, 1 H), 8.18 (dd,
J = 7.8, 1.8 Hz, 1 H), 8.63 (dd, J = 4.6, 1.8 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 245 (100) [M+].
Anal. Calcd for C13H8ClNS: C, 63.54; H, 3.28; N, 5.70. Found: C,
63.28; H, 3.47; N, 5.48.
3-(4-Chlorophenyl)thieno[2,3-b]pyridine (5e)
White solid; mp 152–154 °C (hexane–CH2Cl2).
IR (KBr) 1371, 1088 cm–1.
1H NMR: d = 7.36 (dd, J = 8.2, 4.6 Hz, 1 H), 7.48 (d, J = 8.7 Hz, 2
H), 7.49 (d, J = 8.7 Hz, 2 H), 7.51 (s, 1 H), 8.14 (dd, J = 8.2, 1.8 Hz,
1 H), 8.63 (dd, J = 4.6, 1.8 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 245 (100) [M+].
Anal. Calcd for C13H8ClNS: C, 63.54; H, 3.28; N, 5.70. Found: C,
63.70; H, 3.08; N, 5.59.
3-(4-Chlorophenyl)-2-methylthieno[2,3-b]pyridine (5e¢)
Pale-yellow oil; Rf = 0.28 (THF–hexane, 1:10).
IR (neat): 1387, 1091 cm–1.
1H NMR: d = 2.53 (s, 3 H), 7.24 (dd, J = 7.8, 4.6 Hz, 1 H), 7.31 (d,
J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.72 (dd, J = 7.8, 1.4 Hz,
1 H), 8.51 (dd, J = 4.6, 1.4 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 259 (100) [M+].
Anal. Calcd for C14H10ClNS: C, 64.73; H, 3.88; N, 5.39. Found: C,
64.81; H, 4.02; N, 5.21.
3-(4-Methoxyphenyl)-6-phenylthieno[2,3-b]pyridine (5f)
White solid; mp 97–99 °C (hexane–Et2O).
IR (KBr): 1611, 1361, 1076 cm–1.
(4) Vandromme, L.; Reibig, H.-U.; Gröper, S.; Rabe, J. P. Eur.
J. Org. Chem. 2008, 2049.
(5) Srinivasan, J. M.; Burks, H. E.; Smith, C. R.; Viswanathan,
R. Synthesis 2005, 330.
(6) Kellogg, R. M.; Nieuwenhuijzen, J. W.; Vries, T. R.;
Broxterman, Q. B.; Grimbergen, R. F. P.; Kaptein, B.;
La Crois, R. M.; de Wever, E.; Zwaagstra, K.; van der Laan,
A. C. Synthesis 2003, 1626.
(7) Marsais, F.; Laperdrix, B.; Guengoer, T.; Mallet, M.;
Queguiner, G. J. Chem. Res., Synop. 1982, 278.
1H NMR: d = 3.88 (s, 3 H), 7.04 (d, J = 8.7 Hz, 2 H), 7.41 (s, 1 H),
7.43 (tt, J = 7.3, 1.4 Hz, 1 H), 7.49–7.52 (m, 4 H), 7.77 (d, J = 8.7
Hz, 1 H), 8.11 (dd, J = 7.3, 1.4 Hz, 2 H), 8.20 (d, J = 8.7 Hz, 1 H).
13C NMR: d = 55.38, 114.38, 116.78, 122.38, 127.23, 128.00,
128.80, 129.00, 129.44, 130.03, 131.01, 135.19, 139.11, 154.63,
159.38, 162.85.
Anal. Calcd for C20H15NOS: C, 75.68; H, 4.76; N, 4.41. Found: C,
75.51; H, 4.99; N, 4.27.
Acknowledgment
We are much indebted to Mrs. Miyuki Tanmatsu of Tottori Univer-
sity for her contributions to determining mass spectra and perfor-
ming combustion analyses.
Synthesis 2009, No. 13, 2179–2183 © Thieme Stuttgart · New York