Synthesis of the fused heterobicycles 5-pyridin-2-yl-thieno[3,2-b]pyridine, 6-pyridin-2-yl-thieno[2,3-b]pyridine and 6-pyridin-2-yl-thieno[3,2-c]pyridine

Article abstract of DOI:10.1055/s-2006-926416

Three new pyridyl thienopyridines, 5-pyridin-2-yl-thieno[3,2-b]pyridine, 6-pyridin-2-yl-thieno[2,3-b]pyridine and 6-pyridin-2-yl-thieno[3,2-c]pyridine, have been synthesized, each through a different synthetic sequence. Overall yields ranged from 8% to 32%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926416

PAPER
1295
Synthesis of the Fused Heterobicycles 5-Pyridin-2-yl-thieno[3,2-b]pyridine,
6-Pyridin-2-yl-thieno[2,3-b]pyridine and 6-Pyridin-2-yl-thieno[3,2-c]pyridine
S
ynthesis of Th
a
ree Thieno
s
pyridine
s
s
U
se in
e
M
olecula
r
ElectrJ
Department of Biology and Chemical Engineering, Mälardalen University, Box 325, 631 05 Eskilstuna, Sweden
Fax +46(16)153710; E-mail: simon.dunne@mdh.se
Received 19 September 2005; revised 5 December 2005
S
Abstract: Three new pyridyl thienopyridines, 5-pyridin-2-yl-
thieno[3,2-b]pyridine, 6-pyridin-2-yl-thieno[2,3-b]pyridine and 6-
pyridin-2-yl-thieno[3,2-c]pyridine, have been synthesized, each
through a different synthetic sequence. Overall yields ranged from
8% to 32%.
N
N
N
N
S
1
2
S
Key words: ring closure, fused-ring systems, heterocycles, py-
ridines, conjugation
N
N
3
In our ongoing studies in the field of molecular electron-
ics, we have used 6-thiophen-2-yl-2,2¢-bipyridine and 4-
thiophen-2-yl-2,2¢-bipyridine units both as molecular
switches and chelating end groups for oligothienyl molec-
ular wires.1 Through the development of Stille couplings
using metal-complexed aryl substrates2 it has been possi-
ble to construct a range of polarized bis-metallic complex-
es. Molecular modelling studies, however, indicate that
steric interactions between the thiophene rings and neigh-
boring hydrogen atoms on the adjacent pyridine ring re-
sult in an interannular twist which reduces p-orbital
overlap between the oligothienyl bridge and the chelating
unit. The fusion of the bipyridine unit to the first
thiophene unit of the chain should optimize p-overlap be-
tween them without affecting its chelating ability.
Figure 1 Three new thienopyridines, 5-pyridin-2-yl-thieno[3,2-
b]pyridine (1), 6-pyridin-2-yl-thieno[2,3-b]pyridine (2) and 6-pyri-
din-2-yl-thieno[3,2-c]pyridine (3).
nitro group was intended to lead directly to the thieno-
pyridine 1 (Scheme 1), by analogy with the synthesis of 6-
phenyl-thieno[2,3-b]pyridine as described by Raich and
Hamilton.7 This strategy failed for two reasons. Nitration
of thiophene-2-carbaldehyde produced three mononitrat-
ed isomers of nitrothiophene-2-carbaldehyde [3-nitro-
(62%), 4-nitro- (15%) and 5-nitro- (23%)] and no viable
method to separate these isomers in sufficient quantities
could be found. Trial synthesis also showed that treatment
of this mixture of nitrothiophene-2-carbaldehydes with
NaOH and 2-acetylpyridine resulted in thiophene ring
opening instead of the formation of the corresponding
chalcone precursors. Thus a new pathway was required
(Scheme 2). In this route the problems associated with ni-
tration were circumvented through the use of the commer-
cially available methyl 3-aminothiophene-2-carboxylate
(7) as starting material.
While several related substituted analogues of these py-
ridyl thienopyridines (or their phenanthrene equivalents)
have been reported (Amr et al.,3 Goerlitzer and Kramer,4
Halverson,5 Zhang and Tour6), these methods were not
suitable for the generation of the parent thienopyridines
1–3 (Figure 1) nor were these analogues suitable for com-
plexation due to steric hindrance arising from the substit-
uents present in these systems. Thus, routes to three new
pyridyl thienopyridines 1–3 were devised and are present-
ed in this work. Structural studies, together with electro-
chemical and photophysical measurements on the
ruthenium(II) bis(2,2¢-bipyridine) complexes of these
ligands are currently under investigation.
NO2
HNO3, H2SO4
0 °C
S
S
O
O
5
4
2-acetylpyridine
NaOH
MeOH
r.t.
Our initial approach towards the synthesis of 5-pyridin-2-
yl-thieno[3,2-b]pyridine (1) began with the nitration of
thiophene-2-carbaldehyde (4). 3-Nitrothiophene-2-carb-
aldehyde was then to be reacted with 2-acetylpyridine to
produce the chalcone derivative 3-(3-nitrothiophen-2-yl)-
1-pyridin-2-ylpropenone (6). Subsequent reduction of the
NO2
N
N
[H]
S
N
S
1
6
O
SYNTHESIS 2006, No. 8, pp 1295–1300
Advanced online publication: 29.03.2006
x
x
.
x
x
.2
0
0
6
Scheme 1 The initial strategy towards synthesis of thienopyridine 1
DOI: 10.1055/s-2006-926416; Art ID: T12905SS
© Georg Thieme Verlag Stuttgart · New York

1296
Nurkkala, L. J. et al.
PAPER
O
O
O
O
NH2
O
ethyl
chloroformate
NH
ethyl
chloroformate
O
O
O
H
O
N
O
toluene
reflux
toluene
reflux
S
NH2
S
S
O
O
8
S
7
12
11
94%
97%
1) LiAlH4, Et2O, 0 °C
2) MnO2, CHCl3, r.t.
1) LiAlH4, Et2O
2) MnO2, CHCl3
H
O
N
H
O
S
N
O
O
O
O
2-acetylpyridine,
NaOH
HN
O
2-acetylpyridine,
NaOH
O
S
O
MeOH
r.t.
O
14
S
MeOH
r.t.
N
H
O
S
O
9
10
69%
N
13
N
65%
10%
48% HBr
48% HBr
reflux
N
N
N
N
S
S
2
1
Scheme 3 The initial strategy towards synthesis of thienopyridine 2
with methyl 2-amino-thiophene-3-carboxylate (11) as starting mate-
rial. Due to the low yield of 13 a synthesis of 14 was never attempted.
75%
Scheme 2 The synthesis of 5-pyridin-2-yl-thieno[3,2-b]pyridine (1)
from methyl 3-amino-thiophene-2-carboxylate (7).
The initial strategy for the synthesis of 6-pyridin-2-yl-
thieno[2,3-b]pyridine (2) was to follow a variation of the
pathway successfully utilized in the synthesis of 1, start-
ing with the commercially available methyl 2-amino-
thiophene-3-carboxylate (11) (Scheme 3). Problems
arose, however, in the reduction/oxidation of 2-[(ethoxy-
carbonyl)amino]thiophene-3-carboxylic acid methyl
ester11 (12) with LiAlH4 in Et2O and MnO2 in CHCl3. 1H
NMR analysis showed that only 8–10% of the desired
product, (3-formylthiophen-2-yl)carbamic acid ethyl
ester11 (13) was formed together with many by-products.
The reduction with LiAlH4 was attempted at different
temperatures (–78 °C, –10 °C, 0 °C), but no improvement
of the yield after oxidation was achieved. The reduction
was also attempted with DIBAL-H, but again no improve-
ment was noted. It was decided that because of the low
yield and the many by-products this pathway was not
worth pursuing any further and a synthesis of [3-(3-oxo-
3-pyridin-2-ylpropenyl)thiophen-2-yl]carbamic acid eth-
yl ester (14) was never attempted. A new pathway to 2,
based upon a Beckmann rearrangement,12–17 ring closure
under modified Vilsmeier reaction conditions18,19 and a
Negishi cross-coupling20–23 was devised (Scheme 4).
In the first step the amino group of 7 was protected
through reaction with ethyl chloroformate in refluxing tol-
uene. This high-yielding synthesis (94%) had previously
been described by Fukumi et al.8
The resulting 3-[(ethoxycarbonyl)amino]thiophene-2-
carboxylic acid methyl ester9 (8) was then reduced to its
corresponding alcohol with LiAlH4 in dry diethyl ether
and quenched with water. The alcohol was not isolated
due to its instability. The solvent was removed by evapo-
ration and then a large volume of chloroform was added.
This was necessary as previous experiments had shown
that the oxidation of the alcohol to the aldehyde using
MnO2 did not proceed if significant amounts of diethyl
ether were present. When treated with excess MnO2 (20
equiv) for 1.5 hours (2-formylthiophen-3-yl)carbamic
acid ethyl ester9,10 (9) was isolated in moderate yield
(65%). Attempts to use less MnO2 were unsuccessful,
even when the reaction time was increased.
The aldehyde 9 was then treated with 2-acetylpyridine and
NaOH in MeOH to yield the desired chalcone [2-(3-oxo-
3-pyridin-2-ylpropenyl)thiophen-3-yl]carbamic acid eth-
yl ester (10) as a yellow solid in 69% yield.
In the final step the carbamic acid ethyl ester 10 was hy-
drolysed to an amine by refluxing in 48% HBr. The amine
was never isolated as ring closure occurred immediately,
and the desired product 1 was obtained in good yield
(75%). The overall yield of this five-step synthesis was
32%.
1-(5-Bromothiophen-2-yl)ethanone (15), when treated
with either NH2OH (50 wt% solution in H2O) or a 1:1
mixture of NH2OH·HCl and NaOAc, gave an equimolar
mixture of the stereoisomers (1E)-1-(5-bromothiophen-2-
yl)ethanone oxime (16) and (1Z)-1-(5-bromothiophen-2-
yl)ethanone oxime (17) in 88% yield. Conde et al.12 re-
ported that only the E-isomer of this oxime would yield
the desired amide, N-(5-bromothiophen-2-yl)acetamide
Synthesis 2006, No. 8, 1295–1300 © Thieme Stuttgart · New York

PAPER
Synthesis of Three Thienopyridines for Use in Molecular Electronics
1297
O
O
O
NH2OH
Br
S
Br
Br
O
O
+
S
S
EtOH
reflux
1) n-BuLi
2) DMF
O
N
N
OH
15
16
17
HO
OH
HO
88%
THF
–5 °C
benzene
reflux
S
S
22
97%
S
23
99%
O
21
acetone 1) NaOH
reflux 2) TsCl
DMF,
POCl3
PPh3
O
1) n-BuLi, THF, 0 °C
2) H2O
Br
Br
PPh3
Br
N
N
1,1,2,2-tetra-
chloroethane
125 °C
S
N
Cl
Br
N
19
31%
S
H
24
25
83%
18
86%
O
O
Et2O i) n-BuLi
–35 °C ii) H2O
O
N
KHSO4
N
2-pyridylzinc
bromide
acetone–H2O
55 °C
S
27
S
N
N
86%
26
S
N
THF
reflux
Cl
62%
S
NaOAc,
NH2OH⋅HCl
20
2
EtOH
reflux
79%
85%
Scheme 4 The synthesis of 6-pyridin-2-yl-thieno[2,3-b]pyridine (2)
OH
via a Beckmann rearrangement and a Negishi cross-coupling.
N
N
N
N
Decalin®
reflux
(18) upon Beckmann rearrangement, with the Z-isomer
yielding 5-bromothiophene-2-carboxylic acid methyl-
amide. The E- and Z-isomers could, however, be separat-
ed by repeated trituration of the mixture with CH2Cl2.
S
28
75%
3
20%
S
Scheme 5 The synthesis of 6-pyridin-2-yl-thieno[3,2-c]pyridine (3)
from thiophene-3-carboxaldehyde (21) via Wittig reagent 25.
Several different reaction conditions for obtaining 18 via
a Beckmann rearrangement of 16 were tested. Treatment
of the E-isomer with PCl5 in dry diethyl ether13 gave the
amide 18 in 60% yield together with many by-products,
making this method less than optimal. Treatment of an
equimolar mixture of 16 and 17 with Yb(OTf)3 in reflux-
ing acetonitrile14 for 24 hours afforded 18 in 60% yield
with no by-products, inferring that oxime isomerization
must have occurred. However, this method was not used
for large-scale synthesis due to the high cost of Yb(OTf)3.
Treatment of the E-isomer with NaOH and tosyl chloride
in acetone12 gave 18 in good yield (86%). This was the
method of choice because of the high yield, inexpensive
reagents and short reaction time. The overall yield of the
amide 18 from the ketone 15 was 37%.
Pd(PPh3)4 as catalyst. After 24 hours a gray precipitate
had formed, presumably a complex between the bipyri-
dine 2 and zinc. The complex was broken up by pouring
the reaction mixture into a solution of EDTA. When the
gray precipitate had disappeared, the aqueous phase was
extracted with diethyl ether to give 2 in good yield (79%).
The overall yield of this five-step synthesis was 8%.
The synthesis of 6-pyridin-2-yl-thieno[3,2-c]pyridine (3)
started with the protection of thiophene-3-carboxaldehyde
(21) with ethylene glycol (Scheme 5). A modification of
the procedure by Gronowitz29 yielded nearly quantitative
amounts of 2-(thiophen-3-yl)-1,3-dioxolane (22) (97%),
which was then quantitatively formylated to 23 using the
procedure of Hibino et al.30
Synthesis of 18 from 2-bromo-6-chlorothieno[2,3-b]pyri-
dine (19) under modified Vilsmeier reaction conditions
has been reported by Meth-Cohn et al.18,24,25 The use of
three equivalents of POCl3 and one equivalent of DMF re-
sulted in ring closure and 19 was obtained in a yield of
30%. Without the bromine acting as a blocking group,
formylation in the 5-position could have occurred as a
competing reaction (Vilsmeier–Haack formylation).19 To
avoid competition between the bromine and the chlorine
substituents in the final cross-coupling step, the bromine
was removed by treating 19 with n-BuLi (15% excess) in
dry diethyl ether at –35 °C with subsequent water quench-
ing. Recrystallization from EtOH–H2O gave 6-chlo-
rothieno[2,3-b]pyridine24–28 (20) in good yield (85%).
The Wittig reagent triphenyl(pyridin-2-ylmethyl)phos-
phonium bromide (25)31,32 was prepared using a variation
of a handbook example33 in good yield (83%).
The final synthetic steps towards the target molecule 3
were adaptations of the procedures reported by Hibino et
al.30 for the synthesis of thienopyridines with phenyl and
methyl substituents.
The Wittig reaction between 23 and 25 yielded 2-{2-[3-
(1,3-dioxolan-2-yl)thiophen-2-yl]vinyl}pyridine (26) in a
moderate yield (62%). Loss of product was suspected in
the work-up, due to difficulties in removal of the by-prod-
uct triphenylphosphine oxide. Subsequent deprotection
with potassium hydrogen sulfate in acetone gave the alde-
hyde 27 in good yield (86%).
For the final step a Negishi cross-coupling20,21 was uti-
lized. Under a nitrogen atmosphere, 20 was treated with 2-
pyridylzinc bromide in refluxing dry THF with 3 mol%
Synthesis 2006, No. 8, 1295–1300 © Thieme Stuttgart · New York

1298
Nurkkala, L. J. et al.
PAPER
mL, 2.5 mmol) in MeOH (15 mL) a portion of solid NaOH (0.026 g,
0.65 mmol) was added. The reaction was monitored by TLC (hex-
ane–CH2Cl2–MeOH, 5:4:1). After 70 min, a second portion of solid
NaOH (0.026 g, 0.65 mmol) was added. After 120 min, a pale-or-
ange precipitate had formed; this was removed by suction filtration
and washed with MeOH. The product was dried over P2O5.
Prior to ring closure, 27 was converted into its oxime 28
through reaction with hydroxylamine. Ring closure was
performed by refluxing 28 in Decalin® for several hours.
Recrystallization from hot EtOAc yielded 3 as colorless
crystals (20%). The overall yield of this six-step synthesis
was 8%.
Yield: 0.51 g (69%); yellow crystals; mp 188–189 °C (dec.).
To summarize, thienopyridine 1 was synthesized in five
steps, with an overall yield of 32%, via the HBr–mediated
deprotection and accompanying ring closure of a chal-
cone-like precursor derived from (2-formylthiophen-3-
yl)carbamic acid ethyl ester. Thienopyridine 2 was syn-
thesized by a Beckmann rearrangement of (1E)-1-(5-bro-
mothiophen-2-yl)ethanone oxime to yield N-(5-
bromothiophen-2-yl)acetamide, which was reacted under
modified Vilsmeier conditions to give the ring-closed
product, 2-bromo-6-chlorothieno[2,3-b]pyridine. Debro-
mination, followed by a Negishi cross-coupling with 2-
pyridyl zinc bromide gave 2 in an overall yield of 8%.
Thienopyridine 3 was synthesized via the Wittig reaction
of formylated 2-(thiophen-3-yl)-1,3-dioxolane with tri-
phenyl(pyridin-2-ylmethyl)phosphonium bromide to give
the alkene, 2-{2-[3-(1,3-dioxolan-2-yl)thiophen-2-yl]vi-
nyl}pyridine in moderate yield. Deprotection and ring
closure of the oxime derivative of the resulting aldehyde
gave 3 in an overall yield of 8% for this six-step reaction.
IR (neat): 685, 1027, 1244, 1256, 1320, 1430, 1500, 1563, 1575,
1664, 1662, 1695, 3286 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.74 (m, 1 H), 8.17 (d, J = 7.9 Hz,
1 H), 8.09 (d, J = 15.3 Hz, 1 H), 7.98 (d, J = 15.3 Hz, 1 H), 7.86 (dt,
J = 7.8, 1.7 Hz, 1 H), 7.62 (br, 1 H), 7.48 (ddd, J = 7.5, 2.4, 1.1 Hz,
1 H), 7.37 (d, J = 5.4 Hz, 1 H), 7.28 (br s, 1 H), 4.24 (q, J = 7.1 Hz,
2 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (CDCl3, 75 MHz): d = 188.9, 154.1, 153.2, 148.9, 139.4,
136.9, 132.6, 128.4, 126.9, 123.5, 122.9, 118.2, 61.9, 14.5.
MS (EI): m/z = 302 [M+].
Anal. Calcd for C15H14N2O3S: C, 59.59; H, 4.67; N, 9.27. Found: C,
59.48; H, 4.62; N, 9.13.
5-Pyridin-2-yl-thieno[3,2-b]pyridine (1)
A solution of 10 (0.45 g, 1.5 mmol) in HBr (48%, 20 mL) was re-
fluxed for 2 h, after which the reaction mixture was cooled to r.t.
and diluted with H2O (30 mL). The solution was carefully adjusted
to pH 9 with solid K2CO3. The solution was extracted with CHCl3
(2 × 50 mL) and the organic phases were combined, washed with
brine (50 mL), dried over MgSO4 and evaporated under reduced
pressure to give 1 as brown crystals. The product was recrystallized
from EtOH–H2O and dried over P2O5.
All moisture- and air-sensitive reactions were performed in oven-
dried (120 °C, >12 h) glassware under nitrogen. Analytical TLC
was performed on commercially prepared plates coated with 0.20
mm of Macherey-Nagel silica gel 60. The compounds were visual-
ized by illumination with UV light (254 nm). Column chromatogra-
phy was performed using Matrex Normal Phase Silica 60 (particle
size 35–70 mm). All melting points were determined using an Elec-
trothermal 9200 melting point apparatus and are uncorrected. Infra-
red spectra were measured on a Perkin Elmer Spectrum One
spectrophotometer. Mass spectra were obtained with a Fisions In-
strument Trio 1000 spectrometer equipped with a Hewlett Packard
5MS GC column. NMR spectra were recorded with a Bruker DPX
Avance 300 MHz spectrometer and the chemical shifts are ex-
pressed in ppm from tetramethylsilane as internal standard. All
commercially available chemicals were used as received unless oth-
erwise noted. THF and Et2O were distilled from sodium benzophe-
none ketal immediately prior to use.
Yield: 0.24 g (75%); colorless needles; mp 89–90 °C.
IR (neat): 699, 720, 748, 774, 842, 1046, 1086, 1094, 1396, 1435,
1472, 1538, 1562, 1589 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.72 (ddd, J = 0.9, 1.7, 4.8 Hz,
1 H), 8.52 (d, J = 8.0 Hz, 1 H), 8.42 (d, J = 8.5 Hz, 1 H), 8.32 (dd,
J = 0.7, 8.5 Hz, 1 H), 7.86 (dt, J = 1.8, 7.6 Hz, 1 H), 7.79 (d, J = 5.6
Hz, 1 H), 7.64 (dd, J = 0.7, 5.5 Hz, 1 H), 7.34 (ddd, J = 1.2, 4.8, 7.5
Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 156.6, 156.0, 154.3, 149.3, 137.1,
133.4, 131.2, 131.1, 125.4, 123.8, 121.4, 116.7.
MS (EI): m/z = 212 [M+].
Anal. Calcd for C12H8N2S: C, 67.90; H, 3.80; N, 13.20. Found: C,
67.80; H, 3.72; N 13.09.
(1E)-1-(5-Bromothiophen-2-yl)ethanone Oxime (16)12
Yield: 40%; white crystals; mp 134–136 °C (Lit.12 135–137 °C).
3-[(Ethoxycarbonyl)amino]thiophene-2-carboxylic Acid
Methyl Ester (8)8,9
1H NMR (300 MHz, DMSO-d6): d = 11.35 (s, 1 H), 7.14–7.18 (m,
2 H), 2.1 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 149.3, 142.6, 130.6, 126.9,
112.3, 11.5.
Yield: 94%; pale-yellow needles; mp 63.5–65.5 °C (Lit.9 63–
66 °C).
1H NMR (300 MHz, CDCl3): d = 9.50 (br s, 1 H), 7.89 (d, J = 5.4
Hz, 1 H), 7.45 (d, J = 5.4 Hz, 1 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.9 (s,
3 H), 1.32 (t, J = 7.1 Hz, 3 H).
N-(5-Bromothiophen-2-yl)acetamide (18)12,13
Yield: 86%; white needles; mp 135–136 °C (Lit.12 135–136 °C).
(2-Formylthiophen-3-yl)carbamic Acid Ethyl Ester (9)9,10
1H NMR (300 MHz, DMSO-d6): d = 11.4 (br s, 1 H), 6.95 (d, J = 4.1
Hz, 1 H), 6.41 (d, J = 4.1 Hz, 1 H), 2.1 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): d = 166.7, 140.4, 126.6, 109.8,
102.4, 22.2.
Yield: 65%; mp 58–59 °C (Lit.9 58–59 °C).
1H NMR (300 MHz, CDCl3): d = 9.88 (br s, 1 H), 9.58 (s, 1 H), 7.86
(d, J = 5.2 Hz, 1 H), 7.60 (d, J = 5.3 Hz, 1 H), 4.2 (q, J = 7.1 Hz,
2 H), 1.26 (t, J = 7.1 Hz, 3 H).
2-Bromo-6-chlorothieno[2,3-b]pyridine (19)18,24,25
Yield: 31%; white crystals; mp 114.5–115.5 °C (Lit.18 115–
116 °C).
[2-(3-Oxo-3-pyridin-2-ylpropenyl)thiophen-3-yl]carbamicAcid
Ethyl Ester (10)
To a well-stirred solution of (2-formylthiophen-3-yl)carbamic acid
ethyl ester (9) (0.49 g, 2.5 mmol) and 2-acetylpyridine (0.31 g, 0.28
Synthesis 2006, No. 8, 1295–1300 © Thieme Stuttgart · New York

PAPER
Synthesis of Three Thienopyridines for Use in Molecular Electronics
1299
1H NMR (300 MHz, CDCl3): d = 7.9 (d, J = 8.4 Hz, 1 H), 7.31 (s,
1 H), 7.3 (d, J = 8.4 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d = 10.22 (d, J = 1.2 Hz, 1 H), 7.65
(dd, J = 1.1, 5.0 Hz, 1 H), 7.25 (d, J = 5.0 Hz, 1 H), 6.22 (s, 1 H),
4.09 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 161.5, 148.0, 132.2, 132.1, 123.9,
121.1, 117.2.
13C NMR (75 MHz, CDCl3): d = 183.3, 146.7, 140.8, 133.9, 128.8,
99.2, 65.3.
6-Chlorothieno[2,3-b]pyridine (20)21–25
Yield: 85%; yellow crystals; mp 57–58 °C (Lit.23 56.5–58.5 °C).
2-{2-[3-(1,3-Dioxolan-2-yl)thiophen-2-yl]vinyl}pyridine (26)
Triphenyl(pyridin-2-ylmethyl)phosphonium bromide (25) (6.19
mmol, 2.69 g) was added to dry THF (40 mL) under a nitrogen at-
mosphere and cooled below 0 °C. n-BuLi (1.6 M in hexane, 6.56
mmol, 4.10 mL) was added dropwise to the milky mixture, followed
by dropwise addition of the aldehyde 23 (5.75 mmol, 1.06 g) dis-
solved in dry THF (10 mL). The reaction temperature was kept be-
low 0 °C during both additions. The mixture was stirred for 17 h at
r.t., then the reaction was quenched with brine (40 mL) and extract-
ed with benzene (2 × 50 mL). The organic phase was washed with
brine (50 mL), dried over Na2SO4 and evaporated under reduced
pressure, yielding a brown solid. The solid was triturated with Et2O,
leaving excess PPh3 undissolved. Evaporation of the Et2O extracts
yielded a brown semi-solid, which was further purified by column
chromatography (EtOAc, 100%).
1H NMR (300 MHz, CDCl3): d = 8.1 (d, J = 8.4 Hz, 1 H), 7.52 (d,
J = 6.0 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 5.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 161.2, 148.0, 133.3, 131.5, 127.6,
121.3, 120.3.
6-Pyridin-2-ylthieno[2,3-b]pyridine (2)
6-Chlorothieno[2,3-b]pyridine (20) was dried under vacuo over
P2O5 for 24 h and the reaction was conducted under a dry nitrogen
atmosphere. To a solution of 20 (0.80 g, 4.7 mmol) in THF (50 mL)
was added Pd(PPh3)4 (3 mol%, 0.16 g), followed by 2-pyridylzinc
bromide (0.5 M solution in THF, 15 mL, 7.5 mmol). The mixture
was refluxed for 24 h, during which time a gray precipitate formed.
The reaction was quenched by pouring into a solution of Na2CO3/
EDTA (150 mL H2O, 150 mmol Na2CO3, 20 mmol EDTA), and the
mixture was stirred until the gray precipitate dissolved. The aque-
ous phase was extracted with Et2O (3 × 50 mL) and the organic
phases were combined, washed with brine (50 mL), dried over
Na2SO4 and evaporated to give 2 as brown crystals. Column chro-
matography (hexane–EtOAc, 7:3) and subsequent recrystallization
from EtOH–H2O gave 2.
Yield: 0.92 g (62%); viscous yellow oil.
1H NMR (300 MHz, CDCl3): d = 8.59 (d, J = 4.7 Hz, 1 H), 7.97 (d,
J = 15.8 Hz, 1 H), 7.64 (dt, J = 7.7, 1.8 Hz, 1 H), 7.33 (d, J = 7.9
Hz, 1 H), 7.18 (d, J = 5.3 Hz, 1 H), 7.14 (d, J = 5.3 Hz, 1 H), 7.13
(dt, J = 7.5, 1.1 Hz, 1 H), 7.00 (d, J = 15.8 Hz, 1 H), 6.11 (s, 1 H),
4.1 (m, 4 H).
Yield: 0.79 g (79%); colorless needles; mp 96–97.5 °C.
MS (EI): m/z = 259 [M+].
IR (neat): 699, 702, 796, 849, 877, 1053, 1260, 1330, 1357, 1430,
1480, 1555, 1566, 1590 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.7 (d, J = 4.8 Hz, 1 H), 8.52 (d,
J = 8.0 Hz, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H),
7.84 (dt, J = 1.8, 7.8 Hz, 1 H), 7.56 (d, J = 6.0 Hz, 1 H), 7.3 (dd,
J = 1.2, 4.8 Hz, 1 H), 7.31 (d, J = 6.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 161.8, 156.2, 153.5, 149.4, 137.1,
132.8, 131.9, 127.9, 123.9, 121.7, 121.6, 117.4.
MS (EI): m/z = 212 [M+].
2-(2-Pyridin-2-ylvinyl)thiophene-3-carbaldehyde (27)
2-{2-[3-(1,3-Dioxolan-2-yl)thiophen-2-yl]vinyl}pyridine (26) (3.5
mmol, 0.91 g) was dissolved in acetone (10 mL) and KHSO4 (3.9
mmol, 0.52 g) dissolved in H2O (2 mL) was added, whereupon a
precipitate was formed. The mixture was heated to 55 °C, under
vigorous stirring and the reaction was monitored by TLC with
EtOAc as mobile phase. After 2 h, all starting material had been
consumed. The acetone was evaporated under reduced pressure and
H2O (20 mL) was added, dissolving most of the precipitate. The
mixture was extracted with benzene (4 × 30 mL), and the organic
extracts were combined, dried over Na2SO4 and evaporated, yield-
ing 27 which was used in the next step without further purification.
Anal. Calcd for C12H8N2S: C, 67.90; H, 3.80; N, 13.20. Found: C,
68.0; H, 4.0; N, 12.9.
Yield: 9.65 g (86.3%); yellow oil.
2-(Thiophen-3-yl)-1,3-dioxolane (22)29
1H NMR (300 MHz, CDCl3): d = 10.28 (s, 1 H), 8.63 (d, J = 4.7 Hz,
1 H), 8.42 (d, J = 15.7 Hz, 1 H), 7.71 (dt, J = 7.7, 1.8 Hz, 1 H), 7.46
(d, J = 5.4 Hz, 1 H), 7.43 (d, J = 7.9 Hz, 1 H), 7.17–7.24 (m, 3 H).
Thiophene-3-carboxaldehyde (21) (10.7 g, 95.5 mmol), ethylene
glycol (15% excess, 6.82 g, 110 mmol) and a few crystals of PTSA
were dissolved in benzene (150 mL) in a round-bottomed flask con-
nected to a Dean–Stark trap. The solution was refluxed and the
H2O–benzene azeotrope was continuously drained until it did not
appear cloudy and TLC (hexane–EtOAc, 4:1) confirmed the com-
plete consumption of starting material. After cooling to r.t. the ben-
zene was swiftly washed with H2O (2 × 50 mL), dried over MgSO4
and evaporated under reduced pressure. It was used in the next step
without further purification.
MS (EI): m/z = 215 [M+].
2-(2-Pyridin-2-ylvinyl)thiophene-3-carbaldehyde Oxime (28)
The aldehyde 27 (3.0 mmol, 0.65 g), NH2OH·HCl (6.0 mmol, 0.42
g, 2 equiv) and sodium acetate (6.0 mmol, 0.49 g, 2 equiv) were
added to EtOH (10 mL) and refluxed. The reaction was monitored
by TLC (EtOAc) and terminated when all starting material had been
consumed. The EtOH was evaporated and H2O (20 mL) was added.
The mixture was extracted with CH2Cl2 (4 × 25 mL) and the com-
bined organic extracts were dried over Na2SO4 and evaporated un-
der reduced pressure. The product was used in the next step without
further purification.
Yield: 14.5 g (97%); pale-yellow oil.
1H NMR (300 MHz, CDCl3): d = 7.41 (d, J = 3.0 Hz, 1 H), 7.31 (dd,
J = 3.0, 5.0 Hz, 1 H), 7.15 (dd, J = 5.0, 1.2 Hz, 1 H), 5.90 (s, 1 H),
4.05 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 140.4, 126.8, 126.0, 124.1, 100.9,
65.5.
Yield: 0.52 g (75.3%); white crystals.
1H NMR (300 MHz, CDCl3): d = 8.73 (s, 1 H), 8.64 (d, J = 3.8 Hz,
1 H), 8.15 (d, J = 15.7 Hz, 1 H), 7.68 (dt, J = 7.7, 1.5 Hz, 1 H), 7.35
(d, J = 5.3 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.15–7.18 (m, 2 H),
6.95 (d, J = 15.7 Hz, 1 H).
3-(1,3-Dioxolan-2-yl)thiophene-2-carbaldehyde (23)30
Yield: 99%; yellow oil.
MS (EI): m/z = 230 [M+].
Synthesis 2006, No. 8, 1295–1300 © Thieme Stuttgart · New York

1300
Nurkkala, L. J. et al.
PAPER
6-Pyridin-2-yl-thieno[3,2-c]pyridine (3)
(7) Raich, W. J.; Hamilton, C. S. J. Am. Chem. Soc. 1957, 79,
3800.
(8) Fukumi, H.; Sugiyama, M.; Sakamoto, T. Chem. Pharm.
Bull. 1989, 37, 1197.
(9) Sugiyama, M.; Sakamoto, T.; Tabata, K.; Fukumi, H. Chem.
Pharm. Bull. 1989, 37, 2717.
(10) Barker, J. M.; Huddleston, P. R.; Needs, P. W. J. Chem. Res.,
Miniprint 1989, 351.
The oxime 28 (2.26 mmol, 0.520 g) was dissolved in decahy-
dronaphthalene (Decalin®, 150 mL) and refluxed at 185–200 °C.
The reaction was monitored by TLC (MeOH–CH2Cl2, 1:19). When
all starting material had been consumed, the reaction was allowed
to cool to r.t. and evaporated under reduced pressure. The residual
oil was dissolved in CH2Cl2 (100 mL) and extracted into HCl (1 M,
300 mL). The aqueous phase was neutralized with saturated
Na2CO3 and extracted with CH2Cl2 (250 mL). The organic phase
was evaporated under reduced pressure to give a dark oily residue
that was purified by column chromatography (CH2Cl2, 100% then
MeOH–CH2Cl2, 5:95). The product 3 was recrystallized from hot
EtOAc.
(11) Sugiyama, M.; Sakamoto, T.; Tabata, K.; Endo, K.; Ito, K.
Chem. Pharm. Bull. 1989, 37, 2091.
(12) Conde, S.; Corral, C.; Lissavetzky, J. J. Heterocycl. Chem.
1985, 22, 301.
(13) Meth-Cohn, O.; Narine, B. Synthesis 1980, 133.
(14) Yadav, J. S.; Reddy, B. V. S.; Madhavi, A. V.; Ganesh, Y. S.
S. J. Chem. Res. 2002, 5, 236.
Yield: 0.10 g (20%); colorless crystals; mp 95–97 °C.
IR (neat): 715, 741, 793, 879, 1249, 1425, 1454, 1581, 1708 cm–1.
(15) Cymmerman-Craig, J.; Naik, A. R. J. Am. Chem. Soc. 1962,
1H NMR (300 MHz, CDCl3): d = 9.20 (d, J = 0.9 Hz, 1 H), 8.99 (dd,
J = 0.8, 0.77 Hz, 1 H), 8.72 (ddd, J = 4.79, 1.74, 0.9 Hz, 1 H), 8.51
(dt, J = 8.6, 1.0 Hz, 1 H), 7.86 (dt, J = 7.8, 1.8 Hz, 1 H), 7.58 (d,
J = 5.5 Hz, 1 H), 7.51 (dd, J = 5.5, 0.7 Hz, 1 H), 7.33 (ddd, J = 7.5,
4.8, 1.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 156.6, 150.1, 149.6, 148.9, 145.4,
137.5, 136.4, 129.1, 123.8, 122.8, 121.8, 115.2.
84, 3410.
(16) Donaruma, L. G.; Heldt, W. Z. Org. React. (N.Y.) 1960, 11,
1.
(17) Gawley, R. E. Org. React. (N.Y.) 1988, 35, 1.
(18) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J. Chem. Soc.,
Perkin Trans. 1 1981, 1531.
(19) Meth-Cohn, O.; Stanforth, P. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, 777.
MS (EI): m/z = 212 [M+].
(20) Fang, Y.-Q.; Hanan, G. S. Synlett 2003, 852.
(21) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977,
42, 1821.
Anal. Calcd for C12H8N2S: C, 67.90; H, 3.80; N, 13.20. Found: C,
67.9; H, 4.1; N, 12.9.
(22) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117.
(23) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441.
(24) Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978, 2045.
(25) Meth-Cohn, O.; Narine, B.; Tarnowski, B.; Hayes, R.;
Keyzad, A. J. Chem. Soc., Perkin Trans. 1 1981, 2509.
(26) Klemm, L. H.; Hartling, R. J. Heterocycl. Chem. 1976, 13,
1197.
Acknowledgment
The authors would like to thank Fakultetsnämnden (Naturvetenskap
och Teknik), Mälardalen University, for their generous and continu-
ed support of this project. Robert Steen would like to thank the Den-
tist Gustaf Dahl Memorial Fund for their generous support. The
authors also would like to thank George Blazak at the University of
Queensland, Australia, for performing elemental analysis.
(27) Klemm, L. H.; Bajer, M. J. Heterocycl. Chem. 1979, 16,
1289.
(28) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res.,
Miniprint 1985, 7, 2501.
(29) Gronowitz, S.; Gestblom, B.; Mathiasson, B. Ark. Kemi
1963, 20, 407.
References
(1) Constable, E. C.; Dunne, S. J.; Rees, D. G. F.; Schmitt, C. X.
Chem. Commun. 1996, 1169.
(2) Dunne, S. J.; Constable, E. C. Inorg. Chem. Commun. 1998,
(30) Hibino, S.; Kano, S.; Mochizuki, N.; Sugino, E. J. Org.
Chem. 1984, 49, 5006.
(31) Sugimoto, H.; Kuramoto, K.; Inoue, S. J. Chem. Soc., Perkin
Trans. 1 2002, 15, 1826.
(32) Carsky, P.; Huenig, S.; Stemmler, I.; Scheutzow, D. Liebigs
Ann. Chem. 1980, 2, 291.
(33) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell,
A. R. Vogel’s Textbook of Practical Organic Chemistry , 5th
ed.; Longman Scientific & Technical: Essex, 1989, 498.
1, 167.
(3) Amr, A.-G. E.; Hegab, M. I.; Ibraheim, A. A.; Abdulla, M.
M. Monatsh. Chem. 2003, 134, 1395.
(4) Goerlitzer, K.; Kramer, C. Pharmazie 2000, 55, 645.
(5) Halverson, A. P. J. Heterocycl. Chem. 1996, 727.
(6) Zhang, Q. T.; Tour, J. M. J. Am. Chem. Soc. 1997, 119, 9624.
Synthesis 2006, No. 8, 1295–1300 © Thieme Stuttgart · New York