A facile and general synthesis of 2,4-di- and 2,4,7-trisubstituted thieno[2,3-c]pyridines

Article abstract of DOI:10.1002/jhet.5570450106

(Chemical Equation Presented) Treatment of 3,5-dibromo- or 3,5-dichloro-pyridine-4-carboxaldehyde 2 with one equivalent of methyl thioglycolate, followed by exposure to base, provided 4-bromo- or 4-chloro-thieno[2,3-c]pyridine-2-carboxylate 4 in good yiel

Full text of DOI:10.1002/jhet.5570450106

Jan-Feb 2008
91
A Facile and General Synthesis of 2,4-Di- and 2,4,7-trisubstituted
Thieno[2,3-c]pyridines
Gui-Dong Zhu,* Indrani W. Gunawardana,† Steven A. Boyd,† Laura M. Melcher
Abbott Laboratories, Metabolic Diseases Research, GPRD, Dept. R47S, Bldg. AP10, 100 Abbott Park Rd.,
Abbott Park, IL 60064-6101
Received November 14, 2006
R4
X
CHO
4
7
2
R2
N
N
S
X
R7
1
R2= CO2Me, CONHMe, H, Ph
R4= Br, Cl, Ph, NHR, OPh
R7= H, Br, 2-furyl, n-Bu, NR1R2
X= Br, Cl
Treatment of 3,5-dibromo- or 3,5-dichloro-pyridine-4-carboxaldehyde 2 with one equivalent of methyl
thioglycolate, followed by exposure to base, provided 4-bromo- or 4-chloro-thieno[2,3-c]pyridine-2-
carboxylate 4 in good yields. Oxidation of the thieno[2,3-c]pyridine scaffold such as 7 with mCPBA,
followed by treatment with POBr3, introduced a bromine exclusively at the 7-position of the heterocycle.
The 4- or 7-bromide of the thienopyridines readily underwent Suzuki, Stille coupling, and Buchwald
amination reactions, to afford 4- or 7-substituted analogs 6 or 11. The 2-carboxylate of 4b or 12 was
smoothly removed through saponification and decarboxylation to furnish 15 or 16. Deprotonation of the
thienopyridine at C-2 position, followed by trapping with trimethyltin chloride, afforded a 2-stannyl
analog, which was readily converted to other C-2 derivatives via Stille reaction.
J. Heterocyclic Chem., 45, 91 (2008).
methoxide) employed in the reported procedure could
have resulted in many undesired reactions, including
displacement of bromide and hydrolysis of the
carboxylate. Indeed, after screening a number of bases,
we found that the reaction became much cleaner in the
presence of cesium carbonate, providing 4a in >60% yield
in several trials (Scheme 1).
INTRODUCTION
Thieno[2,3-c]pyridine, an isostere of isoquinoline [1],
has emerged as an attractive structural scaffold in search
for small molecule pharmaceutical agents [2]. Thieno-
[2,3-c]pyridine resembles isoquinoline sterically, but
contains a ꢀ-rich thiophene and a ꢀ-deficient pyridine,
leading to an inherently polarized push-pull system with a
ground-state dipole moment of 2.85 D [1a]. In case of
biological interest, polarization of the thienopyridine
scaffold can be further improved by introduction of
donors to the thiophene and/or acceptors to the pyridine
ring. There are a number of methods available for
synthesis of unsubstituted or less substituted thieno[2,3-c]–
pyridines [3]. However, further functionalization of the
heterocycle is challenging with those methodologies.
Herein we report a facile and general method to
synthesize 2,4-di- and 2,4,7-trisubstituted thieno[2,3-c]-
pyridines 1.
Nucleophilic displacement of one bromide of 2a by
methyl thioglycolate gave a mono-substituted product 3.
Because of the electron-donating effect of the sulfide, the
bromide in 3 was less reactive, leading to predominant
formation of mono-substituted product. Under the same
conditions, the reaction of a relatively cheaper 3,5-
dichloropyridine-4-carboxaldehyde 2b with methyl thio-
glycolate afforded the 4-chloro analog 4b in 80% yield.
While some of the halogenated heterocycles are less
reactive toward transition-metal catalyzed reactions, the
4-bromide in ester 4a smoothly underwent a Suzuki
coupling with phenylboronic acid to afford 4-phenyl
derivative 6a. The 2-carboxylate in 4a was not stable in
our hands under a typical Buchwald amination protocol
(Pd2(dba)3/(-)-BINAP/NaOBut) [4], and thus 4a was
converted to methyl amide 5 by heating in a methanolic
methylamine solution (90% yield). When 5 was heated
with para-chloroaniline and sodium t-butoxide in THF,
under the catalysis of Pd2(dba)3 and (-)-BINAP, its 4-
amino analog 6b was obtained in 84% yield. For reasons
that are not known, the reactions of 5 with the more
nucleophilic morpholine and 1-(3'-aminoethyl)morph-
RESULTS AND DISCUSSION
It has been known that methyl 4-bromothieno[2,3-
c]pyridine carboxylate 4a [1b] can be prepared in very
low yield (10%) from 3,5-dibromopyridine-4-carbox-
aldehyde 2a and methyl thioglycolate in the presence of
sodium methoxide. Given the fact that a bromide
functionality can be potentially converted to a wide
variety of substituents through transition metal-catalyzed
coupling reactions, we further explored this methodology.
We envisioned that a stronger base (i.e. sodium

92
G. –D. Zhu, I. W. Gunawardana, S. A. Boyd, L. M. Melcher
Vol 45
oline, under the same conditions, led to 6c and 6d in much
lower yields (38% and 34% respectively). Attempts to
install a 4-phenoxy group on 4a or 5 by the known
copper-mediated coupling methodologies [5] failed to
provide diaryl ether 6e (Scheme 1). Nevertheless, as
described in our previous report [2a], a 4-phenoxy
derivative 7 can be prepared by a sequential displacement
of two chlorides of 2b with one equivalent of phenoxide
and methyl thioglycolate, followed by exposure to base.
2-tributylstannylfuran in DMF in the presence of catalytic
Pd(OAc)2 and tri-o-tolylphosphine, 7-(2-furyl) analog 11b
was isolated in 87% yield. By employing a typical
Buchwald amination protocol [Pd2(dba)3/(-)-BINAP/18-
crown-6/NaOBut/THF] [4], the 7-bromide in 10 was
converted to a morpholine (11c) and N-(3-aminopropyl)-
morpholine (11d) derivatives in 86% and 94% yields,
respectively.
Scheme 2
Scheme 1
R
R
X
O
OCH3
O
i
O
X
O
X
HS
Cs2CO3
N+
H
N
O
S
-O
OCH3
S
OCH3
H
N
OCH3
N
S
7
8
O
3
2a: X= Br
2b: X= Cl
Cl
ii
R=
O
R
X
a, b, c, or d
O
O
R
R
N
N
S
R'
S
R'
O
O
iv
5
7
N
N
6a R= Ph, R'= OCH3 (via 4a)
6b R=p-Cl-PhNH, R'= NHCH3
6c R= morpholino, R'=NHCH3
S
4a: X= Br, R'= OCH3, 61%
NHCH3
S
R'
CH3NH2
90%
4b: X= Cl, R'= OCH3, 80%
5: X=Br, R'= NHCH3
R"
Br
6d R=
H
9 R'= OCH3
N
N
iii
11a: R"= n-Bu
11b: R"= 2-furyl
O
10 R'= NHCH3
R'=NHCH3
O
6e R=
N
O
11c: R"=
11d: R"=
R'=NHCH3
N
N
H
O
Reagents and conditions: a. PhB(OH)2, Pd(PPh3)4, CsF, DME, 82%.
b. p-Cl-PhNH2, Pd2(dba)3, (-)-BINAP, NaOBut, THF, 84%.
c. morpholine, Pd2(dba)3, (-)-BINAP, NaOBut, THF, 38%. d. 2-morpho-
linylethylamine, Pd2(dba)3, (-)-BINAP, NaOBut, THF, 34%.
Reaction conditions: [i] mCPBA, CH2Cl2, rt, 95%; [ii] POBr3,
CH2Cl2, rt, 62%; [iii] MeNH2, MeOH, 45 °C, 93%; [iva] n-butylboronic
acid, Pd2(dba)3, (t-Bu)3P, Cs2CO3, dioxane, 70%; [ivb] 2-tributyl-
stannylfuran, Pd(OAc)2, (o-tol)3P, Et3N, DMF, 87%; [ivc] morpholine,
Pd2(dba)3, (-)-BINAP, 18-crown-6, NaOBut, THF, 86%; [ivd] 3-(4-
morpholino)propylamine, Pd2(dba)3, (-)-BINAP, 18-crown-6, NaOBut,
THF, 94%.
The 7-position of the thieno[2,3-c]pyridine was func-
tionalized through a two-step sequence as shown in
Scheme 2. mCPBA oxidation of 7, which was synthesized
previously in our laboratory [2a], in methylene chloride
specifically resulted in N-oxide 8 in almost quantitative
yield. Treatment of the N-oxide 8 with POBr3 afforded 7-
bromide 9 (62% yield) as assigned by an NOE
experiment. No regioisomeric 5-bromide was detected in
the reaction mixture.
The 7-bromide was converted to a variety of substi-
tuents through Suzuki (11a), Stille (11b) coupling, or
Buchwald amination (11c and 11d) reactions. When
bromide 10 was coupled with butylboronic acid, the
desired product 11a was obtained in poor yields (<20%)
under a variety of conditions [Pd(OAc)2/DPPF/CsF/DME,
Pd2(dba)3/(o-tol)3P/CsF/THF, Pd(PPh3)4/NaOH/H2O/diox-
ane]. Using tri-t-butylphosphine as the ligand and cesium
carbonate as base, this reaction afforded 11a in a
respectable 70% yield. When 10 was heated with
Scheme 3 demonstrates a typical conversion of 2-
carboxylate of the thienopyridine to other substituents.
Saponification of 12, which was again previously
synthesized in this laboratory, with lithium hydroxide
afforded acid 13. When a suspension of the acid in
diphenyl ether was heated at 230 °C, decarboxylation
proceeded smoothly and furnished 15 in 84% yield.
Lithiation of 15 with n-butyllithium proceeded specif-
ically at the 2-position, giving intermediate 17. Trapping
of the lithio species 17 with trimethyltin chloride afforded
18 in 71% yield. The 2-trimethylstannyl functionality
could be further converted to other substituents through
Stille reaction. As also shown in Scheme 3, a 4-chloro
analog 19 was prepared by a similar protocol. 4-Chloro-2-
trimethylstannylthieno-[2,3-c]pyridine 19 is
a more

Jan-Feb 2008
G. –D. Zhu, I. W. Gunawardana, S. A. Boyd, L. M. Melcher
93
in Hertz (Hz). When peak multiplicities are given the following
abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broadened. Mass spectra were performed as
follows: ESI (electrospray ionization) was performed on a
Finnigan SSQ7000 MS run as a flow injection acquisition; DCI
(desorption chemical ionization) was performed on a Finnigan
SSQ7000 MS using a direct exposure probe with ammonia gas;
APCI (atmospheric pressure chemical ionization) was performed
on a Finnigan Navigator MS run as flow injection acquisition.
Elemental analysis was performed by Robertson Microlit
Laboratories, Inc., Madison, New Jersey. All manipulations
were performed under nitrogen atmosphere unless otherwise
mentioned. All solvents and other reagents were purified when
necessary using standard procedures. Flash column chroma-
tography was performed on silica gel 60 (Merck, 230-400 mesh)
using the indicated solvent. For routine aqueous workup, the
reaction mixture was partitioned between brine and EtOAc, and
the organic layer was washed with brine and dried over MgSO4.
Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (4a).
A solution of 3,5-dibromopyridinecarboxaldehyde (2a) (5 g,
18.9 mmol) in THF (100 mL) was treated with methylthio-
glycolate (1.69 mL, 18.9 mmol) at 0 °C. The reaction mixture
was stirred at ambient temperature for 1 h before powdered
Cs2CO3 (6.15 g, 18,9 mmol) was added. The mixture was stirred
for 18 h, filtered, and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (5% acetone in
flexible intermediate, in which both 2- and 4-positions
could be further functionalized. For example, Stille
coupling of 19 with bromobenzene afforded 20 which
underwent another Stille reaction with 2-trimethyl-
stannylfuran to give 21. Amination of the 4-chloride in
20 proceeded smoothly under Nolan's system [6],
providing, for example, 22 in 91% yield.
Scheme 3
R
R
O
Ph2O/230 o
C
O
LiOH
N
N
S
OCH3
S
OH
13 R= PhO, 92%
14 R=Cl, 92%
12 R= PhO
4b R=Cl
R
R
Me3SnCl
-78 oC
n-BuLi
+
-
Li
-78 - 0 o
C
N
N
S
S
15 R= PhO, 84%
16 R=Cl, 88%
17
1
hexane) to provide 4a. Yield: 3.1 g (62%). H nmr (500 MHz,
R
R
DMSO-d6): ꢀ 3.95 (s, 3 H), 7.99 (s, 1 H), 8.67 (s, 1 H), 9.31 (s, 1
H); ms (APCI): m/e 272, 274 (M+H)+. Anal. Calcd for
C9H6BrNO2S: C, 39.72; H, 2.22; N, 5.15. Found: C, 39.70; H,
2.32; N, 5.07.
PhBr, Pd2(dba)3
SnMe3
N
N
(o-tol)3P, Et3N
S
S
18 R= PhO, 71%
19 R=Cl, 73%
20 R=Cl
Methyl 4-chlorothieno[2,3-c]pyridine-2-carboxylate (4b).
To a solution of 3,5-dichloropyridine-4-carboxaldehyde (2b)
(5.0 g, 28.4 mmol) in THF (50 mL) was added methyl
thioglycolate (2.59 mL, 28.4 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 1 h, and was warmed up to rt for
another hour. Cs2CO3 (9.25 g, 28.4 mmol) was then added. The
reaction mixture was stirred for 18 h, and was partitioned
between ethyl acetate and brine. The organic phase was washed
with water, dried (MgSO4), filtered, and concentrated. The
residue was purified by flash chromatography (20-40% gradient
EtOAc in hexane) to provide 4b. Yield: 5.2 g (80%). 1H nmr
(400 MHz, DMSO-d6): ꢀ 3.96 (s, 3 H), 8.04 (s, 1 H), 8.60 (s, 1
H), 9.32 (s, 1 H); 13C nmr (100 MHz, DMSO-d6): ꢀ 53.2, 125.6,
125.9, 137.8, 139.7, 141.4, 141.9, 144.6, 161.4; ms (DCI/NH3):
m/e 228 (M+H)+. Anal. Calcd for C9H6ClNO2S: C, 47.48; H,
2.66; N, 6.15. Found: 47.40; H, 2.61; N, 6.18.
21 R= 2-furyl, 85%
22 R=PhNH, 91%
In summary, we have developed a facile and general
approach to the synthesis of 2-, 4- and 7-substituted
thieno[2,3-c]pyridines. The bromo and chloro function-
alities of the thieno[2,3-c]pyridine scaffold proceeded
Suzuki, Stille and Buchwald type of reactions smoothly
while poor yields were frequently obtained with some of
the other heterocycles. (t-Bu)3P/Pd2(dba)3/ Cs2CO3 system
was found to be superior in the Suzuki reaction of 10 with
butylboronic acid to the other conditions screened.
4-Chloro-2-trimethylstannylthieno[2,3-c]pyridine
19
represents a more flexible intermediate, with which both
2- and 4-positions of the thienopyridine scaffold can be
readily functionalized.
Methyl 4-bromothieno[2,3-c]pyridine-2-carboxamide (5).
A solution of 4a (5.0 g, 18.4 mmol) in methanol (20 mL) was
treated with methylamine (2 M solution in methanol, 20 mL) at
60 °C for 6 h, and was concentrated. The residue was
recrystallized from acetone, and dried to provide 4.5 g of 5.
Yield: 90%. 1H nmr (400 MHz, DMSO-d6): ꢀ 3.97 (br s, 3H),
8.11 (s, 1H), 8.33 (br s, 1H), 8.43 (s, 1H), 9.24 (s, 1H); ms
Anal. Calcd for
C9H7BrN2OS: C, 39.87; H, 2.60; N, 10.33. Found: C, 40.05; H,
2.58; N, 10.21.
Methyl 4-phenylthieno[2,3-c]pyridine-2-carboxylate (6a).
A 25 mL round bottom flask was charged with 4a (50 mg, 0.18
mmol), phenylboronic acid (25 mg, 0.20 mmol), cesium fluoride
(56 mg, 0.36 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol), and
was purged with nitrogen. Anhydrous DME (4 mL) was added,
EXPERIMENTAL
(DCI/NH3): m/e 271, 273 (M+H)+.
General Spectroscopic and Experimental Data. Infrared
spectra were recorded on Nicolet 5SX and Nicolet Magna-IR
750 spectrometer. The NMR spectra were obtained on Varian
UP-300, Varian M-300, Bruker AMX-400, and Varian U-400
magnetic resonance spectrometer (300/400MHz for 1H and
75/100MHz for 13C) with deuteriochloroform as solvent and
internal standard unless otherwise indicated. The chemical
shifts are given in delta (ꢀ) values and the coupling constants (J)

94
G. –D. Zhu, I. W. Gunawardana, S. A. Boyd, L. M. Melcher
Vol 45
and the reaction mixture was stirred under reflux for 12 h. After
cooling, the reaction mixture was partitioned between ethyl
acetate and brine. The organic phase was washed with water,
dried (MgSO4) and concentrated. The residual oil was separated
by flash chromatography (20% EtOAc in hexane) to give 6a as a
slightly yellow solid. Yield: 40 mg (82%). 1H nmr (300 MHz,
CDCl3): ꢀ 3.98 (s, 3H), 7.5–7.6 (m, 5H), 8.18 (s, 1H), 8.59 (s,
1H), 9.18 (s, 1H); ms (DCI): m/z 270 (M+H)+. Anal. Calcd for
C15H11NO2S: C, 66.89; H, 4.12; N, 5.20. Found: C, 66.95; H,
4.10; N, 5.13.
To a solution of 8 (9.53 g, 28.45 mmol) in CH2Cl2 (120 mL)
was added POBr3 (15.97 g, 56.90 mmol) at 0 °C in one portion.
The formed slightly yellow suspension was stirred while gradually
warming to room temperature overnight, and was then poured into
ice. The mixture was basified to a pH 9, and extracted with
CH2Cl2 (2 x 200 mL). The combined organic phases were washed
with brine (400 mL), dried (MgSO4) and concentrated. The
residual solid was purified by flash chromatography (15% EtOAc
in hexane) to give 9 as white solid. Yield: 7.1 g (62%). 1H nmr
(300 MHz, DMSO-d6): ꢀ 8.10 (s, 1 H), 3.92 (s, 3 H), 7.23 (d, J =
9.0 Hz, 2 H), 7.49 (d, J = 8.9 Hz, 2 H), 8.09 (s, 1 H); ms
(ESI/NH3): m/e 398 (M+H)+. Anal. Calcd for C15H9BrClNO3S:
C, 45.19; H, 2.28; N, 3.51. Found: C, 45.10; H, 2.30; N, 3.63.
Methyl 7-bromo-4-(4-chlorophenoxy)thieno[2,3-c]pyrid-
ine-2-carboxamide (10). A solution of 9 (4.0 g, 10 mmol) in a
methanolic methylamine solution (2 M, 80 mL) was heated at 45
°C in a sealed pressure tube for 4 h. After cooling, the reaction
mixture was concentrated, and the residue was triturated with a
mixture of ether and hexane. The formed white solid was
collected by filtration, and dried to afford 10. Yield: 3.69 g
(93%). 1H nmr (300 MHz, DMSO-d6): ꢀ 2.81 (d, J = 4.4 Hz, 3
H), 7.20 (d, J = 8.8 Hz, 2 H), 7.48 (d, J = 9.2 Hz, 2 H), 8.05 (s, 1
H), 8.21 (s, 1 H), 9.04 (q, J = 4.8 Hz, 1 H); ms (ESI/NH3): m/e
397 (M+H)+. Anal. Calcd for C15H10BrClN2O2S: C, 45.30; H,
2.53; N, 7.04. Found: 45.15; H, 2.63; N, 7.00.
Methyl 4-(4-chloroanilino)thieno[2,3-c]pyridine-2-carbox-
amide (6b). A 25 mL round bottom flask was charged with 5
(68 mg, 0.25 mmol), 4-chloroaniline (96 mg, 0.75 mmol),
Pd2(dba)3 (14 mg, 0.014 mmol), (-)-BINAP (27 mg, 0.044
mmol), 18-crown-6 (196 mg, 0.74 mmol) and sodium tert-
butoxide (71 mg, 0.74 mmol), and was purged with nitrogen.
Anhydrous THF (10 mL) was then added. The formed dark red
solution was purged with nitrogen again, and was heated at 60
°C for 15 h. After cooling to room temperature, the reaction
mixture was partitioned between ethyl acetate and brine. The
organic layer was washed with water, dried (MgSO4) and
concentrated. The residue was purified by flash chromatography
(20-100% gradient EtOAc in hexane) to afford 6b. Yield: 67mg
(84%). 1H nmr (400 MHz, DMSO-d6): ꢀ 2.83 (d, J =4.0 Hz, 3
H), 7.07 (d, J = 9.0 Hz, 2 H), 7.32 (d, J = 9.0 Hz, 2 H), 8.11 (s, 1
H), 8.38 (s, 1 H), 8.67 (s, 1 H), 8.85 (d, J = 4.0 Hz, 1 H), 8.91 (s,
1 H); 13C nmr (100 MHz, DMSO-d6): ꢀ 26.3, 118.1, 121.7,
123.6, 129.1, 133.0, 134.4, 137.1, 137.2, 138.2, 142.6, 143.2,
Methyl 7-n-butyl-4-(4-chlorophenoxy)thieno[2,3-c]pyrid-
ine-2-carboxamide (11a). A 25 mL round bottom flask was
charged with 10 (100 mg, 0.25 mmol), Pd2(dba)3 (22 mg, 0.025
mmol), n-butylboronic acid (51 mg, 0.5 mmol) and Cs2CO3 (163
mg, 0.5 mmol), and was purged with nitrogen. Anhydrous
dioxane (5 mL) and tri-t-butylphosphine (16 μL, 0.0625 mmol)
were added. The suspension was purged with nitrogen again,
and was stirred at 80 °C for 8 h. After cooling to room
temperature, the reaction mixture was partitioned between ethyl
acetate and brine. The organic layer was washed with water,
dried (MgSO4) and concentrated. The residue was separated by
HPLC (Zorbax, C-18, CH3CN/H2O/0.1% TFA as mobile phase)
161.4; ms (APCI): m/z 318 (M+H)+.
Anal. Calcd for
C15H12ClN3OS: C, 56.69; H, 3.81; N, 13.22. Found: C, 56.78;
H, 3.71; N, 13.10.
Methyl 4-(4-morpholinyl)thieno[2,3-c]pyridine-2-carbox-
amide (6c). Compound 6c was prepared as described for 6b,
substituting morpholine for 4-chloroaniline. Yield: 38%. 1H
nmr (400 MHz, DMSO-d6): ꢀ 2.91 (d, J = 4.0 Hz, 3 H), 3.23 (m,
4 H), 3.91 (m, 4 H), 8.14 (s, 1 H), 8.18 (s, 1 H), 8.96 (s, 1 H),
8.99 (d, J = 4.0 Hz, 1 H); 13C nmr (100 MHz, DMSO-d6): ꢀ
26.1, 51.6, 66.3, 121.2, 131.6, 137.1, 137.9, 139.0, 143.3, 143.9,
161.3; ms (APCI): m/z 278 (M+H)+. Anal. Calcd for
C13H15N3O2S: C, 56.30; H, 5.45; N, 15.15. Found: C, 56.10;
5.49; N, 15.08.
Methyl 4-(2-morpholin-4-yl-ethylamino)thieno[2,3-c]pyr-
idine-2-carboxamide (6d). Compound 6d was prepared as
described for 6b, substituting 2-morpholinoethylamine for 4-
chloroaniline. Yield: 34%. 1H nmr (400 MHz, DMSO-d6): ꢀ
2.39-2.45 (m, 4 H), 2.59 (t, J = 6.0 Hz, 2 H), 2.80 (d, J = 6 Hz, 3
H), 3.30-3.39 (m, 2 H), 3.57 (t, J = 6.0 Hz, 4 H), 6.00 (t, J = 5
Hz, 1 H), 7.78 (s, 1 H), 8.16 (s, 1 H), 8.46 (s, 1 H), 8.63 (t, J =
6.0 Hz, 1 H); 13C nmr (100 MHz, DMSO-d6): ꢀ 26.3, 39.9, 53.4,
56.8, 66.2, 69.8, 121.7, 124.1, 131.6, 132.4, 136.6, 139.8,
140.6,161.8; ms (APCI): m/z 321 (M+H)+. Anal. Calcd for
C15H20N4O2S: C, 56.23; H, 6.29; N, 17.49. Found: C, 56.05; H,
6.37; N, 17.36.
Methyl 7-bromo-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-
2-carboxylate (9). To a solution of 7 (10 g, 31.35 mmol) [2a] in
CH2Cl2 (200 mL) was added mCPBA (57%, 11.39 g, 37.62
mmol) at 0 °C. The reaction mixture was stirred while gradually
warming up to room temperature overnight. After dilution with
CH2Cl2 (200 mL), the reaction mixture was washed with 1 N
NaOH (400 mL), brine (400 mL) and H2O (400 mL). The
organic phase was dried (MgSO4), filtered, and concentrated to
provide N-oxide 8 (10.0 g, 95%). This material was directly
used in the following step without further purification.
1
to provide 11a as TFA salt. Yield: 86.1 mg (70%). H nmr (300
MHz, DMSO-d6): ꢀ 0.93 (t, J = 7.3 Hz, 3 H), 1.40 (m, 2 H), 1.79
(m, 2 H), 2.79 (d, J = 4.4 Hz, 3 H), 3.03 (t, J = 7.6 Hz, 2 H),
7.10 (d, J = 8.8 Hz, 2 H), 7.45 (d, J = 9.2 Hz, 2 H), 8.06 (s, 1 H),
8.19 (s, 1 H), 8.98 (q, J = 4.5 Hz, 1 H); ms (ESI/NH3): m/e 375
(M+H)+. Anal. Calcd for C19H19ClN2O2SꢁTFA: C, 51.59; H,
4.12; N, 5.73. Found: C, 51.70; H, 4.08; N, 5.65.
Methyl 4-(4-chlorophenoxy)-7-furan-2-yl-thieno[2,3-c]py-
ridine-2-carboxamide (11b). A 25 mL round bottom flask was
charged with 10 (100 mg, 0.25 mmol), Pd(OAc)2 (10.8 mg, 0.048
mmol) and (o-tol)3P (44 mg, 0.14 mmol), and was purged with
nitrogen. Anhydrous DMF (6 mL), 2-tributylstannylfuran (178
mg, 0.5 mmol) and triethylamine (167 μL, 1.2 mmol) were added.
The suspension was purged with nitrogen again, and was stirred at
80 °C for 15 h. After cooling to room temperature, the reaction
mixture was partitioned between ethyl acetate and brine. The
organic layer was washed with water, dried (MgSO4) and
concentrated. The residual material was purified by HPLC
(Zorbax, C-18, CH3CN/H2O/0.1% TFA as mobile phase) to
provide 11b as TFA salt. Yield: 108.9 mg (87%). m.p. 145-147
1
°C. H nmr (300 MHz, DMSO-d6): ꢀ 2.81 (d, J = 4.4 Hz, 3 H), 6.79
(dd, J = 3.3, 1.8 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 2 H), 7.26 (d, J = 3.7
Hz, 1 H), 7.47 (d, J = 8.8 Hz, 2 H), 8.07 (d, J = 1.7 Hz, 1 H), 8.11 (s,
1 H), 8.26 (s, 1 H), 9.00 (d, J = 4.8 Hz, 1 H); ms (ESI/NH3): m/e
385 (M+H)+. Anal. Calcd for C19H13ClN2O3S•TFA: C, 50.56; H,
2.83; N, 5.62. Found: C, 50.50; H, 2.87; N, 5.54.

Jan-Feb 2008
G. –D. Zhu, I. W. Gunawardana, S. A. Boyd, L. M. Melcher
95
Methyl 4-(4-chlorophenoxy)-7-morpholin-4-ylthieno[2,3-c]-
pyridine-2-carboxamide (11c). A 25 mL round bottom flask
was charged with 10 (100 mg, 0.25 mmol), Pd2(dba)3 (14 mg,
0.014 mmol), (-)-BINAP (27 mg, 0.044 mmol), 18-crown-6 (196
mg, 0.74 mmol) and sodium tert-butoxide (71 mg, 0.74 mmol),
and was purged with nitrogen. Anhydrous THF (10 mL) and
morpholine (64 mg, 0.75 mmol) were added. The dark solution
was purged with nitrogen again, and was stirred at 60 °C for 15
h. After cooling to room temperature, the reaction mixture was
partitioned between ethyl acetate and brine. The organic layer
was washed with water, dried (MgSO4) and concentrated. The
residue was separated by HPLC (Zorbax, C-18, CH3CN/
H2O/0.1% TFA as mobile phase) to provide 11c as TFA salt.
Yield: 112.2 mg (86%). m.p. 170-173 °C. 1H nmr (300 MHz,
DMSO-d6): ꢀ 2.77 (d, J = 4.8 Hz, 3 H), 3.52 (t, J = 4.6 Hz, 4 H),
3.81 (t, J = 4.6 Hz, 4 H), 7.01 (d, J = 9.2 Hz, 2 H), 7.40 (d, J =
9.2 Hz, 2 H), 7.93 (s, 1 H), 7.96 (s, 1 H), 8.93 (q, J = 4.8 Hz, 1
hexane, 1.36 mL, 3.38 mmol) at –78 °C. After addition, the
solution was warmed up to 0 °C, stirred at 0 °C for 10 min and
then cooled to – 78 °C. A solution of trimethyltin chloride
(0.808 g) in THF (5 mL) was then added slowly. The solution
was stirred at –78 °C for 1 h and at rt for 15 min before being
partitioned between EtOAc and brine. The organic phase was
washed with water, and concentrated. The residue was purified
by flash chromatography (10-35% gradient EtOAc in hexane) to
give 18. Yield: 0.936 g (71%). 1H nmr (400 MHz, CDCl3): ꢀ
0.44 (s, 9 H), 7.06 (dd, J = 8.6, 0.9 Hz, 2 H), 7.12 (t, J = 7.5 Hz,
1 H), 7.34 (dd, J = 8.7, 7.5 Hz, 2 H), 7.47 (s, 1 H), 8.08 (s, 1 H),
8.93 (s, 1 H); 13C nmr (100 MHz, DMSO-d6): ꢀ 118.2, 123.6,
127.2, 129.8, 132.2, 138.7, 139.2, 142.6, 147.4, 147.9, 157.1; ms
(DCI/NH3): m/e 392 (M+H)+. Anal. Calcd for C16H17NOSSn:
C, 49.26; H, 4.39; N, 3.59. Found: C, 49.50; H, 4.43; N, 3.56.
4-Chlorothieno[2,3-c]pyridine-2-carboxylic
acid
(14).
Ester 4b (5.80 g, 25.5 mmol) was saponified with LiOH (2.2 g,
51 mmol) under the same conditions as described for 13 to
provide 14. Yield: 5.01 g (92%). ir (KBr): ꢀmax 1709 (s) cm-1;
1H nmr (300 MHz, DMSO-d6): ꢀ 8.06 (s, 1 H), 8.62 (s, 1 H),
9.34 (s, 1 H), 14.21 (s, 1 H); ms (ESI/NH3): m/e 214 (M+H)+.
Anal. Calcd for C8H4ClNO2S: C, 44.98; H, 1.89; N, 6.56.
Found: 45.10; H, 1.81; N, 6.48.
4-Chlorothieno[2,3-c]pyridine (16). Acid 14 (4.98 g, 23.3
mmol) was decarboxylated in phenyl ether (30 mL) under the
same conditions as described for 15 to provide 16. Yield: 3.5 g
(88%). ir (KBr): ꢀmax 1229 (s) cm-1; 1H nmr (300 MHz, CDCl3):
ꢀ 7.54 (d, J = 5.4 Hz, 1 H), 7.80 (d, J = 5.4 Hz, 1 H), 8.48 (s, 1
H), 9.04 (s, 1 H); ms (DCI/NH3) m/e 170 (M+H)+. Anal. Calcd
for C7H4ClNS: C, 49.56; H, 2.38; N, 8.26. Found: 49.70; H,
2.25; N, 8.10.
H); ms (ESI/NH3): m/e 404 (M+H)+.
Anal. Calcd for
C19H18ClN3O3S TFA: C, 48.70; H, 3.70; N, 8.11. Found: C,
48.79; H, 3.76; N, 8.05.
Methyl 4-(4-chlorophenoxy)-7-(3-morpholin-4-ylpropyl-
amino)thieno[2,3-c]pyridine-2-carbox-amide (11d). Compound
11d was prepared by the same protocol as described for 11c,
substituting 4-(3-aminopropyl)-morpholine for morpholine.
Yield: 94%. 1H nmr (300 MHz, DMSO-d6): ꢀ 2.03 (m, 2 H),
2.78 (d, J = 4.7 Hz, 3 H), 3.22 (m, 2 H), 3.30 (m, 4 H), 3.52 (m,
2 H), 3.85 (m, 4 H), 6.97 (d, J = 9.0 Hz, 2 H), 7.40 (d, J = 9.0
Hz, 2 H), 7.82 (s, 1 H), 7.83 (s, 1 H), 8.90 (q, J = 4.7 Hz, 1 H);
ms (ESI/NH3): m/e 461 (M+H)+. Anal. Calcd for
C22H25ClN4O3S•TFA: C, 50.13; H, 4.56; N, 9.74. Found: C,
50.23; H, 4.48; N, 9.87.
4-Phenoxythieno[2,3-c]pyridine-2-carboxylic acid (13). To
a solution of 12 (2.11 g) [2a] in THF (40 mL) was added a
solution of LiOH•H2O (621 mg) in H2O (40 mL) at rt. Methanol
was added until a transparent solution formed (5 mL). This
solution was aged at rt for 2 h, and was acidified with 10% aq.
HCl to a pH 4. The mixture was concentrated at reduced
pressure to ~40 mL. The formed white solid was collected by
filtration, washed with water and dried to give 13. Yield: 1.84 g
(92%). 1H nmr (300 MHz, DMSO-d6): ꢀ 7.13 (dd, J = 8.5, 1.0
Hz, 2 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.44 (dd, J = 8.8, 7.5 Hz, 2
H), 7.82 (s, 1 H), 8.18 (s, 1 H), 9.17 (s, 1 H); 13C nmr (75 MHz,
DMSO-d6): ꢀ 118.1, 124.2, 130.3, 132.9, 136.3, 138.9, 140.6,
141.2, 147.9, 156.5, 162.7; ms (DCI/NH3): m/e 272 (M+H)+.
Anal. Calcd for C14H9NO3S: C, 61.98; H, 3.34; N, 5.16. Found:
62.06; H, 3.42; N, 5.02.
4-Phenoxythieno[2,3-c]pyridine (15). A suspension of acid
13 (1.80 g, 6.6 mmol) in diphenyl ether (12 mL) was purged
with nitrogen, and was heated at 228-230 °C (oil bath) for 20 h.
After cooling, the formed brown solution was diluted with
methylene chloride, and was directly purified by flash
chromatography (8-40% gradient EtOAc in hexane) to give 15.
Yield: 1.27 g (84%). 1H nmr (400 MHz, CDCl3): ꢀ 7.04 (dd, J =
8.6, 0.9 Hz, 2 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.35 (m, 3 H), 7.62
(d, J = 5.5 Hz, 1 H), 8.15 (s, 1 H), 8.94 (s, 1 H); 13C nmr (100
MHz, DMSO-d6): ꢀ 118.1, 120.0, 123.7, 129.9, 131.4, 132.9,
137.7, 138.0, 140.0, 148.0, 157.0; ms (DCI/NH3): m/e 228
(M+H)+. Anal. Calcd for C13H9NOS: C, 68.70; H, 3.99; N,
6.16. Found: C, 68.51; H, 3.96; N, 6.11.
4-Chloro-2-trimethylstannanylthieno[2,3-c]pyridine (19).
19 was prepared from 16 (1.83 g, 10.82 mmol) under the same
conditions as described for 18. Yield: 73%. ir (KBr): ꢀmax 1564
1
(s) cm-1; H nmr (400 MHz, CDCl3): ꢀ 0.49 (s, 9 H), 7.56 (s, 1
H), 8.40 (s, 1 H), 9.00 (s, 1 H); 13C nmr (100 MHz, CDCl3): ꢀ
124.9, 128.7, 141.1, 141.6, 141.9, 144.0, 150.1; ms (ESI/NH3):
m/e 334 (M+H)+. Anal. Calcd for C10H12ClNSSn: C, 36.13; H,
3.64; N, 4.21. Found: 36.22; H, 3.64; N, 4.21.
4-Chloro-2-phenylthieno[2,3-c]pyridine (20). A 100 mL
round bottom flask was charged with 18 (1.0 g, 3.0 mmol),
Pd2(dba)3 (274 mg, 0.3 mmol), tri-o-tolylphosphine (274 mg, 0.9
mmol), and was purged with N2. Anhydrous DMF (30 mL),
bromobenzene (316 μL, 3.0 mmol) and Et3N (1.25 mL, 9.0
mmol) were added via syringe. The solution was purged with
N2 again, and was heated at 70 °C for 5 h. After cooling, ethyl
acetate (150 mL) was added. The mixture was washed with
brine (150 mL) and water (150 mL). The ethyl acetate solution
was concentrated, and the residual oil was separated by flash
chromatography (8-20% gradient EtOAc/hexane) to give 20.
1
Yield: 530 mg (72%). H nmr (400 MHz, CDCl3): ꢀ 7.43 (d, J =
8.0 Hz, 2 H), 7.45 (m, 1 H), 7.61 (s, 1 H), 7.71 (dd, J = 7.8, 1.7
Hz, 2 H), 8.42 (s, 1 H), 8.90 (s, 1 H); ms (DCI/NH3) m/e 246
(M+H)+. Anal. Calcd for C13H8ClNS: C, 63.54; H, 3.28; N,
5.70. Found: 63.33; H, 3.21; N, 5.75.
4-Furan-2-yl-2-phenylthieno[2,3-c]pyridine (21). A 25 mL
round bottom flask was charged with 20 (100 mg, 0.41 mmol),
Pd2(dba)3 (38 mg, 0.04 mmol), and 1,3-bis(2,6-di-i-propyl-
phenyl)imidazolium chloride (33 mg, 0.08 mmol), and was
purged with N2. Anhydrous DMF (7 mL), 2-tributylstannylfuran
(258 μL, 0.82 mmol) and Et3N (172 μL, 1.23 mmol) were added
via syringe. The solution was purged with N2 again, and was
4-Phenoxy-2-trimethylstannanylthieno[2,3-c]pyridine (18).
To a solution of thienopyridine 15 (0.77 g, 3.38 mmol) in THF
(10 mL) was slowly added n-butyllithium (2.5 M solution in

96
G. –D. Zhu, I. W. Gunawardana, S. A. Boyd, L. M. Melcher
Vol 45
483; [c] Nerenz, H.; Meier, M.; Grahn, W.; Reisner, A.; Schmaelzlin, E.
J. Chem. Soc., Perkin Trans. 2, 1998, 437.
heated at 75 °C for 6 h. After cooling, the reaction mixture was
partitioned between ethyl acetate and brine. The organic phase
was washed with water, and concentrated. The residue was
separated by flash chromatography (15-50% gradient EtOAc in
hexane) to give 21. Yield: 96 mg (85%). 1H nmr (300 MHz,
CDCl3): ꢀ 6.61 (dd, J = 3.6, 1.9 Hz, 1 H), 6.91 (d, J = 3.4 Hz, 1
H), 7.47 (m, 3 H), 7.68 (d, J = 1.7 Hz, 1 H), 7.81 (dd, J = 8.0,
1.5 Hz, 2 H), 8.14 (s, 1 H), 8.79 (s, 1 H), 8.99 (s, 1 H); ms
(DCI/NH3): m/e 278 (M+H)+. Anal. Calcd for C17H11NOS: C,
73.62; H, 4.00; N, 5.05. Found: 73.41; H, 3.94; N, 5.18.
4-Phenylamino-2-phenylthieno[2,3-c]pyridine (22). A 25
mL RBF was charged with 20 (100 mg, 0.4 mmol)), Pd2(dba)3
(36 mg, 0.04 mmol), and 1,3-bis(2,6-di-i-propylphenyl)-
imidazolium chloride (34 mg, 0.08 mmol), and was purged with
N2. Anhydrous dioxane (4 mL), aniline (56 mg, 0.62 mmol) and
potassium tert-butoxide (1.0 M solution in THF, 0.62 mL, 0.62
mmol) were added via syringe. The solution was purged with
N2 again, and was heated at 100 °C for 20 h. After cooling, the
reaction mixture was partitioned between ethyl acetate and
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brine.
The organic phase was washed with brine, and
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Fresneda, P.; Hurtado, F. Synthesis 1987, 45; [d] Dressler, M.; Joullie,
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Shabtai, J.; Kiang, W. J. Heterocycl. Chem. 1969, 6, 813; [f] Press, J.;
McNally, J. J. Heterocycl. Chem. 1988, 25, 1571; [g] Lamattina, J.;
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concentrated. The residue was separated by flash chroma-
tography (30-70% gradient EtOAc in hexane) to provide 22.
Yield: 112 mg (91%). 1H nmr (300 MHz, CDCl3): ꢀ 5.92 (br s,
1 H), 6.98 (t, J = 7.5 Hz, 1 H), 7.04 (dd, J = 8.0, 1.0 Hz, 2 H),
7.28 (d, J = 8.1 Hz, 2 H), 7.30 (dd, J = 8.2, 7.4 Hz, 1 H), 7.43 (d,
J = 7.5 Hz, 2 H), 7.46 (s, 1 H), 7.70 (dd, J = 8.0, 1.5 Hz, 2 H),
8.39 (s, 1 H), 8.78 (s, 1 H); ms (DCI/NH3): m/e 303 (M+H)+.
Anal. Calcd for C19H14N2S: C, 75.47; H, 4.67; N, 9.26. Found:
75.38; H, 4.77; N, 9.18.
Acknowledgement. The authors thank the Abbott Analytical
Department for assistance in acquiring NMR, IR and mass
spectra.
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REFERENCES AND NOTES
*
Corresponding author: Tel. (847) 935-1305, e-mail gui-
dong.zhu@abbott.com. †Current address: Array BioPharma Inc., 2620
Trade Centre Ave., Longmont, CO 80503.
[1a] Nerenz, H.; Grahn, W.; Jones, P. Acta Crystal. (sect. C)
1997, 53, 787; [b] Dunn, A. D.; Norrie, R. J. Prakt. Chem. 1992, 334,