Regiocontrolled SNAr reaction on 2,3-dihalopyridines with NaSMe to obtain bromo(methylthio)pyridines as key precursors of 3-halo-2-(hetero) arylthieno[2,3- b ]pyridines and thieno[3,2- b ]pyridines

Article abstract of DOI:10.1055/s-0033-1338442

The synthesis of 3-halo-2-(hetero)arylthieno[2,3-b]pyridines and 3-halo-2-(hetero)arylthieno[3,2-b]pyridines has been performed through a three-step methodology from 3-bromo-2-chloropyridine or 2-bromo-3- fluoropyridine, respectively. The key step of this methodology is the formation of the required bromo(methylthio)pyridines by a regiocontrolled nucleophilic aromatic substitution (S_NAr) with sodium methanethiolate (NaSMe). Then, the Sonogashira coupling with (hetero)arylalkynes followed by a halocyclization with bromine or iodine, afforded the expected 3-halo-2-(hetero)arylthienopyridines.

Full text of DOI:10.1055/s-0033-1338442

PAPER
▌1489
paper
Regiocontrolled SNAr Reaction on 2,3-Dihalopyridines with NaSMe To Obtain
Bromo(methylthio)pyridines as Key Precursors of 3-Halo-2-(hetero)arylthie-
no[2,3-b]pyridines and Thieno[3,2-b]pyridines
Regiocontrolled SNAr on 2,3-Dihalopyridines
Agathe Begouin, Daniela Peixoto, Maria-João R. P. Queiroz*
Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)604382; E-mail: mjrpq@quimica.uminho.pt
Received: 18.01.2013; Accepted after revision: 02.04.2013
t-BuLi at –80 °C, followed by a reaction with dimethyl di-
Abstract: The synthesis of 3-halo-2-(hetero)arylthieno[2,3-b]pyri-
sulfide at –95 °C in anhydrous THF and by a not com-
dines and 3-halo-2-(hetero)arylthieno[3,2-b]pyridines has been per-
pletely regioselective lithiation–bromination at the 2-
position of 3-methylthiopyridine, induced by the BuLi-
formed through a three-step methodology from 3-bromo-2-
chloropyridine or 2-bromo-3-fluoropyridine, respectively. The key
step of this methodology is the formation of the required bro- LiDMAE superbase [DMAE: 2-(dimethylamino)etha-
mo(methylthio)pyridines by a regiocontrolled nucleophilic aromatic
substitution (SNAr) with sodium methanethiolate (NaSMe). Then,
the Sonogashira coupling with (hetero)arylalkynes followed by a
halocyclization giving the corresponding 2-substituted
halocyclization with bromine or iodine, afforded the expected 3-
halo-2-(hetero)arylthienopyridines.
nol]. Then, the 2-bromo-3-methylthiopyridine was sub-
mitted to a Sonogashira coupling followed by a
(Ph or TMS) 3-halothieno[3,2-b]pyridines.
Kawai and co-workers7e have also reported the synthesis
Key words: thienopyridines, nucleophilic aromatic substitution,
of thieno[3,2-b]pyridine derivatives via the formation of
the intermediate 2-bromo-3-(methylthio)pyridine, which
was obtained by treatment of 2,3-dibromopyridine with n-
BuLi and dimethyl disulfide in Et2O. The Sonogashira
coupling of 2-bromo-3-(methylthio)pyridine with tri-
methyl(prop-1-ynyl)silane, followed by a halocyclization
with I2 gave the 3-iodo-2-methylthieno[3,2-b]pyridine.
methanethiolate, Sonogashira coupling, halocyclization
Thienopyridines are of chemical and pharmacological in-
terest, due to their isosterism with quinolines and isoquin-
olines, two important heterocycles that can be found in
various alkaloids.1 Up to now, the chemistry of the thie-
no[2,3-b]pyridines is better known than the chemistry of
the thieno[3,2-b]pyridines. However, many thieno[3,2-
b]pyridines have recently shown to possess a large variety
of biological activities. For instance, diheteroarylamine
derivatives2 and N3-arylmalonamides3 in the thieno[3,2-
b]pyridine series as well as substituted thieno[3,2-b]pyri-
dine ureas4 were shown to be inhibitors of the vascular en-
dothelial growth factor receptor (VEGFR2), mediator of
the biological function of the vascular endothelial growth
factor (VEGF) related to angiogenesis. Other thieno[3,2-
b]pyridine derivatives are inhibitors of the nonreceptor
Src tyrosine kinases5a,b that are overexpressed and/or acti-
vated in several types of cancer and also play a key role in
tumor progression and metastases. This diversity of bio-
logical activities gave an impulse to the development of
new convenient synthetic routes for the thieno[3,2-b]pyr-
idine skeleton.
In the past few years, our research group has been inter-
ested in the synthesis of thieno[3,2-b]pyridine derivatives.
In 2010, the synthesis of the methyl 3-amino-6-bromothi-
eno[3,2-b]pyridine-2-carboxylate has been reported by us
for the first time from 5-bromo-3-nitropicolinonitrile and
methyl thioglycolate in DMF–aqueous KOH.8 Further
functionalizations at the 6-position of the thieno[3,2-
b]pyridine of this compound by C–C (Suzuki, Sonogashi-
ra)9a–c or C–N (Buchwald–Hartwig)9d couplings have giv-
en new derivatives, some of them exhibiting growth
inhibitory activity in human tumor cell lines.
More recently, we have reported10 a simple and efficient
method for the synthesis of 2-(hetero)arylthieno[2,3-
b]pyridines and 2-(hetero)arylthieno[3,2-b]pyridines
from 3-bromo-2-chloropyridine or 2-bromo-3-chloropyr-
idine, respectively, and (hetero)arylalkynes through a
Sonogashira coupling involving selectively the bromine
atom, followed by a reaction with sodium sulfide on the
chlorine. A bromination of some of the thienopyridines
obtained was also performed with Br2 to obtain the corre-
sponding 3-bromo-2-(hetero)arylthienopyridines.
Most of the methods for the synthesis of thieno[3,2-b]pyr-
idines are based on the use of readily accessible 3-amino-
thiophenes or their N-derivatives6a–e and only few
syntheses have already been described starting from the
pyridine ring.7a–e For example, Fort et al.7d have reported
a three-step process allowing the construction of the thio-
phene ring from 3-methylthiopyridine that had to be syn-
thesized through the lithiation of 3-bromopyridine using
Herein, we describe the synthesis of 2-substituted (aryl or
heteroaryl) 3-halothienopyridines from 2,3-dihalopyri-
dines (3-Br-2-Cl, or 2-Br-3-F) through the formation of
bromo(methylthio)pyridines followed by a Sonogashira
coupling and a halocyclization with Br2 or I2, as depicted
in Scheme 1.
SYNTHESIS 2013, 45, 1489–1496
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338442; Art ID: SS-2013-Z0040-OP
© Georg Thieme Verlag Stuttgart · New York

1490
A. Begouin et al.
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Ar(Het)
Ph
Br
W
Z
Br
X
W
Z
Br
W
Z
Br
Ar(Het)
i
ii
83%
NaSMe
Ph
DMF
r.t.
Sonogashira
coupling
83%
S
SMe
N
1
SMe
N
SMe
N
4a
SMe
5a
Total yield 59%
X2
W = N, Z = CH, X = Cl or F
W = CH, Z = N, X = Cl
X2 = I2 or Br2
Scheme 3 Reagents and conditions: (i) PhC≡CH (1.1 equiv),
PdCl2(PPh3)2 (6 mol%), CuI (3 mol%), Et3N (1–2 mL), 100 °C, over-
night; (ii) Br2 (1.5 equiv), anhyd Et2O, 0 °C to r.t., 0.5 h, under argon.
X
W
Ar(Het)
S
Z
Another strategy was also experimented for the synthesis
of 5a: first a Sonogashira coupling was performed fol-
lowed by a SNAr reaction with NaSMe and a halocycliza-
tion. Using this strategy, the expected 2-chloro-3-
(phenylethynyl)pyridine was obtained in 80% yield
through the Sonogashira coupling of the 3-bromo-2-chlo-
ropyridine with phenylacetylene. However, the reaction
with NaSMe did not afford the 2-(methylthio)-3-(phenyl-
ethynyl)pyridine (4a), but the 2-chloro-3-(2-methylsulfa-
nyl-2-phenylvinyl)pyridine resulting from the addition of
SMe to the triple bond of the Sonogashira product instead
of the expected nucleophilic substitution of the chlorine
atom of the pyridine ring (Scheme 4).
Scheme 1 Strategy envisaged for the three-step synthesis of 3-halo-
thienopyridines from 2,3-dihalopyridines
In the present work, the synthesis of 3-halo-2-(hetero)ar-
ylthienopyridines was carried out through an initial nu-
cleophilic
aromatic
substitution
with
sodium
methanethiolate (NaSMe). Thus, the synthesis of the re-
quired bromo(methylthio)pyridines 1 and 2 was achieved
in high to excellent yields using 3-bromo-2-chloropyri-
dine and 2-bromo-3-fluoropyridine, respectively. Never-
theless starting from 2-bromo-3-chloropyridine, only the
3-chloro-2-(methylthio)pyridine (3) was obtained
(Scheme 2). The presence of the fluorine atom in the 3-po-
sition allows the regiocontrol of the SNAr reaction by off-
setting the reactivity of the bromine in the 2-position of
the pyridine, thus permitting the synthesis of the thie-
no[3,2-b]pyridine derivatives starting from compound 2.
Ph
Br
Ph
i
ii
SMe
80%
N
Cl
N
Cl
N
Cl
2-chloro-3-(2-methylsulfanyl-2-phenylvinyl)pyridine
major product
Br
Cl
F
Br
i
Scheme 4 Reagents and conditions: (i) PhC≡CH (1.1 equiv),
PdCl2(PPh3)2 (6 mol%), CuI (3 mol%), Et3N (1–2 mL), 100 °C, over-
night; (ii) NaSMe (1.5 equiv), DMF, r.t., 1 h.
85%
N
N
N
1
SMe
SMe
Br
i
Having these results in hands, the strategy depicted in
Scheme 1 was used to obtain the 3-(hetero)arylethynyl-2-
(methylthio)pyridines 4a–f and the 2-(hetero)ethynyl-3-
(methylthio)pyridines 6a–f, from compounds 1 and 2,
respectively, in good to excellent yields (70–93%).
Sonogashira couplings were also performed with two het-
eroarylalkynes, the electron-deficient 3-ethynylpyridine
and the electron-rich 3-ethynylthiophene, giving com-
pounds 4e, f and 6e, f in high yields (Table 1). After halo-
cyclization of compounds 4 and 6, the 3-halo-2-
(hetero)arylthieno[2,3-b]pyridines 5a–h and the 3-halo-2-
(hetero)arylthieno[3,2-b]pyridines 7a–g were obtained,
respectively (Table 1).
96%
Br
N
2
i
Cl
Cl
Br
i
78%
N
SMe
N
3
Scheme 2 Reagents and conditions: (i) NaSMe (1.5 equiv), DMF,
0 °C to r.t.
The Sonogashira coupling of compound 1 was first per-
formed with phenylacetylene using conditions previously
optimized by our research group for the coupling of bro-
mochloropyridines.10 Using these conditions, the expect-
ed 2-(methylthio)-3-(phenylethynyl)pyridine (4a) was
obtained in 83% yield. Then, a bromocyclization was per-
formed with Br2, which afforded the 3-bromo-2-phenyl-
thieno[2,3-b]pyridine (5a) also in 83% yield, with a total
yield of 59% (Scheme 3). This yield is far better than the
one previously obtained by us in the synthesis of the same
thieno[2,3-b]pyridine 5a through a Sonogashira coupling
followed by a reaction with Na2S and at the end a bromi-
nation step (only 40% yield).10
In our previous work, related to the synthesis of 2-(het-
ero)arylthienopyridines from 2,3-dihalopyridines, (het-
ero)arylalkynes and Na2S, hydroxylated thienopyridines
were obtained from the ortho-methoxylated Sonogashira
coupling products, instead of the expected 2-(2-methoxy-
phenyl)thienopyridines. This result was probably due to
the spatial proximity of the sulfide anion intermediate
with the methoxy group.10 This led us to propose the most
probable mechanism consisting in the preliminary addi-
tion of Na2S to the triple bond of the alkynylpyridine, fol-
lowed by a SNAr/cyclization (Scheme 5).
Synthesis 2013, 45, 1489–1496
© Georg Thieme Verlag Stuttgart · New York

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Regiocontrolled SNAr on 2,3-Dihalopyridines
1491
This is in accordance with the observation made in the oxyphenyl)ethynyl]-3-(methylthio)pyridine (6d), and
present work while following the strategy depicted in then to the expected 3-bromo-2-(2-methoxyphenyl)thie-
Scheme 4: the reaction of NaSMe was carried out after the no[2,3-b]pyridine (5e) and 3-bromo-2-(2-methoxyphe-
Sonogashira coupling leading to the addition of SMe to nyl)thieno[3,2-b]pyridine (7e), respectively, in high
the triple bond, thus avoiding the formation of the cy- yields after halocyclization with Br2.
clized products.
In summary, we have described an efficient three-step
Herein the Sonogashira couplings of compounds 1 and 2 methodology for the synthesis of 3-halo-2-(hetero)arylthi-
were also performed with 2-ethynylanisole, leading to the eno[2,3-b]pyridines and 3-halo-2-(hetero)arylthieno[3,2-
formation of the corresponding 3-[(2-methoxyphe- b]pyridines using 3-bromo-2-chloropyridine or 2-bromo-
nyl)ethynyl]-2-(methylthio)pyridine (4d) and 2-[(2-meth- 3-fluoropyridine as starting materials, respectively. The
Table 1 Synthesis of (Methylthio)pyridines and 3-Halo-2-(hetero)arylthienopyridinesa
3-(Hetero)aryl-2-(methyl-
thio)pyridines
4a–f
3-Halo-2-(hetero)aryl-
thieno[2,3-b]pyridines 5a–h
2-(Hetero)aryl-3-
(methylthio)pyridines
6a–f
3-Halo-2-(hetero)aryl-
thieno[3,2-b]pyridines
7a–g
X
Ph
Ph
Br
N
N
Ph
Ph
S
S
N
N
SMe
SMe
5a X = Br, 83%
5b X = I, 73%
7a, 89%
4a, 83%
6a, 88%
X
F
I
F
N
F
F
N
S
S
N
N
SMe
SMe
7b X = Br, 90%
7c X = I, 80%
5c, 76%
4b, 79%
6b, 81%
OMe
OMe
Br
I
N
N
OMe
OMe
S
S
N
SMe
N
SMe
7d, 98%
5d, 99%
4c, 79%
6c, 93%
Br
Br
N
N
OMe
OMe
S
S
N
MeO
MeO
SMe
N
SMe
5e, 80%
7e, 87%
6d, 70%
4d, 87%
I
I
N
N
N
N
S
N
S
S
N
S
N
N
SMe
SMe
7f, 90%b
5f, 80%b
4e, 80%
6e, 81%
X
S
S
I
N
N
S
N
S
N
SMe
SMe
5g X = Br, 81%
5h X = I, 77%
7g, 77%
4f, 74%
6f, 75%
a Sonogashira coupling: PdCl2(PPh3)2 (6 mol%), CuI (3 mol%), Et3N (1–2 mL), 100 °C, overnight (from 1) or 1 h (from 3). Halocyclization:
Br2 or I2 (1.5 equiv), anhyd Et2O, 0 °C to r.t., 0.5 h.
b Halocyclization was performed in anhyd CH2Cl2 due to the poor solubility of 4e and 6e in Et2O.
© Georg Thieme Verlag Stuttgart · New York
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MeO
W
Z
W
Z
W
Z
Na2S
S
OMe
DMF, 130 °C
overnight
S
Cl
Cl
HO
Z, W = N or CH
Scheme 5 Formation of 2-(thieno[2,3-b] or [3,2-b]pyridin-2-yl)phenols by the reaction of chloro(2-methoxyphenylethynyl)pyridines with
Na2S10
2-Bromo-3-(methylthio)pyridine (2)
key step of this methodology consists in the regiocon-
trolled SNAr reaction of these 2,3-dihalopyridines with
NaSMe, allowing the formation of the bromo(methyl-
thio)pyridines needed for the Sonogashira coupling. From
3-bromo-2-chloropyridine, the 3-chloro-2-(methyl-
thio)pyridine was the only product isolated. However, the
change of the halide from chlorine to fluorine allowed the
formation of the required 2-bromo-3-(methylthio)pyri-
dine. Finally, the halocyclization step afforded the expect-
ed 3-bromo- or 3-iodo-2-(hetero)arylthienopyridines in
high yields. It is worth noting that the Sonogashira cou-
pling has to be performed after the SNAr with NaSMe,
Yield: 195 mg (96%); pale yellow oil (Lit.7d brown gummy solid).
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H, SCH3), 7.27 (dd, J =
7.8, 4.6 Hz, 1 H, 5-H), 7.40 (dd, J = 7.8, 1.8 Hz, 1 H, 4-H), 8.14 (dd,
J = 4.6, 1.8 Hz, 1 H, 6-H).
MS-EI: m/z = 204.94 ([81BrM+], 98), 202.94 ([79BrM+], 100),
124.02 (9).
HRMS: m/z [M+] calcd for C6H679BrNS: 202.9404: found 202.9407.
[M+] calcd for C6H681BrNS: 204.9384; found: 204.9382.
3-Chloro-2-(methylthio)pyridine (3)
Yield: 124 mg (78%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3 H, SCH3), 6.98 (dd, J =
otherwise this reaction leads to the addition of SMe to the 7.8, 4.8 Hz, 1 H, 5-H), 7.56 (dd, J = 7.8, 1.6 Hz, 1 H, 4-H), 8.39 (dd,
J = 4.8, 1.6 Hz, 1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 13.51 (SCH3), 119.46 (5-CH),
129.36 (C), 135.90 (4-CH), 146.63 (6-CH), 158.01 (C).
triple bond, thus preventing the formation of the thieno-
pyridines.
MS-EI: m/z = 160.99 ([37ClM+], 36), 158.99 ([35ClM+], 100), 149.03
(46), 124.02 (85).
Melting points were determined in a Stuart SMP3 and are uncor-
rected. 1H and 13C NMR spectra were recorded on a Bruker Avance
III at 400 and 100.6 MHz or on a Varian Unity Plus at 300 and 75.4
(Hetero)aryl-2 and 3-(Methylthio)pyridines 4a–f and 6a–f;
General Procedure
1
MHz, respectively. Heteronuclear correlations, H-13C, HMQC or
HSQC and HMBC were performed to assign some signals. MS-EI
and HRMS on the M+ data were recorded by the mass spectrometry
service of the University of Vigo (C.A.C.T.I.), Spain.
In a dry Schlenk tube, bromo(methylthio)pyridine 1 or 2 (1 equiv),
CuI (10 mol%), and PdCl2(PPh3)2 (5 mol%) were added under ar-
gon in Et3N (1–2 mL) and the mixture was stirred for 5–10 min at
r.t. Then, the (hetero)arylalkyne (1.1 equiv) was added dropwise
under argon and the mixture was heated at 100 °C overnight for 3-
bromo-2-(methylthio)pyridine (1) or 1 h for 2-bromo-3-(methyl-
thio)pyridine (2). After cooling, the solution was diluted with
CHCl3 (10 mL) and the solvent was evaporated to give a brown oil
that was submitted to column chromatography (Table 1).
Column chromatography was performed on Macherey-Nagel silica
gel 230–400 mesh. Petroleum ether (PE) refers to the fraction with
boiling range 40–60 °C. The increase of polarity in solvent gradient
was made from neat PE to mixtures of Et2O–PE, increasing 10% of
Et2O each time, until the isolation of the products. Known com-
pounds were not fully described.
2-(Methylthio)-3-(phenylethynyl)pyridine (4a)
Halo(methylthio)pyridines 1–3; General Procedure
From 1 (204.0 mg) and phenylacetylene (112.0 mg), and after puri-
fication by column chromatography (Et2O–PE, 0:1 to 1:9); yield:
187 mg (83%); yellow solid; mp 53–55 °C.
To a solution of 3-bromo-2-chloropyridine, 2-bromo-3-chloropyri-
dine (192 mg, 1.00 mmol), or 2-bromo-3-fluoropyridine (176 mg,
1.00 mmol) in DMF (5 mL/mmol) at 0 °C (ice bath) was added
NaSMe (105 mg, 1.5 mmol, 1.5 equiv) and the reaction mixture was
allowed to stir for 1 h at 0 °C. EtOAc (15 mL) and H2O (3 × 10 mL)
were added and the phases were separated. The organic phase was
dried (MgSO4), filtered, and removal of the solvent gave the expect-
ed halo(methylthio)pyridines 1–3 as depicted in Scheme 2.
1H NMR (400 MHz, CDCl3): δ = 2.64 (s, 3 H, SCH3), 7.01 (dd, J =
7.2, 5.0 Hz, 1 H, 5-H), 7.37–7.39 (m, 3 H), 7.59–7.61 (m, 2 H), 7.67
(br d, 1 H, 4-H), 8.43 (br s, 1 H, 6-H).
13C NMR (100.6 MHz, MHz, CDCl3): δ = 13.43 (SCH3), 84.32
(C≡C), 98.59 (C≡C), 118.08 (C), 118.40 (5-CH), 128.40 (2 × CH),
128.90 (CH), 131.60 (2 × CH), 138.73 (4-CH), 147.46 (6-CH),
161.74 (CSMe).
3-Bromo-2-(methylthio)pyridine (1)
Yield: 174 mg (85%); pale yellow oil.
MS-EI: m/z = 226.06 ([M+ + 1], 8), 225.06 ([M+], 62), 224.06 ([M+
1H NMR (400 MHz, CDCl3): δ = 2.57 (s, 3 H, SCH3), 6.90 (dd, J =
7.8, 4.8 Hz, 1 H, 5-H), 7.71 (dd, J = 7.8, 1.6 Hz, 1 H, 4-H), 8.42 (dd,
J = 4.8, 1.6 Hz, 1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 14.24 (SCH3), 119.07 (C),
119.65 (5-CH), 136.90 (4-CH), 147.44 (6-CH), 159.34 (C).
MS-EI: m/z = 204.94 ([81BrM+], 24), 202.94 ([79BrM+], 25), 124.02
(100).
– 1], 100), 223.05 ([M+ – 2], 37).
HRMS: m/z [M+] calcd for C14H11NS: 225.0612; found: 225.0612.
3-[(3-Fluorophenyl)ethynyl]-2-(methylthio)pyridine (4b)
From 1 (70.0 mg) and 1-ethynyl-3-fluorobenzene (45.0 mg), and af-
ter purification by column chromatography (Et2O–PE, 0:1 to 1:9);
yield: 66.0 mg (79%); yellow solid; mp 77–79 °C.
1H NMR (400 MHz, CDCl3): δ = 2.62 (s, 3 H, SCH3), 7.01 (dd, J =
7.6, 4.8 Hz, 1 H, 5-H), 7.06–7.11 (m, 1 H,), 7.27–7.30 (m, 1 H),
HRMS: m/z [M+] calcd for C6H679BrNS: 202.9405; found:
202.9404. [M+] calcd for C6H681BrNS: 204.9383; found: 204.9384.
Synthesis 2013, 45, 1489–1496
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Regiocontrolled SNAr on 2,3-Dihalopyridines
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7.33–7.38 (m, 2 H), 7.66 (dd, J = 7.6, 1.2 Hz, 1 H, 4-H), 8.43 (dd,
J = 4.8, 1.2 Hz, 1 H, 6-H).
J = 5.0, 3.0 Hz, 1 H, 5′-H), 7.60 (dd, J = 3.0, 1.2 Hz, 1 H, 2′-H), 7.63
(dd, J = 7.4, 1.8 Hz, 1 H, 4-H), 8.40 (dd, J = 5.0, 1.8 Hz, 1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 13.18 (SCH3), 85.38 (C≡C),
96.87 (d, J = 3.0 Hz, C≡C), 116.16 (d, J = 21.0 Hz, CH), 117.34 (3-
C), 118.18 (5-CH), 118.25 (d, J = 22.0 Hz, CH), 124.39 (d, J = 10.0
Hz, 1′-C), 127.40 (d, J = 3.0 Hz, 6′-CH), 129.92 (d, J = 8.0 Hz, 5′-
CH), 138.56 (4-CH), 148.12 (6-CH), 161.97 (CSMe), 162.36 (d, J =
245.0 Hz, CF).
13C NMR (100.6 MHz, CDCl3): δ = 13.16 (SCH3), 84.08 (C≡C),
93.45 (C≡C), 117.75 (C), 118.23 (5-CH), 121.63 (C), 125.53 (5′-
CH), 129.33 (2′-CH), 129.71 (4′-CH), 138.33 (4-CH), 147.81 (6-
CH), 161.99 (CSMe).
MS-EI: m/z (%) = 232.01 ([M+ + 1], 20), 231.02 ([M+], 72), 230.01
([M+ – 1], 100), 229.00 ([M+ – 2], 29).
MS-EI: m/z (%) = 244.05 ([M+ + 1], 11), 243.05 ([M+], 56), 242.05
HRMS: m/z [M+] calcd for C12H9N2S: 231.0176; found: 231.0175.
([M+ – 1], 100).
HRMS: m/z [M+] calcd for C14H10FNS: 243.0518; found: 243.0523.
3-(Methylthio)-2-(phenylethynyl)pyridine (6a)
From 2 (68.0 mg) and phenylacetylene (37.0 mg), and after purifi-
cation by column chromatography (Et2O–PE, 0:1 to 2:3); yield:
66.0 mg (88%); brown solid; mp 78–80 °C (Lit.7d mp 75–77 °C).
3-[(4-Methoxyphenyl)ethynyl]-2-(methylthio)pyridine (4c)
From 1 (60.0 mg) and 4-ethynylanisole (43.0 mg), and after purifi-
cation by column chromatography (Et2O–PE, 0:1 to 1:9); yield:
60.0 mg (79%); yellow gummy solid.
1H NMR (400 MHz, CDCl3): δ = 2.62 (s, 3 H, SCH3), 3.85 (s, 3 H,
OCH3), 6.90 (d, J = 8.8 Hz, 2 H, 3′- and 5′-H), 6.99 (dd, J = 7.6, 5.2
Hz, 1 H, 5-H), 7.53 (d, J = 8.8 Hz, 2 H, 2′- and 6′-H), 7.64 (dd, J =
7.6, 2.0 Hz, 1 H, 4-H), 8.40 (br d, 1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 13.26 (SCH3), 55.33 (OCH3),
83.33 (C≡C), 98.58 (C≡C), 114.07 (3′- and 5′-CH), 114.67 (C),
118.30 (5-CH), 133.13 (2′- and 6′-CH), 134.02 (C), 138.21 (4-CH),
147.42 (6-CH), 160.10 (COMe), 161.54 (CSMe).
1H NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H, SCH3), 7.23 (dd, J =
8.0, 4.8 Hz, 1 H, 5-H), 7.37–7.40 (m, 3 H), 7.50 (dd, J = 8.0, 1.6 Hz,
1 H, 4-H), 7.65–7.67 (m, 2 H), 8.38 (dd, J = 4.8, 1.6 Hz, 1 H, 6-H).
2-[(3-Fluorophenyl)ethynyl]-3-(methylthio)pyridine (6b)
From 2 (60.0 mg) and 1-ethynyl-3-fluorobenzene (39.0 mg), and af-
ter purification by column chromatography (Et2O–PE, 0:1 to 2:3);
yield: 57.0 mg (81%); yellow solid; mp 82–84 °C.
1H NMR (400 MHz, acetone-d6): δ = 2.60 (s, 3 H, SCH3), 7.27–7.32
(m, 1 H), 7.40–7.43 (m, 1 H), 7.48–7.59 (m, 3 H), 7.76 (br d, 1 H,
4-H), 8.53 (br s, 1 H, 6-H).
13C NMR (100.6 MHz, acetone-d6): δ = 14.29 (SCH3), 89.10 (C≡C),
93.80 (d, J = 4.0 Hz, C≡C), 117.34 (d, J = 21.1 Hz, CH), 118.89 (d,
J = 22.0 Hz, CH), 125.08 (d, J = 10.0 Hz, 1′-C), 128.71 (d, J = 3.0
Hz, 6′-CH), 129.37 (5-CH), 131.67 (d, J = 9.1 Hz, 5′-CH), 132.08
(4-CH), 132.67 (6-CH), 140.24 (C), 145.84 (C), 163.30 (d, J =
244.5 Hz, CF).
MS-EI: m/z (%) = 256.07 ([M+ + 1], 9), 255.07 ([M+], 78), 254.06
([M+ – 1], 100).
HRMS: m/z [M+] calcd for C15H13NOS: 255.0718; found 255.0721.
3-[(2-Methoxyphenyl)ethynyl]-2-(methylthio)pyridine (4d)
From 1 (45.0 mg) and 2-ethynylanisole (32.0 mg), and after purifi-
cation by column chromatography using a solvent gradient from
(Et2O–PE, 0:1 to 1:4); yield: 49.0 mg (87%); pale yellow solid; mp
105–107 °C.
MS-EI: m/z (%) = 244.05 ([M+ + 1], 12), 243.05 ([M+], 78), 242.04
([M+ – 1], 100).
1H NMR (400 MHz, CDCl3): δ = 2.67 (s, 3 H, SCH3), 3.94 (s, 3 H,
OCH3), 6.92–6.99 (m, 2 H, 3′- and 5′-H), 7.03 (dd, J = 7.8, 4.8 Hz,
1 H, 5-H), 7.33–7.38 (m, 1 H, 4′-H), 7.56 (dd, J = 7.8, 1.8 Hz, 1 H,
4-H), 7.73 (dd, J = 7.8, 1.6 Hz, 1 H, 6′-H), 8.44 (dd, J = 4.8, 18 Hz,
1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 13.47 (SCH3), 55.88 (OCH3),
88.22 (C≡C), 95.25 (C≡C), 110.79 (3′-CH), 111.76 (C), 118.30 (5-
CH), 118.43 (C), 120.51 (CH), 130.44 (CH), 133.57 (CH), 138.77
(4-CH), 147.21 (6-CH), 160.07 (CSMe), 161.67 (COMe).
HRMS: m/z [M+] calcd for C14H10FNS: 243.0518; found: 243.0519.
2-[(4-Methoxyphenyl)ethynyl]-3-(methylthio)pyridine (6c)
From 2 (60.0 mg) and 4-ethynylanisole (43.0 mg), and after purifi-
cation by column chromatography (Et2O–PE, 0:1 to 2:3); yield:
70.0 mg (93%); yellow oil.
1H NMR (400 MHz, acetone-d6): δ = 2.59 (s, 3 H, SCH3), 3.90 (s, 3
H, OCH3), 7.05 (d, J = 8.8 Hz, 2 H, 3′- and 5′-H), 7.42 (dd, J = 8.2,
4.6 Hz, 1 H, 5-H), 7.62 (d, J = 8.8 Hz, 2 H, 2′- and 6′-H), 7.76 (br d,
1 H, 4-H), 8.41 (br d, 1 H, 6-H).
13C NMR (100.6 MHz, acetone-d6): δ = 14.29 (SCH3), 55.77
(OCH3), 86.37 (C≡C), 96.95 (C≡C), 114.82 (C), 115.23 (3′- and 5′-
CH), 124.22 (5-CH), 132.69 (4-CH), 134.25 (2′- and 6′-CH), 140.55
(C), 140.92 (C), 144.69 (6-CH), 161.63 (COMe).
2-(Methylthio)-3-[(pyridin-3-yl)ethynyl]pyridine (4e)
From 1 (80.0 mg) and 3-ethynylpyridine (45.0 mg), and after puri-
fication by column chromatography (Et2O–PE, 1:4 to 2:3); yield:
54.0 mg (80%); yellow solid; mp 73–75 °C.
1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3 H, SCH3), 6.99 (dd, J =
7.6, 4.8 Hz, 1 H, 5-H), 7.36 (br s, 1 H, 5′-H), 7.66 (dd, J = 7.6, 1.6
Hz, 1 H, 4-H), 7.88 (br d, 1 H, 4′-H), 8.42 (dd, J = 4.8, 1.6 Hz, 1 H,
6-H), 8.69 (br s, 1 H, 6′-H), 7.93 (br s, 1 H, 2′-H).
MS-EI: m/z (%) = 256.07 ([M+ + 1], 18), 255.07 ([M+], 100), 254.07
([M+ – 1], 90).
HRMS: m/z [M+] calcd for C15H13NOS: 255.0718; found: 255.0721.
13C NMR (100.6 MHz, CDCl3): δ = 13.09 (SCH3), 88.02 (C≡C),
94.45 (C≡C), 116.89 (C), 118.24 (5-CH), 120.17 (C), 123.28 (5′-
CH), 138.53 (CH), 138.62 (CH), 148.51 (CH), 148.65 (CH), 151.78
(CH), 161.99 (CSMe).
2-[(2-Methoxyphenyl)ethynyl]-3-(methylthio)pyridine (6d)
From 2 (90.0 mg) and 2-ethynylanisole (64.0 mg), compound 24
and after purification by column chromatography (Et2O–PE, 0:1 to
3:2); yield: 80.0 mg (70%); yellow solid; mp 151–152 °C.
MS-EI: m/z (%) = 227.06 ([M+ + 1], 4), 226.05 ([M+], 13), 225.05
1H NMR (400 MHz, CDCl3): δ = 2.52 (s, 3 H, SCH3), 3.93 (s, 3 H,
OCH3), 6.91–6.95 (m, 2 H, 3′- and 5′-H), 7.21 (dd, J = 8.0, 4.8 Hz,
1 H, 5-H), 7.33–7.37 (m, 1 H, 4′-H), 7.51 (dd, J = 8.0, 1.6 Hz, 1 H,
4-H), 7.62 (dd, J = 7.6, 1.6 Hz, 1 H, 6′-H), 8.37 (dd, J = 4.8, 1.6 Hz,
1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 30.27 (SCH3), 55.81 (OCH3),
90.15 (C≡C), 92.94 (C≡C), 110.73 (3′-CH), 111.42 (C), 120.41 (5′-
CH), 120.65 (5-CH), 130.71 (4′-CH), 131.80 (4-CH), 133.98 (6′-
CH), 139.18 (CSMe), 140.62 (C), 145.09 (6-CH), 160.54 (COMe).
([M+ – 1], 100), 224.04 ([M+ – 2], 19).
HRMS: m/z [M+] calcd for C13H10N2S: 226.0565; found: 226.0565.
2-(Methylthio)-3-[(thien-3-yl)ethynyl]pyridine (4f)
From 1 (60.0 mg) and 3-ethynylthiophene (35.0 mg), and after pu-
rification by column chromatography (Et2O–PE, 0:1 to 1:9); yield:
50.0 mg (74%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3 H, SCH3), 6.98 (dd, J =
7.4, 5.0 Hz, 1 H, 5-H), 7.25 (dd, 5.0, 1.2 Hz, 1 H, 4′-H), 7.33 (dd,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1489–1496

1494
A. Begouin et al.
PAPER
MS-EI: m/z (%) = 256.05 ([M+ + 1], 20), 255.05 ([M+], 100), 254.04
13C NMR (100.6 MHz, CDCl3): δ = 76.29 (CI), 120.78 (5-CH),
128.61 (2 × CH), 129.28 (4′-CH), 129.90 (2 × CH), 133.73 (4-CH),
134.04 (C), 136.36 (C), 142.92 (C), 147.27 (6-CH), 160.29 (C).
MS-EI: m/z (%) = 336.94 ([M+], 100), 210.04 ([M+ – I], 24).
HRMS: m/z [M+] calcd for C13H8INS: 336.9422; found: 336.9417.
([M+ – 1], 88).
HRMS: m/z [M+] calcd for C15H13NOS: 255.0718; found: 255.0720.
3-(Methylthio)-2-[(pyridin-3-yl)ethynyl]pyridine (6e)
From 2 (65.0 mg) and 3-ethynylpyridine (37.0 mg), and after puri-
fication by column chromatography (Et2O–PE, 2:3 to 4:1); yield:
59.0 mg (81%); yellow gummy solid.
1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3 H, SCH3), 7.22 (dd, J =
8.0, 4.8 Hz, 1 H, 5-H), 7.27–7.31 (m, 1 H, 5′-H), 7.48 (dd, J = 8.0,
1.2 Hz, 1 H, 4-H), 7.88–7.91 (m, 1 H, 4′-H), 8.35 (dd, J = 4.8, 1.2
Hz, 1 H, 6-H), 8.57 (dd, J = 5.2, 1.6 Hz, 1 H, 6′-H), 8.85 (d, J = 1.2
Hz, 1 H, 2′-H).
13C NMR (100.6 MHz, CDCl3): δ = 14.55 (SCH3), 89.41 (C≡C),
91.81 (C≡C), 119.44 (C), 123.05 (5′-CH), 123.31 (5-CH), 131.43
(4-CH), 138.87 (4′-CH), 139.61 (CSMe), 145.43 (6-CH), 149.11
(6′-CH), 152.33 (2′-CH).
2-(3-Fluorophenyl)-3-iodothieno[2,3-b]pyridine (5c)
From 4b (45.0 mg) in anhyd Et2O, compound 5c was obtained as a
pure product after extraction; yield: 50.0 mg (76%); yellow solid;
mp 117–119 °C.
1H NMR (400 MHz, CDCl3): δ = 7.16–7.21 (m, 1 H), 7.43–7.49 (m,
4 H), 8.07 (dd, J = 8.0, 1.2 Hz, 1 H, 4-H), 8.59 (br d, 1 H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 76.94 (CI), 116.27 (d, J = 20.1
Hz, 4′- or 2′-CH), 116.95 (d, J = 23.1 Hz, 2′- or 4′-CH), 120.95 (5-
CH), 125.75 (d, J = 3.0 Hz, 6′-CH), 130.31 (d, J = 9.1 Hz, 5′-CH),
134.07 (4-CH), 135.99 (d, J = 8.0 Hz, 1′-C), 136.34 (C), 141.39 (d,
J = 2.01 Hz, 2-C), 147.46 (6-CH), 160.05 (C), 165.52 (d, J = 247.5
Hz, CF).
MS-EI: m/z (%) = 227.06 ([M+ + 1], 10), 226.05 ([M+], 76), 225.05
([M+ – 1], 100), 224.04 ([M+ – 2], 25).
MS-EI: m/z (%) = 354.92 ([M+], 100), 228.03 ([M+ – I], 19), 184.05
(16), 157.04 (10).
HRMS: m/z [M+] calcd for C13H10N2S: 226.0565; found: 226.0566.
HRMS: m/z [M+] calcd for C13H7FINS: 354.9328; found: 354.9316.
3-(Methylthio)-2-[(thien-3-yl)ethynyl]pyridine (6f)
From 2 (60.0 mg) and 3-ethynylthiophene (35.0 mg), and after pu-
rification by column chromatography (Et2O–PE, 1:4 to 1:1); yield:
51.0 mg (75%); brown oil.
2-(4-Methoxyphenyl)-3-bromothieno[2,3-b]pyridine (5d)
From 4c (29.0 mg) in anhyd Et2O, compound 5d was obtained as a
pure product after extraction; yield: 35.0 mg (99%); brown solid;
mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 2.51 (s, 3 H, SCH3), 7.29–7.33 (m,
3 H), 7.51 (br d, 1 H, 4-H), 7.69 (br d, 1 H), 8.37 (br s, 1 H, 6-H).
1H NMR (400 MHz, DMSO-d6): δ = 3.83 (s, 3 H, OCH3), 7.12 (d,
J = 8.8 Hz, 2 H, 3′- and 5′-H), 7.59 (dd, J = 8.0, 4.6 Hz, 1 H, 5-H),
7.72 (d, J = 8.8 Hz, 2 H, 2′- and 6′-H), 8.14 (br d, 1 H, 4-H), 8.66
(br s, 1 H, 6-H).
13C NMR (100.6 MHz, DMSO-d6): δ = 55.37 (OCH3), 101.39
(CBr), 114.49 (3′- and 5′-CH), 121.36 (C), 123.79 (5-CH), 130.70
(2′- and 6′-CH), 130.88 (4-CH), 132.76 (C), 137.91 (C), 147.79 (6-
CH), 157.69 (C), 160.15 (COMe).
13C NMR (100.6 MHz, CDCl3): δ = 14.68 (SCH3), 85.84 (C≡C),
91.44 (C≡C), 121.22 (C), 122.84 (5-CH), 125.50 (CH), 129.93
(CH), 130.40 (CH), 131.53 (4-CH), 139.23 (CSMe), 140.19 (C),
145.08 (6-CH).
MS-EI: m/z (%) = 232.01 ([M+ + 1], 20), 231.02 ([M+], 91), 230.01
([M+ – 1], 100), 229.00 ([M+ – 2], 25).
HRMS: m/z [M+] calcd for C12H9N2S: 231.0176; found: 231.0173.
MS-EI: m/z (%) = 320.97 ([81BrM+], 100), 318.97 ([79BrM+], 96),
3-Halo-2-[(hetero)aryl]thieno[2,3-b]pyridines 5a–h and 3-Halo-
2-[(hetero)aryl]thieno[3,2-b]pyridines 7a–g; General Procedure
To a stirred solution of 2,3-(hetero)arylethynyl(methylthio)pyridine
4 or 6 (1 equiv) in anhyd Et2O (3–5 mL) or anhyd CH2Cl2 (3–5 mL)
at 0 °C was added I2 or Br2 (1.1 equiv) gradually. The reaction was
performed under argon and the mixture stirred at r.t. for 30 min.
When a precipitate was formed during the reaction, the 3-halo-2-
[(hetero)aryl]thienopyridines were directly obtained as pure prod-
ucts after filtration. Otherwise, the mixture was diluted with Et2O
(15 mL) or CH2Cl2 (15 mL) and washed with 10% aq Na2S2O3 (3 ×
10 mL) and H2O (3 × 10 mL). The organic phase was dried
(MgSO4), filtered, and the removal of the solvent under reduced
pressure gave either the pure product, or a crude that was submitted
to column chromatography (Table 1).
305.95 (54), 303.94 (53), 277.95 (29), 275.95 (30).
HRMS: m/z [M+] calcd for C14H1079BrNOS: 318.9666; found:
318.9678. [M+] calcd for C14H1081BrNOS: 320.9646; found:
320.9656.
2-(2-Methoxyphenyl)-3-bromothieno[2,3-b]pyridine (5e)
From 4d (10.0 mg) in anhyd Et2O, compound 5e was obtained as a
pure product after extraction; yield: 10.0 mg (80%); yellow solid;
mp 147–148 °C.
1H NMR (400 MHz, acetone-d6): δ = 3.93 (s, 3 H, OCH3), 7.16–7.20
(m, 1 H, 5′-H), 7.26–7.29 (m, 1 H, 3′-H), 7.57–7.62 (m, 2 H, 4′ and
6′-H), 7.98 (dd, J = 8.4, 5.2 Hz, 1 H, 5-H), 8.61 (dd, J = 8.4, 1.2 Hz,
1 H, 4-H), 8.91 (br d, J = 5.2 Hz, 1 H, 6-H).
13C NMR (100.6 MHz, acetone-d6): δ = 56.16 (OCH3), 105.64 (C),
112.71 (3′-CH), 114.90 (C), 120.56 (C), 121.59 (5′-CH), 122.45 (5-
CH), 132.78 (4′ or 6′-CH), 132.82 (4′ or 6′-CH), 139.51 (C), 143.64
(6-CH), 155.01 (C), 158.07 (C).
3-Bromo-2-phenylthieno[2,3-b]pyridine (5a)
From 4a (90.0 mg) in anhyd Et2O, compound 5a was obtained after
purification by column chromatography (Et2O–PE: 0:1 to 2:3);
yield: 96.0 mg (83%); yellow solid; mp 56–57 °C (Lit.10 mp 54–55
°C).
1H NMR (400 MHz, CDCl3): δ = 7.47–7.52 (m, 4 H), 7.78–7.80 (m,
2 H), 8.14 (br d, 1 H, 4-H), 8.06 (br s, 1 H, 6-H).
3-Iodo-2-(pyridin-3-yl)thieno[2,3-b]pyridine (5f)
From 4e (44.0 mg) in anhyd CH2Cl2, compound 5f was obtained as
a pure product after extraction; yield: 48.0 mg (80%); yellow solid;
mp 73–75 °C.
3-Iodo-2-phenylthieno[2,3-b]pyridine (5b)
From 4a (90.0 mg) in anhyd Et2O, compound 5b was obtained as a
pure product after extraction; yield: 98.0 mg (73%); yellow solid;
mp 136–138 °C.
1H NMR (400 MHz, CDCl3): δ = 7.42 (dd, J = 7.4, 5.0 Hz, 1 H, 5-
H), 7.46–7.53 (m, 3 H), 7.71 (m, 2 H), 8.06 (br d, 1 H, 4-H), 8.57
(br d, 1 H, 6-H).
1H NMR (400 MHz, CDCl3): δ = 7.45 (dd, J = 8.0, 4.4 Hz, 1 H, 5-
H), 7.48 (br s, 1 H, 5′-H), 8.03 (br d, 1 H, 4′-H), 8.06 (dd, J = 8.0,
1.6 Hz, 1 H, 4-H), 8.61 (dd, J = 4.4, 1.6 Hz, 1 H, 6-H), 8.77 (br s, 1
H, 6′-H), 9.01 (br s, 1 H, 2′-H).
13C NMR (100.6 MHz, CDCl3): δ = 78.00 (CI), 121.03 (5-CH),
123.52 (5′-CH), 130.91 (C), 133.86 (4-CH), 136.02 (C), 137.22 (4′-
CH), 138.94 (C), 148.06 (6-CH), 149.96 (CH), 150.16 (CH), 160.66
(C).
Synthesis 2013, 45, 1489–1496
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Regiocontrolled SNAr on 2,3-Dihalopyridines
1495
MS-EI: m/z (%) = 337.93 ([M+], 100), 225.05 (38), 211.03 ([M+ –
I], 30).
HRMS: m/z [M+] calcd for C12H7IN2S: 337.9375; found: 337.9367.
1H NMR (400 MHz, CDCl3): δ = 7.19–7.24 (m, 1 H, 4′- or 2′-H),
7.44 (dd, J = 7.0, 4.2 Hz, 1 H, 6-H), 7.47–7.55 (m, 3 H), 8.25 (br d,
1 H, 7-H), 8.91 (br s, 1 H, 5-H).
13C NMR (100.6 MHz, CDCl3): δ = 82.39 (CI), 116.64 (d, J = 21.1
Hz, 4′- or 2′-CH), 116.88 (d, J = 23.1 Hz, 2′ or 4′-CH), 120.26 (6-
CH), 125.63 (d, J = 3.0 Hz, 6′-CH), 130.44 (d, J = 8.0 Hz, 5′-CH),
131.60 (7-CH), 133.35 (C), 135.82 (d, J = 8.0 Hz, 1′-C), 145.42 (C),
147.63 (5-CH), 154.55 (C), 162.59 (d, J = 248.5 Hz, CF).
3-Bromo-2-(thien-3-yl)thieno[2,3-b]pyridine (5g)
From 4f (50.0 mg) in anhyd Et2O, compound 5g was obtained as a
pure product after extraction; yield: 52.0 mg (81%); brown gummy
solid.
1H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 5.0, 3.0 Hz, 1 H, 5′-
H), 7.55 (br s, 1 H, 5-H), 7.64 (dd, J = 5.0, 1.2 Hz, 1 H, 4′-H), 8.01
(dd, J = 2.8, 1.2 Hz, 1 H, 2′-H), 8.23 (br d, 1 H, 4-H), 8.63 (br s, 1
H, 6-H).
13C NMR (100.6 MHz, CDCl3): δ = 101.59 (CBr), 120.83 (5-CH),
126.32 (2′-CH), 126.58 (5′-CH), 127.69 (4′-CH), 132.15 (4-CH),
132.78 (C), 135.10 (C), 135.44 (C), 144.66 (6-CH), 155.90 (C).
MS-EI: m/z (%) = 354.93 ([M+], 100), 228.03 ([M+ – I], 32).
HRMS: m/z [M+] calcd for C13H7FINS: 354.9328; found: 354.9331.
2-(4-Methoxyphenyl)-3-iodothieno[3,2-b]pyridine (7d)
From 6c (40.0 mg) in anhyd Et2O, compound 7d was obtained as a
pure product after extraction;
yield: 55.0 mg (98%); yellow solid; mp 148–150 °C.
MS-EI: m/z (%) = 296.91 ([81BrM+], 100), 294.91 ([79BrM+], 98),
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H, OCH3), 7.04 (d, J =
8.8 Hz, 2 H, 3′- and 5′-H), 7.33 (dd, J = 7.8, 4.6 Hz, 1 H, 6-H), 7.70
(d, J = 8.8 Hz, 2 H, 2′- and 6′-H), 8.14 (br d, 1 H, 7-H), 8.82 (br s, 1
H, 5-H).
13C NMR (100.6 MHz, CDCl3): δ = 55.38 (OCH3), 81.72 (C-I),
114.11 (3′- and 5′-CH), 119.69 (6-CH), 126.25 (C), 130.61 (7-CH),
131.09 (2′- and 6′-CH), 132.79 (C), 146.27 (C), 147.76 (5-CH),
155.37 (C), 160.59 (COMe).
215.99 (M+ – Br], 18), 172.02 (43).
HRMS: m/z [M+] calcd for C11H679BrNS2: 294.9125; found:
294.9134. [M+] calcd for C11H681BrNS2: 296.9105; found:
296.9113.
3-Iodo-2-(thien-3-yl)thieno[2,3-b]pyridine (5h)
From 4f (35.0 mg) in anhyd Et2O, compound 5h was obtained as a
pure product after extraction; yield: 40.0 mg (77%); yellow solid;
mp 93–95 °C.
1H NMR (400 MHz, CDCl3): δ = 7.40 (dd, J = 8.0, 4.8 Hz, 1 H, 5-
H), 7.48 (dd, J = 5.2, 2.8 Hz, 1 H, 5′-H), 7.59 (dd, J = 5.2, 1.4 Hz, 1
H, 4′-H), 7.91 (dd, J = 2.8, 1.4 Hz, 1 H, 2′-H), 8.02 (dd, J = 8.0, 1.4
Hz, 1 H, 4-H), 8.55 (dd, J = 4.8, 1.4 Hz, 1 H, 6-H).
MS-EI: m/z (%) = 366.95 ([M+], 100), 351.93 ([M+ – Me], 27),
323.94 (9), 241.06 ([M+ – I], 32).
HRMS: m/z [M+] calcd for C14H10INOS: 366.9528; found:
366.9529.
3-Bromo-2-(2-methoxyphenyl)thieno[3,2-b]pyridine (7e)
From 6d (70.0 mg) compound 7e was obtained as a pure product af-
ter filtration from the reaction mixture; yield: 75.0 mg (87%); yel-
low solid; mp 151–152 °C.
1H NMR (400 MHz, DMSO-d6): δ = 3.80 (s, 3 H, OCH3), 7.09–7.13
(m, 1 H, 5′-H), 7.21 (dd, J = 8.4, 1.2 Hz, 1 H, 3′-H), 7.48 (dd, J =
7.4, 2.0 Hz, 1 H, 6′-H), 7.49–7.54 (m, 2 H, 6- and 4′-H), 8.54 (dd,
J = 8.2, 1.6 Hz, 1 H, 7-H), 8.76 (dd, J = 4.8, 1.6 Hz, 1 H, 5-H).
13C NMR (100.6 MHz, DMSO-d6): δ = 55.67 (OCH3), 109.34
(CBr), 112.02 (3′-CH), 120.30 (6-CH), 120.51 (C), 120.53 (5′-CH),
131.49 (4′-CH), 131.52 (6′-CH), 131.59 (7-CH), 132.12 (C), 139.67
(C), 147.89 (5-CH), 151.35 (C), 156.64 (COMe).
13C NMR (100.6 MHz, CDCl3): δ = 75.35 (CI), 120.81 (5-CH),
125.92 (2′-CH), 126.20 (5′-CH), 128.14 (4′-CH), 133.47 (4-CH),
134.16 (C), 136.54 (C), 137.87 (C), 147.32 (6-CH), 159.57 (C).
MS-EI: m/z (%) = 342.90 ([M+], 100), 215.19 ([M+ – I], 11), 172.02
(24).
HRMS: m/z [M+] calcd for C11H6INS2: 342.8986; found: 342.8989.
3-Bromo-2-phenylthieno[3,2-b]pyridine (7a)
From 6a (20.0 mg) in anhyd Et2O, and after purification by column
chromatography (Et2O–PE, 0:1 to 2:3); yield: 23.0 mg (89%); yel-
low solid; mp 111–112 °C (Lit.7d mp 110–112 °C).
1H NMR (300 MHz, CDCl3): δ = 7.39 (dd, J = 7.8, 4.5 Hz, 1 H, 6-
H), 7.49–7.57 (m, 3 H), 7.81–7.84 (m, 2 H), 8.22 (dd, J = 7.8, 1.1
Hz, 1 H, 7-H), 8.87 (br s, 1 H, 5-H).
MS-EI: m/z (%) = 320.97 ([81BrM+], 47), 318.97 ([79BrM+], 45),
240.05 ([M+ – Br], 49), 225.03 ([M+ – Br – Me], 100).
HRMS: m/z [M+] calcd for C14H1079BrNOS: 318.9666; found:
318.9673. [M+] calcd for C14H1081BrNOS: 320.9655; found:
320.9646.
3-Bromo-2-(3-fluorophenyl)thieno[3,2-b]pyridine (7b)
From 6b (70.0 mg) in anhyd Et2O, compound 7b was obtained as a
solid, which was filtered from the reaction mixture; yield: 80.0 mg
(90%); yellow solid; mp 113–114 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.19–7.24 (m, 1 H, 4′- or 2′-
H), 7.54 (dd, J = 8.2, 4.8 Hz, 1 H, 6-H), 7.58–7.66 (m, 3 H), 8.60
(dd, J = 8.2, 1.2 Hz, 1 H, 7-H), 8.80 (dd, J = 4.8, 1.2 Hz, 1 H, 5-H).
13C NMR (100.6 MHz, DMSO-d6): δ = 107.84 (CBr), 115.94 (d, J =
23.1 Hz, 4′- or 2′-CH), 116.52 (d, J = 21.1 Hz, 2′ or 4′-CH), 120.82
(6-CH), 125.48 (d, J = 3.0 Hz, 6′-CH), 131.22 (d, J = 9.0 Hz, 5′-
CH), 131.70 (7-CH), 132.13 (C), 133.15 (C), 134.17 (d, J = 9.0 Hz,
1′-C), 148.38 (5-CH), 151.81 (C), 161.96 (d, J = 245.5 Hz, CF).
3-Iodo-2-(pyridin-3-yl)thieno[3,2-b]pyridine (7f)
From 6e (20.0 mg) in anhyd CH2Cl2, compound 7f was obtained as
a pure product after extraction; yield: 27.0 mg (90%); yellow solid;
mp 89–91 °C.
1H NMR (400 MHz, CDCl3): δ = 7.39 (dd, J = 8.2, 4.6 Hz, 1 H, 6-
H), 7.55–7.58 (m, 1 H, 5′-H), 8.18–8.20 (m, 2 H, 7-H and 4′-H),
8.77 (br s, 1 H, 6′-H), 8.86 (dd, J = 4.6, 1.6 Hz, 1 H, 5-H), 9.02 (br
s, 1 H, 2′-H).
13C NMR (100.6 MHz, CDCl3): δ = 85.56 (CI), 120.52 (6-CH),
123.85 (5′-CH), 130.49 (7-CH), 131.23 (C), 132.93 (C), 138.32 (4′-
CH), 140.93 (C), 148.79 (2 × CH), 148.89 (CH), 155.40 (C).
MS-EI: m/z (%) = 337.93 ([M+], 100), 212.04 (68), 211.03 ([M+ –
I], 47).
MS-EI: m/z (%) = 308.95 ([81BrM+], 96), 306.95 ([79BrM+], 100).
HRMS: m/z [M+] calcd for C13H779BrFNS: 306.9470; found:
306.9467. [M+] calcd for C13H781BrFNS: 308.9458; found:
308.9446.
HRMS: m/z [M+] calcd for C12H7IN2S: 337.9375; found: 337.9387.
2-(3-Fluorophenyl)-3-iodothieno[3,2-b]pyridine (7c)
From 6b (45.0 mg) in anhyd Et2O, compound 7c was obtained as a
pure product after extraction; yield: 53.0 mg (80%); yellow solid;
mp 72–74 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1489–1496

1496
A. Begouin et al.
PAPER
3-Iodo-2-(thien-3-yl)thieno[3,2-b]pyridine (7g)
From 6f (50.0 mg) in anhyd Et2O, compound 7g was obtained as a
pure product after extraction; yield: 57.0 mg (77%); yellow solid;
mp 78–80 °C.
1H NMR (400 MHz, CDCl3): δ = 7.33 (dd, J = 7.6, 4.4 Hz, 1 H, 6-
H), 7.48 (dd, J = 4.8, 2.8 Hz, 1 H, 5′-H), 7.64 (dd, J = 4.8, 1.2 Hz, 1
H, 4′-H), 8.01 (dd, J = 2.8, 1.2 Hz, 1 H, 2′-H), 8.14 (br d, 1 H, 7-H),
8.82 (br s, 1 H, 5-H).
13C NMR (100.6 MHz, CDCl3): δ = 81.39 (CI), 114.09 (C), 119.88
(6-CH), 126.14 (2′-CH), 126.31 (5′-CH), 127.92 (4′-CH), 130.68
(7-CH), 134.13 (C), 141.22 (C), 147.82 (5-CH), 155.38 (C).
MS-EI: m/z (%) = 342.90 ([M+], 100), 215.99 ([M+ – I], 20), 172.02
(15).
(4) (a) Claridge, S.; Raeppel, F.; Granger, M.-C.; Bernstein, N.;
Saavedra, O.; Zhan, L.; Llewellyn, D.; Wahhab, A.; Deziel,
R.; Rahil, J.; Beaulieu, N.; Nguyen, H.; Dupont, I.; Barsalou,
A.; Beaulieu, C.; Chute, I.; Gravel, S.; Robert, M.-F.;
Lefebvre, S.; Dubay, M.; Pascal, R.; Gillespie, J.; Jin, Z.;
Wang, J.; Besterman, J. M.; MacLeod, A. R.; Vaisburg, A.
Bioorg. Med. Chem. Lett. 2008, 18, 2793. (b) Raeppel, S.;
Claridge, S.; Saavedra, O.; Gaudette, F.; Zhan, L.; Mannion,
M.; Zhou, N.; Raeppel, F.; Granger, M.-C.; Isakovic, L.;
Déziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont,
I.; Robert, M.-F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang,
J.; Ste-Croix, H.; Macleod, A. R.; Besterman, J.; Vaisburg,
A. Bioorg. Med. Chem. Lett. 2009, 19, 1323.
(5) (a) Boschelli, D. H.; Wu, B.; Sosa, A. C. B.; Durutlic, H.;
Ye, F.; Raifeld, Y.; Golas, J. M.; Boschelli, F. J. Med. Chem.
2004, 47, 6666. (b) Boschelli, D. H.; Sosa, A. C. B.;
Durutlic, H.; Chen, J. J.; Wang, Y.; Golas, J. M.; Lucas, J.;
Boschelli, F. J. Med. Chem. 2005, 48, 3891.
HRMS: m/z [M+] calcd for C11H6INS2: 342.8986; found: 342.8986.
Acknowledgment
(6) (a) Berkaoui, M.; Outurquin, F.; Paulmier, C. Tetrahedron
1998, 54, 9055. (b) Ragan, J. A.; Raggon, J. W.; Hill, P. D.;
Jones, B. P.; McDermott, R. E.; Munchhof, M. J.; Marx, M.
A.; Casavant, J. M.; Cooper, B. A.; Doty, J. L.; Lu, Y. Org.
Process Res. Dev. 2003, 7, 676. (c) Nurkkala, L. J.; Steen, R.
O.; Dunne, S. J. Synthesis 2006, 1295. (d) Song, Y-H.; Jo, B.
S. J. Heterocycl. Chem. 2009, 46, 1132. (e) Shestopalov, A.
M.; Rodinovskaya, L. A.; Shestopalov, A. A. J. Comb.
Chem. 2010, 12, 9.
(7) (a) Bremner, D. H.; Dunn, A. D.; Wilson, K. A. Synthesis
1992, 528. (b) Bremner, D. H.; Dunn, A. D.; Wilson, K. A.;
Sturrock, K. R.; Wishart, C. Synthesis 1997, 949.
(c) Bremner, D. H.; Dunn, A. D.; Wilson, K. A.; Sturrock, K.
R.; Wishart, C. Synthesis 1998, 1095. (d) Comoy, C.;
Banaszak, E.; Fort, Y. Tetrahedron 2006, 62, 6036.
(e) Nakashima, T.; Fujii, R.; Kawai, T. Chem. Eur. J. 2011,
17, 10951.
We acknowledge the Foundation for the Science and Technology
(FCT-Portugal) for financial support through the NMR Portuguese
network (Bruker 400 Avance III - Univ Minho), FCT and FEDER
(European Fund for Regional Development)-COMPETE/
QREN/EU for financial support through the research unity
PEst-C/QUI/UI686/2011, the research project PTDC/QUI-
QUI/111060/2009 and through the post-doctoral grant attributed to
A.B. (SFRH/BPD/36753/2007) also financed by POPH (Programa
Operacional do Potencial Humano) and FSE (Social European
Fund).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1489–1496
© Georg Thieme Verlag Stuttgart · New York