Synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from 2,3-dihalopyridines, (hetero)arylalkynes, and Na2S. Further functionalizations

Article abstract of DOI:10.1016/j.tet.2012.06.057

A simple and efficient three-step methodology is described for the first time for the synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines. The first step is a Sonogashira coupling from 3-bromo-2-chloropyridine or 2-bromo-3-chloropyridine with several (hetero)arylalkynes to obtain the corresponding 2- or 3-chloro(hetero)arylethynylpyridines. These were cyclized by treatment with Na₂S affording the expected 2-(hetero) arylthienopyridines. As an improvement, these reactions were also performed in one-pot, without the isolation of the Sonogashira product, giving the thienopyridines in similar or better yields, reducing significantly the reaction time after the addition of Na₂S. Further functionalizations were achieved in the thienopyridine system either by bromination in the thiophene ring or chlorination in the pyridine ring via a N-oxide intermediate, allowing metal-catalyzed coupling reactions and/or nucleophilic substitutions. The functionalization of some substituents is also possible and as an example a 1,3-diarylurea was obtained from the reaction of an aniline derivative with an arylisocyanate.

Full text of DOI:10.1016/j.tet.2012.06.057

Tetrahedron 68 (2012) 7082e7094
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from
2,3-dihalopyridines, (hetero)arylalkynes, and Na2S. Further functionalizations
*
~
Daniela Peixoto, Agathe Begouin, Maria-Joao R.P. Queiroz
Departamento/Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Received in revised form 4 June 2012
Accepted 14 June 2012
Available online 23 June 2012
A simple and efficient three-step methodology is described for the first time for the synthesis of
2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines. The first step is a Sonogashira coupling from 3-bromo-2-
chloropyridine or 2-bromo-3-chloropyridine with several (hetero)arylalkynes to obtain the
corresponding 2- or 3-chloro(hetero)arylethynylpyridines. These were cyclized by treatment with Na2S
affording the expected 2-(hetero)arylthienopyridines. As an improvement, these reactions were also
performed in one-pot, without the isolation of the Sonogashira product, giving the thienopyridines in
similar or better yields, reducing significantly the reaction time after the addition of Na2S. Further
functionalizations were achieved in the thienopyridine system either by bromination in the thiophene
ring or chlorination in the pyridine ring via a N-oxide intermediate, allowing metal-catalyzed coupling
reactions and/or nucleophilic substitutions. The functionalization of some substituents is also possible
and as an example a 1,3-diarylurea was obtained from the reaction of an aniline derivative with an
arylisocyanate.
Keywords:
Thienopyridines
Sonogashira coupling
Sodium sulfide
Intramolecular cyclization
Halogenation
1,3-Diarylureas
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
a
one-pot two-step synthesis of the methyl 3-amino-6-
from 5-bromo-3-
bromothieno[3,2-b]pyridine-2-carboxylate
Pyridine derivatives have attracted considerable interest because
of their great practical usefulness due to their various biological
activities. Among them, fused analogues are often much more bi-
ologically active. More particularly, thienopyridines have been
shown to exhibit a large variety of biological activities.1 Nowadays
the chemistry of the [2,3-b]-isomers is better known in comparison
with the [3,2-b]-isomers. The diversity of biological activities gave
an impulse to the development of convenient synthetic routes for
the synthesis of the thieno[3,2-b]pyridine system. Most of the
methods for the synthesis of thieno[3,2-b]pyridines are based on the
use of readily accessible 3-aminothiophenes or their N-derivatives2
and only few synthesis have already been described starting from
the pyridine ring.3 For example, Fort et al. have reported a three-step
process allowing the construction of the thiophene ring. The key
step was the almost regioselective lithiationebromination of the 3-
methylthiopyridine induced by the BuLi-LiDMAE superbase (DMAE:
2-(dimethylamino)ethanol) followed bya Sonogashira coupling and
a halogenocyclization to give the corresponding 2-substituted (Ph or
TMS) 3-halothieno[3,2-b]pyridines.3d
nitropicolinonitrile and methyl thioglycolate in DMF/KOH(aq).4
This product was obtained in excellent yield and it was further
functionalized by CeC (Suzuki, Sonogashira)5a,b or CeN (Buch-
waldeHartwig)5c couplings, to give new derivatives exhibiting in-
hibitory growth activity in human tumor cell lines.5
Herein, we describe a newand general method for the synthesis of
thieno[2,3-b] and [3,2-b]pyridines bearing a (hetero)aryl substituent
in the 2-position, from 2- or 3-chloro(hetero)arylethynylpyridines
obtained by Sonogashira coupling of 2,3-dihalopyridines with (het-
ero)arylalkynes, followed by treatment with sodium sulfide (Na2S) as
depicted in Scheme 1.
Ar(Het)
Na2S
Br
Cl
Ar(Het)
Ar(Het)
N
S
S
N
N
Cl
Cl
N
N
Sonogashira
coupling
(Het)Ar
In the last few years our group has been interested in the syn-
thesis of thieno[3,2-b]pyridine derivatives. We have reported
Cl
Br
Na2S
N
Ar(Het)
* Corresponding author. Tel.: þ351 253604378; fax: þ351 253604382; e-mail
Scheme 1. Strategy for the synthesis of 2-(hetero)arylthieno[2,3-b] and [3,2-b]
pyridines.
address: mjrpq@quimica.uminho.pt (M.-J.R.P. Queiroz).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.057

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7083
2. Results and discussion
thienopyridines 27, 28, 30e32, 36e41, 43e45, and 49e52 were
obtained in good to excellent yields (Table 2). The expected thie-
nopyridines were purified by recrystallization or dry flash chro-
matography. The yields obtained under this one-pot procedure
were at least as good and often higher than those obtained when
the reactions were performed with isolation of the Sonogashira
coupling product.
Optimization experiments were first carried out on the Sono-
gashira reaction6 of the 3-bromo-2-chloropyridine with phenyl-
acetylene using PdCl2(PPh3)2 as the catalyst, CuI as the co-catalyst.
The best conditions were the ones presented in Scheme 2, using
Et3N as the base and the solvent, with only a slight excess of phe-
nylacetylene (1.1 equiv), as it is well known that an important side
reaction, namely the Glaser-type oxidative dimerization of the al-
kyne, usually occurs in the presence of Cu(I).7
After adding Na2S, the reaction was much faster when per-
formed in one-pot, as only 2 h of heating were required for the
9
€
reaction to reach completion. This is agreement with Muller et al.
that for the synthesis of several annulated 4H-thiopyran-4-ones by
one-pot microwave-assisted reaction, from ortho-chloro or fluo-
ro(hetero)aroylchlorides, alkynes, and Na2S, postulated that the
cyclizing step is assisted by Pd and/or Cu.
Ph
Ph
PdCl2(PPh3)2 (3 mol%)
Br
Cl
CuI (6 mol%)
Et3N
+
+
To valorize this work, some of the thienopyridines obtained were
further functionalized. Our group is interested in the synthesis of
di(hetero)arylureas from thienopyridine derivatives bearing an
amine moiety. Indeed, it has been well established that urea de-
rivatives have got a significant place in modern medicinal chemistry
as they have been reported in the literature as anticancer agents,10
anticonvulsant,11 and CXCR3 antagonist.12 1,3-Diarylurea derivatives,
and particularly in the thienopyridine series, were also reported as
cell growth factor receptor tyrosine kinase inhibitors, as anticancer
and/or antiangiogenic compounds.1f,13 The reaction of 2-(thieno[3,2-
b]pyridin-2-yl)aniline 43 with 4-methoxyphenylisocyanate was
performed at room temperature and successfully provided the
Ph
N
100 oC, 2h
N
Cl
N
Ph
1, 80%
6%
Scheme 2. Sonogashira coupling of 3-bromo-2-chloropyridine with phenylacetylene.
The isolation of the 2,3-bis(phenylethynyl)pyridine as a minor
product has been observed and its formation increases with the
reaction time.
Using these conditions various 2-chloro-3-ethynylpyridines
were synthesized in moderate to good yields (Table 1, products
1e13). The reaction time being quite low, the moderate yields that
were obtained with some aryl and heteroarylalkynes were mostly
related to the dimerization of the alkyne, and not to the formation
of the di(hetero)arylethynylpyridine, as it occurred when phenyl-
acetylene was used (Scheme 2).
The synthesis of the corresponding 3-chloro-2-ethynylpyridines
was also performed, using the same conditions (Table 1, products
14e26). As expected, the yields were much higher when 2-bromo-
3-chloropyridine was used as the starting material, due to the
better activation of the bromine in the 2-position for the Sonoga-
shira coupling. Thus, all the expected 3-chloro-2-(hetero)aryle-
thynylpyridines were synthesized in very good to excellent yields
from either electron-rich or electron-poor (hetero)arylalkynes
(from 70% to 93%).
The synthesis of annulated thiophene rings from ortho-hal-
oalkynyl antraquinones, benzenes, naphthalenes, and pyrazoles to
give antrathiophenediones,8a benzo[b]thiophenes,8b,c naph-
thodithiophenes,8d,e and thieno[2,3-c]pyrazoles,8f respectively, has
already been described using Na2S.
In the present work the reaction of the Sonogashira coupling
products 1e26 with Na2S overnight, gave the thieno[2,3-b]pyri-
dines 27e39 and the thieno[3,2-b]pyridines 40e52 in good to ex-
cellent yields (Table 1). This methodology was applied by us for the
first time to the synthesis of thienopyridine derivatives.
A plausible mechanism is a nucleophilic attack (SNAr) of the
hydrosulfide ion on the ortho-chloroalkynylpyridine followed by an
intramolecular addition on the triple bond but on the other hand an
addition of the hydrosulfide ion to the triple bond may occur, fol-
lowed by a SNAr/cyclization (Scheme 3).
Unexpected results were obtained for the cyclization of the ortho-
methoxylatedSonogashira coupling products 7 and20: instead of the
expected 2-(2-methoxyphenyl)thienopyridines, the cyclization with
Na2S gave the corresponding hydroxylated thienopyridines 33 and
46ingood to highyields (Table 1), may bedue tothe spatialproximity
of the sulfide anion intermediate with the methoxy group.
We have also used this methodology through a one-pot pro-
cedure. Thus, after coupling the 2,3-dihalopyridines with (hetero)
arylalkynes at 100 ꢀC for 2 h, Na2S was added to the reaction
mixture without the isolation of the Sonogashira coupling product
and the solution was allowed to stir at 130 ꢀC for a further 2 h. Some
examples were performed using these conditions and the
expected
1-(4-methoxyphenyl)-3-[2-(thieno[3,2-b]pyridin-2-yl)
phenyl]urea 53 in excellent yield (Scheme 4).
The halogenation of some thienopyridines was also performed.
The presence of a bromine or a chlorine atom will allow further
functionalizations by metal-catalyzed coupling reactions (CeC,
CeN, and CeO) or nucleophilic substitution, leading to the syn-
thesis of new thienopyridine derivatives.
The
2-phenylthienopyridines 27 and 40 was done using Br2 in dry ether
at
ꢀC, affording the corresponding 3-bromo-2-phenyl-
bromination
in
the
3-position
of
the
0
thienopyridines 54 and 55 in moderate yields (Scheme 5). With 2-
(pyridin-3-yl)thieno[2,3-b]pyridine 37, the expected 3-bromo de-
rivative 56 was obtained in a good yield (65%) using dry CH2Cl2 as
the solvent due to the low solubility of the starting material.
Compound 55 was already obtained by Fort et al.3d in a total
yield of 32% in
a three-step methodology starting from 3-
methylthiopyridine (that has to be previously synthesized by
reacting 3-bromopyridine with tBuLi and dimethylsulfur). However
this methodology implies the use of delicate reaction conditions
t
(the use of nBuLi and BuLi requires to work in extremely dry con-
ditions, under argon, and at temperatures as low as ꢁ90 ꢀC), and
the reactions were not completely regioselective. In our case,
product 55 was synthesized from the commercially available 2-
bromo-3-chloropyridine also in three steps in a better total yield
(40% through the one-pot procedure for compound 40), using
simple and regioselective reactions.
Chlorination in the 4-position of the thieno[2,3-b]pyridine 32
was also performed, following a procedure via the preparation of
the N-oxide using 3-chloroperoxybenzoic acid (MCPBA).14 After
evaporation of the solvents the solid obtained was treated with
POCl3 using CHCl3 as the solvent15 to afford the 4-chlorothieno[2,3-
b]pyridine 57 in high yield (Scheme 6). This will allow the func-
tionalization of the pyridine ring of the system, which is also im-
portant for the synthesis of biologically active compounds.
3. Conclusion
We have developed a general and efficient methodology for the
synthesis of 2-(hetero)arylthieno[2,3-b] or [3,2-b]pyridines from
2,3-dihalopyridines, (hetero)arylalkynes, and Na2S, that works also

7084
D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
Table 1
Synthesis of 2-(hetero)arylthienopyridines
Ar(Het)
Ar(Het)
Na2S
130 oC,
overnight
Ar(Het)
S
Cl
Br
Cl
PdCl2(PPh3)2 (3 mol%)
CuI (6 mol%)
Na2S
Ar(Het)
Cl
Br
PdCl2(PPh3)2 (3 mol%)
CuI (6 mol%)
Ar(Het)
Yields
90%
130 oC,
overnight
N
40-52
N
14-26
N
S
Et3N, 100ºC, 2h
N
Cl
N
27-39
N
Et3N, 100ºC, 2h
Ar(Het)
1-13
Ethynylpyridines
Yields
Thieno[2,3-b]pyridines
Ethynylpyridines
Yields
Thieno[3,2-b]pyridines
Yields
Ph
Cl
S
Ph
Ph
80%
40%
88%
70%
80%
85%
S
N
27
N
N
N
1
Cl
Cl
Ph
40
14
NH2
Cl
S
NH2
NH2
N
91%
S
N
N
28
41
15
N
2
NH2
NH2
Cl
NH2
NH2
NH2
S
N
55%
50%
65%
96%
82%
91%
83%
89%
90%
86%
94%
97%
S
N
N
16
N
3
Cl
Cl
29
42
Cl
H2N
H2N
S
NH2
N
NH2
S
N
N
17
N
4
43
30
OMe
Cl
S
OMe
OMe
N
S
N
N
31
18
44
N
5
Cl
Cl
Cl
OMe
Cl
OMe
OMe
S
OMe
N
74%
64%
40%
91%
86%
71%
92%
90%
85%
95%
64%
94%
OMe
S
N
N
19
N
6
32
45
Cl
HO
HO
S
OMe
N
OMe
S
N
34
N
N
20
N
7
33
46
Br
Cl
S
Br
Br
N
S
N
N
21
47
N
8
Cl
Br
F
Cl
F
F
S
F
N
70%
70%
87%
82%
60%
70%
85%
80%
S
N
22
N
9
Cl
Cl
35
48
Cl
S
S
N
S
S
S
N
N
36
23
49
N
10
S

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7085
Table 1 (continued )
Ar(Het)
Ar(Het)
Na2S
130 oC,
overnight
Ar(Het)
S
Cl
Br
Cl
PdCl2(PPh3)2 (3 mol%)
CuI (6 mol%)
Na2S
Ar(Het)
Cl
Br
PdCl2(PPh3)2 (3 mol%)
CuI (6 mol%)
Ar(Het)
130 oC,
overnight
N
40-52
N
14-26
N
S
Et3N, 100ºC, 2h
N
Cl
N
27-39
N
Et3N, 100ºC, 2h
Ar(Het)
1-13
Ethynylpyridines
Yields
Thieno[2,3-b]pyridines
Yields
Ethynylpyridines
Yields
Thieno[3,2-b]pyridines
Yields
Cl
N
S
N
60%
70%
87%
70%
S
S
N
N
N
N
24
50
37
N
11
Cl
N
Cl
S
N
N
50%
55%
86%
71%
93%
80%
71%
54%
N
N
N
N
38
51
25
N
12
Cl
Cl
N
N
Cl
S
N
N
N
N
S
N
N
N
N
N
39
26
52
N
13
N
S
Ar(Het)
Ar(Het)
O
C
W
N
Ar(Het)
Na2S
N
OMe
HN
O
W
W
Z
S
NH
Z
S H
Ar(Het)
DMF, 130 ºC
overnight
or
THF/CH2Cl2 (1:1)
rt
S
N
Cl
Z
H2N
W
Z =N, W =CH
Z =CH, W =N
43
53, 90%
OMe
S
Z
Cl
Scheme 4. Synthesis of the new 1,3-diarylurea 53 from thieno[3,2-b]pyridine 43 and
4-methoxyphenylisocyanate.
Scheme 3. Plausible mechanisms for the synthesis of 2-(hetero)arylthieno[2,3-b] or
[3,2-b]pyridines from the ortho-choroalkynylpyridines.
Table 2
Synthesis of 2-(hetero)arylthienopyridines in one-pot
Cl
CuI (6 mol%)
W
W
Z
W
Z
Cl
Br
S
PdCl2(PPh3)2 (3 mol%)
Na2S
+
(Het)Ar
1.1 equiv.
Ar(Het)
Et3N
Z
DMF
100ºC, 2h
130ºC, 2h
Ar(Het)
Z, W = N or CH
Thieno[2,3-b]
Yields
Thieno[3,2-b]
Yields
pyridines
pyridines
One-pot
fashion
Two-pot
fashiona
One-pot
fashion
Two-pot
fashiona
27
28
30
31
32
36
37
38
39
85%
40%
45%
74%
62%
60%
70%
66%
66%
72%
36%
41%
59%
67%
57%
42%
68%
39%
40
41
43
44
45
49
50
51
52
94%
65%
80%
86%
84%
73%
77%
78%
69%
71%
60%
84%
87%
87%
56%
61%
66%
43%
a
Global yields calculated for the synthesis in two-pot of thienopyridines.
in a one-pot procedure, reducing significantly the time of the last
steps. The compounds obtained were submitted to further func-
tionalizations. A 1,3-diarylurea was prepared as an example of
functionalization of thienopyridines bearing an aniline with an
arylisocyanate. The corresponding 3-bromo-2-(hetero)arylth-
ienopyridines were successfully obtained after bromination with
bromine. An example of chlorination in the pyridine ring was also
presented with the synthesis of the 4-chloro-2-(3-methoxyphenyl)

7086
D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
Br
pyridine). After stirring for 10 min, the (hetero)arylacetylene
i
(1.0 or 1.1 equiv) was added, and the solution was heated to
100 ꢀC in a silicone bath for 2 h. The reactions were monitored
by TLC, following the disappearance of the starting materials.
After completion, the mixture was allowed to cool to room
temperature. Then ethyl acetate and water were added and the
organic phase was separated, dried (MgSO4), and filtered.
Removal of the solvent under reduced pressure gave either oils,
which were submitted to column chromatography or pure
Ph
Ph
Ph
S
S
N
27
N
54, 40%
S
S
i
Ph
N
N
N
Br
55, 42%
40
Br
ii
N
products
corresponding
to
the
expected
(hetero)
arylethynylpyridines.
S
N
S
N
37
56, 65%
4.2.1. 2-Chloro-3-(phenylethynyl)pyridine (1) and 2,3-bis(phenyleth-
ynyl)pyridine. From 3-bromo-2-chloropyridine (192 mg, 1.00 mmol)
and phenylacetylene (1.1 equiv) and after purification by column
chromatography using a solvent gradient from neat petroleum ether
to 10% ether/petroleum ether, compound 1 was obtained as a yellow
solid (170 mg, 80%). Recrystallization from ether/petroleum ether
gave yellow crystals, mp 57e59 ꢀC. 1H NMR (400 MHz, CDCl3):
Scheme 5. i: Br2 (1.1 equiv), dry Et2O, 0 ꢀC, 30e60 min ii: dry CH2Cl2 used as the
solvent.
OMe
OMe
4
3
5
6
MCPBA
2
DME / hexane (1:2)
rt, 40h
S
d
¼7.23e7.26 (dd, J¼7.6 and 4.8 Hz,1H, 5-H), 7.38e7.40 (m, 3H, AreH),
N
7
S
N
O
1
7.58e7.60 (m, 2H, AreH), 7.86 (dd, J¼7.6 and 2.0 Hz, 1H, 4-H), 8.35
32
(dd, J¼4.8 and 2.0 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼83.20 (C), 95.82 (C), 119.60 (3-C), 120.85 (5-CH), 121.21 (C), 127.46
POCl3, CHCl3
100 oC, 3h
(2ꢂ CH), 128.15 (40-CH), 130.75 (2ꢂ CH), 140.17 (4-CH), 147.15 (6-CH),
151.30 (2-C) ppm. MS-EI: m/z (%) 215 (Mþ 37Cl, 25) 213 (Mþ 35Cl, 25).
HRMS: calcd for C13H385ClN [Mþ] 213.0345. Found 213.0346. Calcd for
C13H387ClN [Mþ] 215.0316. Found 215.0322.
Cl
N
OMe
In another fraction of the column chromatography eluted with
20% ether/petroleum ether, 2,3-bis(2-phenylethynyl)pyridine was
isolated as a brownish oil (17.0 mg, 6%). 1H NMR (400 MHz, CDCl3):
S
57, 86%
Scheme 6. Chlorination in the 4-position of thieno[2,3-b]pyridine 32.
d¼7.26 (dd, J¼8.0 and 5.2 Hz,1H, 5-H), 7.36e7.39 (m, 6H), 7.58e7.61
(m, 2H), 7.64e7.66 (m, 2H), 7.87 (dd, J¼8.0 and 1.6 Hz,1H, 4-H), 8.57
(dd, J¼5.2 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
85.84 (C), 87.73 (C), 93.64 (C), 96.17 (C), 122.03 (5-CH), 122.29 (C),
122.64 (C),123.08 (C), 128.41 (2ꢂ CH), 128.48 (2ꢂ CH), 128.95 (CH),
129.18 (CH), 131.69 (2ꢂ CH), 132.16 (2ꢂ CH), 138.96 (4-CH), 144.90
(C), 148.57 (6-CH) ppm. MS-EI: m/z (%) 279 (Mþ, 100). HRMS: calcd
for C21H13N [Mþ] 279.1048. Found 279.1049.
thieno[2,3-b]pyridine, via the corresponding N-oxide followed by
the reaction with POCl3. These thienopyridines may be used as
precursors to synthesize biologically active compounds.
4. Experimental section
4.1. General methods
4.2.2. 4-[(2-Chloropyridin-3-yl)ethynyl]aniline (2). From 3-bromo-
2-chloropyridine (144 mg, 0.750 mmol) and 4-ethynylaniline
(1.1 equiv) and after purification by column chromatography us-
ing a solvent gradient from 40% ether/petroleum ether to 50%
ether/petroleum ether, compound 2 was obtained as a yellow pale
solid (68.0 mg, 40%). Recrystallization from ether/petroleum ether
gave pale yellow crystals, mp 111e113 ꢀC. 1H NMR (400 MHz,
Melting points (ꢀC) were determined in a Stuart SMP3 and are
uncorrected. 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 MHz, respectively. Heteronuclear correlations 1He13C,
HMQC or HSQC, and HMBC were performed to attribute some
signals. Elemental analyses were determined on a LECO CHNS 932
elemental analyzer. MS-EI, MS-ESI, and HRMS on the Mþ or on the
[MþþH] data were recorded by the mass spectrometry service of
the University of Vigo, Spain.
Column chromatography was performed on MachereyeNagel
silica gel 230e400 mesh or on silica gel. Preparative layer chro-
matography (PLC) was performed on MachereyeNagel 20ꢂ20 cm2
silica plates, layer 2 mm SIL G-200 UV254. Petroleum ether refers to
the boiling range 40e60 ꢀC. Ether refers to diethyl ether. The in-
crease of polarity in solvent gradient was made from neat petro-
leum ether to mixtures of ether/petroleum ether, increasing 10% of
ether each time until the isolation of the products, unless stated
otherwise. The most polar products were isolated using neat ether,
mixtures of ether/ethyl acetate or neat ethyl acetate.
CDCl3):
d
¼3.96 (br s, 2H, NH2), 6.65 (d, J¼8.4 Hz, 2H, 3 and 5-H),
7.21 (dd, J¼7.6 and 4.8 Hz, 1H, 50-H), 7.39 (d, J¼8.4 Hz, 2H, 2 and 6-
H), 7.81 (dd, J¼7.6 and 2.0 Hz, 1H, 40-H), 8.29 (br d, 1H, 60-H) ppm.
13C NMR (100.6 MHz, CDCl3):
d¼82.52 (C), 98.03 (C), 111.39 (C),
114.69 (3 and 5-CH), 121.25 (C), 121.81 (50-CH), 132.67 (C), 133.22 (2
and 6-CH), 140.72 (40-CH), 147.42 (60-CH), 151.93 (C) ppm. MS-EI: m/
z (%) 230 (Mþ 37Cl, 25), 228 (Mþ 35Cl, 100). HRMS: calcd for
C13H395ClN2 [Mþ] 228.0454. Found 228.0452. Calcd for C13H937ClN2
[Mþ] 228.0425. Found 228.0435.
4.2.3. 3-[(2-Chloropyridin-3-yl)ethynyl]aniline (3). From 3-bromo-
2-chloropyridine (150 mg, 0.770 mmol) and 3-ethynylaniline
(1.1 equiv) and after purification by column chromatography us-
ing a solvent gradient from 35% ether/petroleum ether to 50%
ether/petroleum ether, compound 3 was obtained as a yellow oil
4.2. General experimental conditions for the Sonogashira
reactions
(95.2 mg, 55%). 1H NMR (400 MHz, CDCl3):
d
¼3.65 (br s, 2H, NH2),
6.70e6.73 (m, 1H, 6-H), 6.88e6.92 (m, 1H, 2-H), 6.92e6.99 (m, 1H,
4-H), 7.16 (apparent t, J¼8.0 Hz, 1H, 5-H), 7.23 (dd, J¼8.0 and 4.8 Hz,
1H, 50-H), 7.84 (dd, J¼8.0 and 1.6 Hz, 1H, 40-H), 8.33 (dd, J¼4.8 and
In a dry Schlenk tube, the dihalopyridine, CuI (6 mol %), and
PdCl2(PPh3)2 (3 mol %) were added in Et3N (2 mL per mmol of
1.6 Hz, 1H, 60-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼83.57 (C),

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7087
97.17 (C), 116.15 (6-CH), 117.78 (2-CH), 120.69 (C), 121.83 (50-CH),
122.11 (4-CH), 122.83 (C), 129.39 (5-CH), 141.14 (40-CH), 146.35 (C),
148.03 (60-CH), 152.27 (C) ppm. MS-EI: m/z (%) 230 (Mþ 37Cl, 27),
228 (Mþ 35Cl, 100). HRMS: calcd for C13H935ClN2 [Mþ] 228.0454.
Found 228.0449. Calcd for C13H397ClN2 [Mþ] 230.0425. Found
230.0430.
7.89 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.32 (dd, J¼4.8 and 1.6 Hz, 1H,
6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼55.88 (OMe), 88.10 (C),
93.52 (C), 110.83 (CH), 111.48 (C), 120.54 (CH), 120.92 (C), 121.76 (5-
CH), 130.70 (60-CH), 133.67 (4-CH), 141.16 (C), 147.94 (6-CH), 152.20
(C), 160.25 (C) ppm. MS-EI: m/z (%) 245 (Mþ 37Cl, 41), 243 (Mþ 35Cl,
35
100). HRMS: calcd for C14
H
10
ClNO [Mþ] 243.0451. Found 243.0450.
37
Calcd for C14
H
ClNO [Mþ] 245.0421. Found 245.0415.
10
4.2.4. 2-[(2-Chloropyridin-3-yl)ethynyl]aniline (4). From 3-bromo-
2-chloropyridine (192 mg, 1.00 mmol) and 2-ethynylaniline
(1.1 equiv) and after purification by column chromatography us-
ing a solvent gradient from 50% ether/petroleum ether to 60%
ether/petroleum ether, compound 4 was obtained as a brown solid
(116 mg, 50%). Recrystallization from ether/petroleum ether gave
pale brown crystals, mp 97e98 ꢀC. 1H NMR (400 MHz, CDCl3):
4.2.8. 3-[(4-Bromophenyl)ethynyl]-2-chloropyridine (8). From 3-
bromo-2-chloropyridine (150 mg, 0.770 mmol) and 1-bromo-4-
ethynylbenzene (1.0 equiv) and after purification by column chro-
matography using a solvent gradient from 25% ether/petroleum
ether to 30% ether/petroleum ether, compound 8 was obtained
a yellow solid (90 mg, 40%), mp 99e100 ꢀC. 1H NMR (400 MHz,
d
¼4.35 (br s, 2H, NH2), 6.71e6.77 (m, 2H), 7.17e7.22 (m, 1H), 7.25
acetone-d6):
d
¼7.49e7.51 (m, 1H, 5-H), 7.67 (d, J¼8.8 Hz, 2H, 20 and
(dd, J¼7.6 and 4.8 Hz, 1H, 50-H), 7.39 (dd, J¼7.6 and 1.2 Hz, 1H, 5-H),
7.86 (dd, J¼7.6 and 1.8 Hz, 1H, 40-H), 8.33 (br d, 1H, 60-H) ppm. 13C
60-H), 7.69 (d, J¼8.8 Hz, 2H, 30 and 50-H), 8.09e8.12 (m, 1H, 4-H),
8.44e8.46 (m, 1H, 6-H) ppm. 13C NMR (100.6 MHz, acetone-d6):
NMR (100.6 MHz, CDCl3):
d¼89.67 (C), 94.13 (C), 106.60 (C), 114.53
d
¼90.57 (C), 96.54 (C), 120.58 (C), 122.17 (C), 123.56 (5-CH), 124.06
(CH), 117.94 (CH), 120.69 (C), 121.99 (50-CH), 130.69 (CH), 132.08 (5-
CH), 140.64 (40-CH), 147.87 (60-CH), 148.44 (C), 151.58 (C) ppm. MS-
EI: m/z (%) 230 (Mþ 37Cl, 27), 228 (Mþ 35Cl, 100). HRMS: calcd for
C13H395ClN2 [Mþ] 228.0454. Found 228.0450. Calcd for C13H937ClN2
[Mþ] 230.0425. Found 230.0429.
(C), 132.85 (20 and 60-CH), 134.17 (30 and 50-CH), 142.57 (4-CH),
149.87 (6-CH), 152.39 (C) ppm. MS-ESI: m/z (%) 296 (Mþ
81Br37ClþH, 25), 294 (Mþ 81Br35Cl or 79Br37ClþH, 100), 292 (Mþ
79Br35ClþH, 81). HRMS: calcd for C13H779Br35ClN [MþþH] 291.9529.
Found 291.9524. Calcd for C13H871Br35ClN [MþþH] 293.9502. Found
293.9502. Calcd for C13H779Br37ClN [MþþH] 293.9499. Found
293.9502. Calcd for C13H871Br37ClN [MþþH] 295.9479. Found
295.9478.
4.2.5. 2-Chloro-3-[(4-methoxyphenyl)ethynyl]pyridine(5). From 3-
bromo-2-chloropyridine (150 mg, 0.780 mmol) and 1-ethynyl-4-
methoxybenzene (1.0 equiv) and after purification by column
chromatography using a solvent gradient from 25% ether/petro-
leum ether to 30% ether/petroleum ether, compound 5 was
obtained a yellow solid (120.0 mg, 65%) mp 59e60 ꢀC. 1H NMR
4.2.9. 2-Chloro-3-[(3-fluorophenyl)ethynyl]pyridine (9). From 3-
bromo-2-chloropyridine (100 mg, 0.530 mmol) and 1-ethynyl-3-
fluorobenzene (1.0 equiv) and after purification by column chro-
matography using a solvent gradient from 25% ether/petroleum
ether to 30% ether/petroleum ether, compound 9 was obtained as
(400 MHz, CDCl3):
d
¼3.85 (s, 3H, OMe), 6.91 (d, J¼8.8 Hz, 2H, 30
and 50-H), 7.24 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.52 (d, J¼8.8 Hz,
2H, 20 and 60-H), 7.84 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.32 (dd,
J¼4.8 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
a
colorless oil (80.0 mg, 70%). 1H NMR (400 MHz, CDCl3):
d
¼7.08e7.13 (m, 1H), 7.24e7.28 (m, 2H), 7.35e7.37 (m, 2H), 7.87 (dd,
J¼8.0 and 1.6 Hz, 1H, 4-H), 8.37 (dd, J¼4.8 and 1.6 Hz, 1H, 6-H) ppm.
13C NMR (100.6 MHz, CDCl3):
¼84.93 (C), 95.34 (d, J¼4.0 Hz, C),
d
¼55.33 (OMe), 83.05 (C), 97.25 (C), 114.13 (30 and 50-CH), 114.22
(C), 121.05 (C), 121.88 (5-CH), 133.32 (20 and 60-CH), 141.05 (4-CH),
d
147.57 (6-CH), 151.94 (C), 160.34 (C) ppm. MS-EI: m/z (%) 245 (Mþ
116.53 (d, J¼21.1 Hz, CH),118.51 (d, J¼23.1 Hz, CH),120.17 (C),121.88
(5-CH), 124.00 (d, J¼10.1 Hz, 10-C), 127.66 (d, J¼3.0 Hz, 60-CH),
130.10 (d, J¼9.1 Hz, 50-CH), 141.29 (4-CH), 148.48 (6-CH), 152.37 (C),
162.35 (d, J¼247.5 Hz, CF) ppm. MS-EI: m/z (%) 233 (Mþ 37Cl, 36),
231 (Mþ 35Cl, 100). HRMS: calcd for C13H375ClFN [Mþ] 231.0251.
Found 231.0259. Calcd for C13H377ClFN [Mþ] 233.0222. Found
233.0230.
35
37Cl, 28), 243 (Mþ 35Cl, 100). HRMS: calcd for C14
H
ClNO [Mþ]
10
37
243.0451. Found 243.0450. Calcd for C14
Found 245.0427.
H
ClNO [Mþ] 245.0421.
10
4.2.6. 2-Chloro-3-[(3-methoxyphenyl)ethynyl]pyridine(6). From 3-
bromo-2-chloropyridine (150 mg, 0.780 mmol) and 1-ethynyl-3-
methoxybenzene (1.0 equiv) and after purification by column
chromatography using a solvent gradient from 25% ether/petro-
leum ether to 30% ether/petroleum ether, compound 6 was
obtained as a colorless oil (140 mg, 74%) 1H NMR (400 MHz, CDCl3):
4.2.10. 2-Chloro-3-[(thiophen-3-yl)ethynyl]pyridine (10). From 3-
bromo-2-chloropyridine (150 mg, 0.770 mmol) and 3-ethynylt
hiophene (1.1 equiv) and after purification by column chromatog-
raphy using 30% ether/petroleum ether, compound 10 was
obtained as a colorless oil (117 mg, 70%). 1H NMR (400 MHz, CDCl3):
d
¼3.84 (s, 3H, OMe), 6.94e6.97 (m, 1H, 40-H), 7.09e7.11 (m, 1H, 20-
H), 7.17e7.20 (m, 1H, 60-H), 7.24 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H),
7.27e7.31 (m, 1H, 50-H), 7.86 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.34
(dd, J¼4.8 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼7.23e7.25 (m, 2H), 7.33e7.35 (m,1H), 7.62e7.65 (m,1H), 7.85 (dd,
J¼8.0 and 2.0 Hz,1H, 4-H), 8.34 (dd, J¼4.8 and 2.0 Hz,1H, 6-H) ppm.
13C NMR (100.6 MHz, CDCl3):
d
¼55.32 (OMe), 83.96 (C), 96.73 (C), 115.74 (40-CH), 116.48 (20-CH),
d
¼83.77 (C), 92.05 (C), 120.61 (C),
120.53 (C), 121.84 (5-CH), 123.76 (C), 124.31 (60-CH), 129.54 (50-CH),
141.20 (4-CH), 148.18 (6-CH), 152.30 (C), 159.38 (C) ppm. MS-EI: m/z
(%) 245 (Mþ 37Cl, 29), 243 (Mþ 35Cl, 100). HRMS: calcd for
121.29 (C), 121.84 (CH), 125.72 (CH), 129.72 (CH), 129.95 (CH), 141.14
(4-CH), 148.05 (6-CH), 152.12 (C) ppm. MS-ESI: m/z (%) 222 (Mþ
37ClþH, 40), 220 (Mþ 35ClþH, 100) HRMS: calcd for C11H7ClNS [Mþ
35Cl] 219.9988. Found 219.9993. Calcd for C11H7ClNS [Mþ 37Cl]
221.9958. Found 221.9952.
ClNO [Mþ] 243.0451. Found 243.0443. Calcd for C14
35
37
C14
H H ClNO
1
0
1
0
[Mþ] 245.0421. Found 245.0430.
4.2.7. 2-Chloro-3-[(2-methoxyphenyl)ethynyl]pyridine(7). From 3-
bromo-2-chloropyridine (150 mg, 0.780 mmol) and 1-ethynyl-2-
methoxybenzene (1.0 equiv) and after purification by column
chromatography using a solvent gradient from 25% ether/petro-
leum ether to 30% ether/petroleum ether, compound 7 was
obtained as a colorless oil (118 mg, 64%) 1H NMR (400 MHz, CDCl3):
4.2.11. 2-Chloro-3-(pyridin-3-ylethynyl)pyridine
bromo-2-chloropyridine (192 mg, 1.00 mmol)
(11). From
and
3-
3-
ethynylpyridine (1.1 equiv) and after purification by column chro-
matography using a solvent gradient from 40% ether/petroleum
ether to 50% ether/petroleum ether, compound 11 was obtained as
a white-off solid (130 mg, 60%). Recrystallization from ether/pe-
troleum ether gave off-white crystals, mp 64e66 ꢀC. 1H NMR
d
¼3.93 (s, 3H, OMe), 6.92e6.99 (m, 2H), 7.23 (dd, J¼8.0 and 4.8 Hz,
1H, 5-H), 7.34e7.39 (m, 1H), 7.54 (dd, J¼8.0 and 2.0 Hz, 1H, 60-H),
(400 MHz, CDCl3):
d¼7.24e7.27 (dd, J¼7.6 and 4.8 Hz, 1H, 5-H),

7088
D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7.31e7.34 (m, 1H), 7.85e7.88 (m, 2H), 8.37 (dd, J¼4.8 and 1.6 Hz, 1H,
6-H), 8.60 (dd, J¼5.2 and 1.6 Hz, 1H, 60-H), 8.81 (br s, 1H, 20-H) ppm.
13C NMR (100.6 MHz, CDCl3): 87.33 (C), 93.10 (C), 119.51 (C), 119.85
(C), 121.89 (5-CH), 123.16 (CH), 138.68 (CH), 141.30 (CH), 148.72 (6-
CH), 149.21 (60-CH), 152.11 (20-CH), 152.33 (C) ppm. Anal. Calcd for
C12H7ClN2 (214.65): C, 67.15; H, 3.29; N, 13.05. Found: C, 66.99; H,
3.42; N, 12.76.
96.29 (C), 111.00 (C), 114.59 (2 and 6-CH), 122.63 (50-CH), 133.50 (C),
133.78 (3 and 5-CH), 136.50 (40-CH), 142.66 (C), 147.64 (60-CH),
147.68 (C) ppm. MS-EI: m/z (%) 230 (Mþ 37Cl, 30), 228 (Mþ 35Cl,100).
HRMS: calcd for C13H395ClN2 [Mþ] 228.0454. Found 228.0462. Calcd
for C13H397ClN2 [Mþ] 230.0425. Found 230.0434.
4.2.16. 3-[(3-Chloropyridin-2-yl)ethynyl]aniline
(16). From
and
2-
3-
bromo-3-chloropyridine (96.0 mg, 0.500 mmol)
4.2.12. 2-Chloro-3-(pyridin-2-ylethynyl)pyridine
(12). From 3-
ethynylaniline (1.1 equiv) and after purification by column chro-
matography using a solvent gradient from 50% ether/petroleum
ether to 70% ether/petroleum ether, compound 16 was obtained as
a beige solid (95.0 mg, 83%). Recrystallization from ether/petro-
leum ether gave beige crystals, mp 109e111 ꢀC. 1H NMR (400 MHz,
bromo-2-chloropyridine (150.0 mg, 0.770 mmol) and 2-
ethynylpyridine (1.0 equiv) and after purification by column chro-
matography using a solvent gradient from 35% ether/petroleum
ether to 40% ether/petroleum ether, compound 12 was obtained as
a colorless oil (83.0 mg, 50%) 1H NMR (400 MHz, acetone-d6):
CDCl3):
d
¼3.16 (br s, 2H, NH2), 6.72 (br d, 1H), 6.96 (br s, 1H, 2-H),
d
¼7.46e7.49 (m, 1H), 7.53 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.70e7.73
7.05 (br d, 1H), 7.14e7.22 (m, 2H, 50-H and ArH), 7.75 (dd, J¼8.2 and
(m, 1H), 7.89e7.93 (m, 1H), 8.16 (dd, J¼8.0 and 2.0 Hz, 1H, 4-H), 8.48
1.4 Hz, 1H, 40-H), 8.51 (br d, 1H, 60-H) ppm. 13C NMR (100.6 MHz,
(dd, J¼4.8 and 2.0 Hz, 1H, 6-H) 8.68e8.70 (m, 1H, 30-H) ppm. 13C
CDCl3):
d
¼85.26 (C), 95.12 (C), 116.43 (CH), 118.28 (2-CH), 122.56
NMR (100.6 MHz, acetone-d6):
d¼83.62 (C), 96.44 (C), 120.19 (C),
(C), 122.69 (CH), 123.27 (50-CH), 129.34 (CH), 134.13 (C), 136.64 (40-
CH), 142.16 (C), 146.21 (C), 147.72 (60-CH) ppm. MS-EI: m/z (%)¼230
(Mþ 37Cl, 30), 228 (Mþ 35Cl, 100). HRMS: calcd for C13H935ClN2 [Mþ]
228.0454. Found 228.0457 [Mþ]. Calcd for C13H397ClN2 [Mþ]
230.0425. Found 230.0434.
123.57 (5-CH), 124.72 (CH), 128.48 (CH), 137.39 (CH), 143.03 (4-CH),
143.28 (C),150.24 (6-CH),151.23 (60-CH) 152.62 (C) ppm. MS-EI: m/z
(%) 216 (Mþ 37Cl, 29), 214 (Mþ 35Cl, 100). HRMS: calcd for
C12H375ClN2 [Mþ] 214.0298. Found 214.0297. Calcd for C12H377ClN2
[Mþ] 216.0268. Found 216.0274.
4.2.17. 2-[(3-Chloropyridin-2-yl)ethynyl]aniline
bromo-3-chloropyridine (120 mg, 0.624 mmol)
(17). From
and
2-
2-
4.2.13. 2-Chloro-3-[(1-methyl-1H-imidazol-5-yl)ethynyl]pyridine
(13). From 3-bromo-2-chloropyridine (192 mg, 1.00 mmol) and 5-
ethynyl-1-methyl-1H-imidazole (1.1 equiv) and after purification
by column chromatography using neat ethyl acetate as the solvent,
compound 13 was obtained as an off-white solid (116 mg, 55%).
Recrystallization from ether/petroleum ether gave yellow crystals,
ethynylaniline (80.0 mg, 0.687 mmol) and after purification by
column chromatography using a solvent gradient from 50% ether/
petroleum ether to 70% ether/petroleum ether, compound 17 was
obtained as a yellow solid (126 mg, 89%). Recrystallization from
ether/petroleum ether gave beige crystals, mp 111e112 ꢀC. 1H NMR
mp 120e122 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d¼3.74 (s, 3H,
(400 MHz, DMSO-d6):
d
¼5.53 (br s, 2H, NH2), 6.57e6.61 (m, 1H, 4-
NMe), 7.42 (br s, 1H), 7.50 (dd, J¼7.8 and 4.8 Hz, 1H, 5-H), 7.86 (br s,
1H), 8.17 (dd, J¼7.8 and 2.0 Hz, 1H, 4-H), 8.42 (dd, J¼4.8 and 2.0 Hz,
H), 6.77e6.80 (m, 1H, 6-H), 7.15e7.19 (m, 1H, 5-H), 7.28e7.32 (m,
1H, 3-H), 7.42 (dd, J¼8.0 and 4.8 Hz, 1H, 50-H), 8.05 (dd, J¼8.0 and
1.6 Hz, 1H, 40-H), 8.55 (dd, J¼4.8 and 1.6 Hz, 1H, 60-H). 13C NMR
1H, 6-H) ppm. 13C NMR (75.4 MHz, DMSO-d6):
d
¼30.65 (NMe),
85.38 (C), 91.09 (C), 118.98 (C), 123.06 (5-CH), 135.63 (C), 141.46 (4-
CH), 149.01 (6-CH), 150.11 (C) ppm. MS-ESI: m/z (%) 220 (Mþ
37ClþH, 37), 218 (Mþ 35ClþH, 100). HRMS: calcd for C11H935ClN3
[MþþH] 218.0480. Found 218.0472. Calcd for C11H937ClN3 [MþþH]
220.0455. Found 220.0451.
(100.6 MHz, DMSO-d6):
d
¼91.03 (C), 91.95 (C), 103.79 (C), 114.17 (6-
CH), 116.17 (4-CH), 124.18 (50-CH), 131.11 (5-CH), 132.03 (3-CH),
132.33 (C), 137.00 (40-CH), 140.99 (C), 148.38 (60-CH), 150.27 (C).
MS-EI: m/z (%) 230 (Mþ 37Cl, 27), 228 (Mþ 35Cl, 100). HRMS: calcd
for C13H395ClN2 [Mþ] 228.0454. Found 228.0465 [Mþ]. Calcd for
C13H937ClN2 [Mþ] 230.0425. Found 230.0436.
4.2.14. 3-Chloro-2-(phenylethynyl)pyridine (14). From 2-bromo-3-
chloropyridine (96.0 mg, 0.500 mmol) and phenylacetylene
(1.1 equiv) and after purification by column chromatography using
a solvent gradient from neat petroleum ether to 20% ether/petro-
leum ether, compound 14 was obtained as a yellow solid (94.0 mg,
88%). Recrystallization from ether/petroleum ether gave yellow
4.2.18. 3-Chloro-2-[(4-methoxyphenyl)ethynyl]pyridine (18). From
2-bromo-3-chloropyridine (100 mg, 0.530 mmol) and 1-ethynyl-4-
methoxybenzene (1.0 equiv), compound 18 was obtained a yellow
solid (114.0 mg, 90%). Recrystallization from ether/petroleum ether
gave beige crystals, mp 64e65 ꢀC. 1H NMR (400 MHz, CDCl3):
crystals, mp 48e50 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼7.22 (dd, J¼8.0
d
¼3.83 (s, 3H, OMe), 6.90 (d, J¼8.8 Hz, 2H, 30 and 50-H), 7.21e7.22
and 4.8 Hz, 1H, 5-H), 7.37e7.41 (m, 3H, 30, 40and 50-H), 7.64e7.67
(m, 2H, 20 and 60-H), 7.77 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.52 (br d,
(m,1H, 5-H), 7.59 (d, J¼8.8 Hz, 2H, 20 and 60-H), 8.73e8.77 (m,1H, 4-
H), 8.50e8.54 (m, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼85.78 (C), 94.83 (C),
d
¼55.29 (OMe), 84.87 (C), 95.56 (C), 113.85 (C), 114.08 (30 and 50-
121.91 (C), 123.36 (5-CH), 128.41 (30and 50-CH), 129.37 (40-CH),
132.20 (20and 60-CH), 134.14 (C), 136.72 (4-CH), 142.04 (C), 147.70
(6-CH) ppm. Anal. Calcd for C13H8ClN (213.66): C, 73.08; H, 3.77; N,
6.56. Found: C, 72.77; H, 3.80; N, 6.59.
CH), 123.04 (5-CH), 133.81 (20 and 60-CH), 133.97 (C), 136.68 (4-CH),
142.23 (C), 147.47 (6-CH), 160.53 (C) ppm. MS-EI: m/z (%) 245 (Mþ
37Cl, 29), 243 (Mþ 35Cl, 100). HRMS: calcd for C14
H
ClNO [Mþ]
35
10
243.0451. Found 243.0449. Calcd for C14
Found 245.0427.
H
10
ClNO [Mþ] 245.0421.
37
4.2.15. 4-[(3-Chloropyridin-2-yl)ethynyl]aniline
bromo-3-chloropyridine (96.0 mg, 0.500 mmol)
(15). From
and
2-
4-
4.2.19. 3-Chloro-2-[(3-methoxyphenyl)ethynyl]pyridine (19). From
2-bromo-3-chloropyridine (100 mg, 0.530 mmol) and 1-ethynyl-3-
methoxybenzene (1.0 equiv) compound 19 was obtained as oil
ethynylaniline (1.1 equiv) and after purification by column chro-
matography using a solvent gradient from 50% ether/petroleum
ether to 70% ether/petroleum ether, compound 15 was obtained as
an orange solid (80.0 mg, 70%). Recrystallization from ether/pe-
troleum ether gave yellow crystals, mp 161e163 ꢀC. 1H NMR
(120.0 mg, 92%). 1H NMR (400 MHz, CDCl3):
d
¼3.79 (s, 3H, OMe),
6.91e6.94 (m, 1H), 7.14e7.25 (m, 4H), 7.71 (dd, J¼8.2 and 1.2 Hz, 1H,
4-H), 8.50 (dd, J¼4.8 and 1.2 Hz, 1H, 6-H) ppm. 13C NMR
(400 MHz, CDCl3):
d
¼3.92 (br s, 2H, NH2), 6.65 (d, J¼8.4 Hz, 2H, 2-
(100.6 MHz, CDCl3):
d
¼55.20 (OMe), 85.44 (C), 94.83 (C), 116.04
and 6-H), 7.15 (dd, J¼8.2 and 4.6 Hz, 1H, 50-H), 7.45 (d, J¼8.4 Hz, 2H,
(CH), 116.64 (CH), 122.68 (C), 123.34 (CH), 124.50 (CH), 129.37 (CH),
134.03 (C), 136.60 (4-CH), 141.79 (C), 147.76 (6-CH), 159.19 (C) ppm.
MS-EI: m/z (%) 245 (Mþ 37Cl, 31), 243 (Mþ 35Cl, 100). HRMS: calcd
3- and 5-H), 7.73 (dd, J¼8.2 and 1.4 Hz,1H, 40-H), 8.48 (dd, J¼4.6 and
1.4 Hz, 1H, 60-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d¼84.47 (C),

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7089
35
for C14
H
10
ClNO [Mþ] 243.0451. Found 243.0454. Calcd for
ether to 70% ether/petroleum ether, compound 24 was obtained as
an off-white solid (93.0 mg, 87%). Recrystallization from ether/pe-
troleum ether gave off-white crystals, mp 58e60 ꢀC. 1H NMR
37
C14
H
ClNO [Mþ] 245.0421. Found 245.0428.
10
4.2.20. 3-Chloro-2-[(2-methoxyphenyl)ethynyl]pyridine (20). From
2-bromo-3-chloropyridine (100 mg, 0.530 mmol) and 1-ethynyl-2-
methoxybenzene (1.0 equiv), compound 20 was obtained as oil
(400 MHz, CDCl3):
d
¼7.23 (dd, J¼8.2 and 4.6 Hz,1H, 5-H), 7.29e7.33
(m, 1H, 50-H), 7.76 (dd, J¼8.2 and 1.2 Hz, 1H, 4-H), 7.89e7.92 (m, 1H,
40-H), 8.51 (dd, J¼4.6 and 1.2 Hz, 1H, 6-H), 8.59 (dd, J¼5.0 and
1.6 Hz, 1H, 60-H), 8.85 (br s, 1H, 20-H) ppm. 13C NMR (100.6 MHz,
(118.0 mg, 90%) 1H NMR (400 MHz, CDCl3):
d
¼3.89 (s, 3H, OMe),
6.88e6.95 (m, 2H), 7.17 (dd, J¼8.4 and 4.8 Hz, 1H, 5-H), 7.31e7.36
CDCl3):
d
¼88.75 (C), 90.75 (C), 119.17 (C), 123.07 (50-CH), 123.84 (5-
(m, 1H), 7.56e7.58 (m, 1H), 7.70e7.73 (m, 1H), 7.50 (dd, J¼4.8 and
CH), 134.26 (C), 136.75 (4-CH), 139.00 (40-CH), 141.36 (C), 147.86 (6-
CH), 149.40 (60-CH), 152.52 (20-CH) ppm. Anal. Calcd for C12H7ClN2
(214.65): C, 67.15; H, 3.29; N, 13.05. Found: C, 66.85; H, 3.46; N,
12.74.
1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼55.77 (OMe),
89.60 (C), 91.80 (C), 110.72 (CH), 111.03 (C), 120.35 (CH), 123.12 (5-
CH), 130.91 (CH), 133.88 (C), 133.94 (CH), 136.62 (CH), 142.11 (C),
147.59 (6-CH),160.59 (C) ppm. MS-EI: m/z (%) 245 (Mþ 37Cl, 40), 243
35
(Mþ 35Cl, 100). HRMS: calcd for C14
H
ClNO [Mþ] 243.0451. Found
4.2.25. 3-Chloro-2-(pyridin-2-ylethynyl)pyridine (25). From 2-
bromo-3-chloropyridine
10
37
243.0459. Calcd for C14
H
10
ClNO [Mþ] 245.0421. Found 245.0429.
(96.0 mg,
0.500 mmol)
and
2-
ethynylpyridine (1.1 equiv) and after purification by column chro-
matography using a solvent gradient from 50% ether/petroleum
ether to 100% ether, compound 25 was obtained as an off-white
solid (100 mg, 93%). Recrystallization from ether/petroleum ether
gave yellow crystals, mp 57e59 ꢀC. 1H NMR (400 MHz, CDCl3):
4.2.21. 2-[(4-Bromophenyl)ethynyl]-3-chloropyridine (21). From 2-
bromo-3-chloropyridine (150 mg, 0.770 mmol) and 1-bromo-4-
ethynylbenzene (1.0 equiv) and after purification by column chro-
matography using a solvent gradient from 25% ether/petroleum
ether to 30% ether/petroleum ether, compound 21 was obtained
a brown solid (192 mg, 85%), mp 71e72 ꢀC. 1H NMR (400 MHz,
d
¼7.25 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.29e7.31 (m, 1H), 7.64 (br d,
1H), 7.69e7.73 (m,1H), 7.75e7.77 (m,1H), 8.52 (br d,1H, H), 8.67 (br
s, 1H) ppm. 13C NMR (100.6 MHz, CDCl3):
acetone-d6):
d
¼7.47 (dd, J¼8.2 and 4.4 Hz, 1H, 5-H), 7.65 (d,
d
¼84.40 (C), 92.80 (C),
J¼8.4 Hz, 2H, 20 and 60-H), 7.70 (d, J¼8.4 Hz, 2H, 30 and 50-H), 8.00
123.58 (CH), 123.96 (5-CH), 127.93 (CH), 134.67 (C), 136.15 (CH),
136.73 (4-CH), 141.29 (C), 142.31 (C), 147.84 (CH), 150.24 (CH) ppm.
MS-EI: m/z (%) 216 (Mþ 37Cl, 34), 214 (Mþ 35Cl, 100), 179 (Mþꢁ35,
60). HRMS: calcd for C12H375ClN2 [Mþ] 214.0298, found 214.0301.
Calcd for C12H377ClN2 [Mþ] 216.0268, found 216.0277.
(dd, J¼8.2 and 1.6 Hz, 1H, 4-H), 8.60 (dd, J¼4.8 and 1.6 Hz, 1H, 6-H)
ppm. 13C NMR (100.6 MHz, acetone-d6):
d¼87.83 (C), 93.21 (C),
121.85 (C), 124.31 (C), 125.29 (5-CH), 132.87 (30 and 50-CH), 134.43
(20 and 60-CH), 134.57 (C), 137.70 (4-CH), 142.07 (C), 149.16 (6-CH)
ppm. Anal. Calcd for C13H7BrClN (292.56): C, 53.37; H, 2.41; N, 4.79.
Found: C, 53.04; H, 2.62; N, 4.74.
4.2.26. 3-Chloro-2-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]pyridine
(26). From 2-bromo-3-chloropyridine (96.0 mg, 0.500 mmol) and
5-ethynyl-1-methyl-1H-imidazole (1.1 equiv) and after purification
by column chromatography using neat ethyl acetate, compound 26
was obtained as a yellow solid (86.0 mg, 80%). Recrystallization
from ether/petroleum ether gave yellow crystals, mp 149e151 ꢀC.
4.2.22. 3-Chloro-2-[(3-fluorophenyl)ethynyl]pyridine (22). From 2-
bromo-3-chloropyridine (60.0 mg, 0.300 mmol) and 1-ethynyl-3-
fluorobenzene (1.0 equiv) and after purification by column chro-
matography using a solvent gradient from 25% ether/petroleum
ether to 30% ether/petroleum ether, compound 22 was obtained as
1H NMR (400 MHz, DMSO-d6):
d
¼3.78 (s, 3H, NMe), 7.47 (dd, J¼8.2
an oil (40.0 mg, 60%). 1H NMR (400 MHz, CDCl3):
d
¼7.08e7.14 (m,
and 4.6 Hz, 1H, 5-H), 7.64 (br s, 1H), 8.07 (dd, J¼8.2 and 1.4 Hz, 1H,
1H), 7.24 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.31e7.38 (m, 2H),
7.42e7.44 (m, 1H), 7.77 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.53 (dd,
J¼4.8 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
4-H), 8.11 (br s, 1H), 8.56 (dd, J¼4.6 and 1.4 Hz, 1H, 6-H) ppm. 13C
NMR (100.6 MHz, DMSO-d6):
d
¼32.40 (NMe), 81.97 (C), 93.16 (C),
114.89 (C), 124.83 (5-CH), 132.59 (C), 134.38 (CH), 137.23 (4-CH),
140.18 (C), 140.53 (CH), 148.57 (6-CH) ppm. MS-ESI: m/z (%) 220
(Mþ 37ClþH, 37), 218 (Mþ 35ClþH, 100). HRMS: calcd for C11H935ClN3
[MþþH] 218.0479. Found 218.0475. Calcd for C11H937ClN3 [MþþH]
220.0455. Found 220.0437.
d
¼86.38 (C), 93.19 (d, J¼3.0 Hz, C), 116.82 (d, J¼21.1 Hz, CH), 118.89
(d, J¼23.0 Hz, CH),123.66 (5-CH),128.09 (d, J¼3.0 Hz, 60-CH),130.04
(d, J¼6.0 Hz, 50-CH), 130.13 (d, J¼6.0 Hz, C) 134.33 (C), 136.80 (4-
CH), 141.60 (C), 147.76 (6-CH), 162.29 (d, J¼247.5 Hz, CF) ppm. MS-
EI: m/z (%) 233 (Mþ 37Cl, 33), 231 (Mþ 35Cl, 100). HRMS: calcd for
C13H7ClFN [Mþ 35Cl] 231.0251. Found 231.0243. Calcd for C13H7ClFN
[Mþ 37Cl] 233.0222. Found 233.0223.
4.3. General conditions for the synthesis of thienopyridines
Two-pots: a suspension of the (hetero)arylethynylpyridines
with Na2S (4.0 equiv) in DMF was stirred in an oil bath at 130 ꢀC
overnight. Then the mixture was diluted with H2O and extracted
three times with ethyl acetate. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated to dryness under reduced pressure, affording the
expected thienopyridines as solids.
One-pot: the Sonogashira reaction was performed according to
4.2. After completion, Na2S (4.0 equiv) in DMF was added and the
mixture was heated at 130 ꢀC during 2 h. After workup (described
in 4.3) the crude product was purified by recrystallization or dry
flash chromatography.
4.2.23. 3-Chloro-2-[(thiophen-3-yl)ethynyl]pyridine (23). From 2-
bromo-3-chloropyridine
(150 mg,
0.770 mmol)
and
3-
ethynylthiophene (1.1 equiv) and after purification by column
chromatography using 30% ether/petroleum ether, compound 23
was obtained as an oil (130.7 mg, 70%). 1H NMR (400 MHz, CDCl3):
d
¼7.23 (dd, J¼8.2 and 4.8 Hz, 1H, 5-H) 7.28e7.35 (m, 1H), 7.32e7.34
(m, 1H), 7.69e7.74 (m, 1H), 7.78 (dd, J¼8.2 and 1.6 Hz, 1H, 4-H), 8.52
(dd, J¼4.8 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼85.13 (C), 90.86 (C), 120.91 (C), 123.31 (5-CH), 125.65 (CH), 130.01
(CH), 131.13 (CH), 134.02 (C), 137.11 (4-CH), 141.70 (C), 147.29 (6-CH)
ppm. MS-ESI: m/z (%) 222 [Mþ 37ClþH, 40], 220 [Mþ 35ClþH, 100].
HRMS: calcd for C11H375ClNS [Mþ] 219.9982, found 219.9982. Calcd
for C11H377ClNS [Mþ] 221.9958, found 221.9953.
4.3.1. 2-Phenylthieno[2,3-b]pyridine (27). From compound
1
(91.0 mg, 0.426 mmol), compound 27 was obtained as an orange
solid (81.0 mg, 90%). Recrystallization from ether/petroleum ether
gave orange crystals, mp 88e90 ꢀC. 1H NMR (400 MHz, CDCl3):
4.2.24. 3-Chloro-2-(pyridin-3-ylethynyl)pyridine (24). From 2-
bromo-3-chloropyridine
(96.0 mg,
0.500 mmol)
and
3-
ethynylpyridine (1.1 equiv) and after purification by column chro-
matography using a solvent gradient from 50% ether/petroleum
d
¼7.29 (dd, J¼8.0 and 4.8 Hz 1H, 5-H), 7.36e7.41 (m, 1H), 7.44e7.48
(m, 3H), 7.73 (m, 2H), 8.02 (dd, J¼8.0 and 1.6 Hz,1H, 4-H), 8.53 (br d,

7090
D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼116.62 (CH), 119.79
and 50-CH), 115.26 (3-CH), 119.76 (5-CH), 126.47 (C), 127.86 (20 and
(5-CH), 126.56 (2ꢂ CH), 128.80 (CH), 129.03 (2ꢂ CH), 130.66 (4-CH),
133.81 (C), 134.24 (C), 144.55 (C), 146.24 (6-CH), 161.46 (C) ppm.
MS-EI: m/z (%)¼211 (Mþ, 100). HRMS: calcd for C13H9NS [Mþ]
211.0456. Found 211.0458.
In one-pot, from 3-bromo-2-chloropyridine (70.0 mg,
0.364 mmol) and phenylacetylene (1.1 equiv) and after purification
by dry flash chromatography using a solvent gradient from neat
petroleum ether to 10% ether/petroleum ether, compound 27 was
obtained as an orange solid (65.0 mg, 85%).
60-CH), 130.41 (4-CH), 134.60 (C), 144.59 (C), 145.60 (6-CH), 160.24
(C), 161.04 (C) ppm. MS-EI: m/z (%) 241 (Mþ, 100). HRMS: calcd for
C14H11NOS [Mþ] 241.0561. Found 241.0561.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 4-ethynylanisole (1.1 equiv) and after re-
crystallization from ether/petroleum ether, compound 31 was
obtained as a yellow solid (60.0 mg, 74%).
4.3.6. 2-(3-Methoxyphenyl)thieno[2,3-b]pyridine (32). From com-
pound 6 (102 mg, 0.420 mmol), compound 32 was obtained as
a yellow solid (92.0 mg, 91%), mp 85e86 ꢀC. 1H NMR (300 MHz,
4.3.2. 4-(Thieno[2,3-b]pyridin-2-yl)aniline (28). From compound 2
(50.0 mg, 0.220 mmol), compound 28 was obtained as a yellow oil
CDCl3):
7.46 (s, 1H, 3-H), 8.03 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.53 (dd, J¼4.8
and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (75.4 MHz, CDCl3):
¼55.36
d
¼3.90 (s, 3H, OMe), 6.91e6.95 (m, 1H), 7.24e7.39 (m, 4H),
(45.0 mg, 91%). 1H NMR (400 MHz, CDCl3):
d
¼3.65 (br s, 2H, NH2),
6.60 (d, J¼8.4 Hz, 2H, 2 and 6-H), 6.97 (dd, J¼8.0 and 4.8 Hz, 1H, 50-
H), 7.03 (s, 1H, 30-H), 7.23 (d, J¼8.4 Hz, 2H, 3 and 5-H), 7.68 (dd,
J¼8.0 and 1.6 Hz, 1H, 40-H), 8.12 (dd, J¼4.8 and 1.6 Hz, 1H, 60-H)
d
(OMe), 112.20 (CH), 114.31 (CH), 116.83 (3-CH), 119.12 (CH), 119.81
(CH), 130.08 (CH), 130.87 (4-CH), 134.26 (C), 135.06 (C), 144.51 (C),
146.05 (6-CH), 160.00 (C), 161.15 (C) ppm. MS-EI: m/z (%) 241 (Mþ,
100). HRMS: calcd for C14H11NOS [Mþ] 241.0561. Found 241.0563.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 3-ethynylanisole (1.1 equiv) and after re-
crystallization from ether/petroleum ether, compound 32 was
obtained as a yellow solid (50.0 mg, 62%).
ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼113.82 (30-CH), 116.12 (2 and
6-CH), 119.09 (50-CH), 124.30 (C), 126.78 (3 and 5-CH), 129.45 (40-
CH), 133.81 (C), 143.88 (C), 144.16 (C), 144.73 (60-CH), 159.97 (C)
ppm. MS-EI: m/z (%) 226 (Mþ, 100). HRMS: calcd for C13H10N2S [Mþ]
226.0565. Found 226.0567.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 4-ethynylaniline (1.1 equiv) and after purification
by dry flash chromatography using a solvent gradient from 40%
ether/petroleum ether to 60% ether/petroleum ether, compound 25
was obtained as a beige solid (31.0 mg, 40%).
4.3.7. 2-(Thieno[2,3-b]pyridin-2-yl)phenol (33). From compound 7
(58.0 mg, 0.240 mmol), compound 33 was obtained as a yellow
solid (60.0 mg, 86%), mp 191e192 ꢀC. 1H NMR (400 MHz, acetone-
d6):
d
¼6.99e7.04 (m, 1H, 5-H), 7.11e7.13 (m, 1H, 3-H), 7.26e7.30 (m,
4.3.3. 3-(Thieno[2,3-b]pyridin-2-yl)aniline (29). From compound 3
(50.0 mg, 0.220 mmol), compound 29 was obtained as a yellow
solid (45.0 mg, 96%), mp 145e146 ꢀC. 1H NMR (400 MHz, DMSO-
1H, 4-H), 7.40 (dd, J¼8.0 and 4.8 Hz, 1H, 50-H), 7.75e7.78 (m, 1H, 6-
H), 7.94 (s, 1H, 30-H), 8.20 (dd, J¼8.0 and 1.6 Hz, 1H, 40-H), 8.53 (dd,
J¼4.8 and 1.6 Hz, 1H, 60-H), 9.42 (br s, 1H, OH) ppm. 13C NMR
d6):
d
¼5.47 (br s, 2H, NH2), 6.61e6.64 (br d, 1H, 6-H), 6.96e6.98 (m,
(100.6 MHz, acetone-d6):
d
¼117.46 (3-CH), 120.57 (30-CH), 120.60
2H, 2 and 4-H), 7.11e7.15 (m, 1H, 5-H), 7.41 (dd, J¼8.0 and 4.8 Hz,
1H, 50-H), 7.67 (s, 1H, 30-H), 8.20 (dd, J¼8.0 and 1.6 Hz, 1H, 40-H),
8.50 (dd, J¼4.8 and 1.6 Hz, 1H, 60-H) ppm. 13C NMR (100.6 MHz,
(50-CH), 121.05 (5-CH), 121.49 (C), 129.91 (6-CH), 130.59 (4-CH),
131.38 (40-CH), 134.53 (C), 141.41 (C), 146.95 (60-CH), 155.38 (C),
162.27 (C) ppm. MS-EI: m/z (%)¼227 (Mþ, 100). HRMS: calcd for
C13H9NOS [Mþ] 227.0405. Found 227.0405.
DMSO-d6):
d¼111.49 (2-CH), 113.88 (4-CH), 114.87 (6-CH), 116.90
(30-CH), 120.30 (50-CH), 129.77 (5-CH), 131.18 (40-CH), 133.59 (C),
133.97 (C), 143.96 (C), 146.32 (60-CH), 149.02 (C), 160.15 (C) ppm.
MS-EI: m/z (%) 226 (Mþ, 100). HRMS: calcd for C13H10N2S [Mþ]
226.0565. Found 226.0567.
4.3.8. 2-(4-Bromophenyl)thieno[2,3-b]pyridine (34). From com-
pound 8 (50.0 mg, 0.170 mmol), compound 34 was obtained as
a yellow solid (35.0 mg, 71%) mp 104e105 ꢀC. 1H NMR (400 MHz,
acetone-d6):
d
¼7.46 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.72 (d,
4.3.4. 2-(Thieno[2,3-b]pyridin-2-yl)aniline (30). From compound 4
(100 mg, 0.430 mmol), compound 30 was obtained as a brownish
J¼8.8 Hz, 2H, 20 and 60-H), 7.82 (d, J¼8.8 Hz, 2H, 30 and 50-H), 7.84
(s, 1H, 3-H), 8. 25 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.57 (dd, J¼4.8
and 1.6 Hz, 1H, 6-H) ppm. 13C NMR (100.6 MHz, acetone-d6):
oil (80.0 mg, 82%). 1H NMR (400 MHz, DMSO-d6):
d
¼5.53 (br s, 2H,
NH2), 6.66 (dt, J¼7.6 and 1.2 Hz, 1H, 4-H), 6.84 (dd, J¼7.6 and 1.2 Hz,
1H, 6-H), 7.11 (dt, J¼7.6 and 1.2 Hz, 1H, 5-H), 7.26 (dd, J¼7.6 and
1.2 Hz, 1H, 3-H), 7.41 (dd, J¼8.2 and 4.8 Hz, 1H, 50-H), 7.54 (s, 1H, 30-
H), 8.19 (dd, J¼8.2 and 1.6 Hz, 1H, 40-H), 8.51 (dd, J¼4.8 and 1.6 Hz,
d
¼119.10 (3-CH), 121.21 (6-CH), 123.25 (C), 129.01 (30 and 50-CH),
130.09 (C), 132.10 (4-CH), 133.15 (20 and 60-CH), 135.13 (C), 143.15
(C), 147.73 (6-CH), 162.07 (C) ppm. MS-EI: m/z (%) 291 (Mþ 81Br,
100), 289 (Mþ 79Br, 100). HRMS: calcd for C13H789BrNS [Mþ]
288.9561. Found 288.9565. Calcd for C13H881BrNS [Mþ] 290.9540.
Found 290.9551.
1H, 60-H) ppm. 13C NMR (100.6 MHz, DMSO-d6):
d
¼116.10 (6-CH),
116.74 (4-CH), 117.41 (C), 119.76 (30-CH), 120.05 (50-CH), 129.62 (5-
CH), 130.36 (3-CH), 131.01 (40-CH), 133.76 (C), 141.51 (C),þ146.00
(C), 146.08 (60-CH), 160.40 (C) ppm. MS-EI: m/z (%) 226 (M , 100).
HRMS: calcd for C13H10N2S [Mþ] 226.0565. Found 226.0566.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 2-ethynylaniline (1.1 equiv) and after purification
by dry flash chromatography using a solvent gradient from 40%
ether/petroleum ether to 60% ether/petroleum ether, compound 27
was obtained as a beige solid (35.0 mg, 45%).
4.3.9. 2-(3-Fluorophenyl)thieno[2,3-b]pyridine (35). From com-
pound 9 (60.0 mg, 0.280 mmol), compound 35 was obtained as
a yellow solid (50.0 mg, 87%), mp78e79 ꢀC. 1H NMR (400 MHz,
acetone-d6):
d
¼7.21e7.26 (m, 1H), 7.46 (dd, J¼8.2 and 4.4 Hz, 1H, 5-
H), 7.56e7.70 (m, 3H), 7.87 (s, 1H, 3-H), 8.25 (dd, J¼8.2 and 1.6 Hz,
1H, 4-H), 8.56 (dd, J¼4.4 and 1.6 Hz, 1H, 6-H) ppm. 13C NMR
(100.6 MHz, acetone-d6):
d¼113.73 (d, J¼24.1 Hz, CH), 116.38 (d,
J¼22.1 Hz, CH), 119.55 (3-CH), 121.21 (5-CH), 123.32 (d, J¼3.0 Hz, 60-
CH), 132.07 (d, J¼9.1 Hz, 50-CH), 132.18 (4-CH), 134.97 (C), 136.99 (d,
J¼8.0 Hz, 10-C), 142.95 (C), 147.87 (6-CH), 162.13 (C), 164.06 (d,
J¼244.5 Hz, CF) ppm. MS-EI: m/z (%) 229 (Mþ, 100). HRMS: calcd for
C13H8FNS [Mþ] 229.0361. Found 229.0365.
4.3.5. 2-(4-Methoxyphenyl)thieno[2,3-b]pyridine (31). From com-
pound 5 (62.0 mg, 0.250 mmol), compound 31 was obtained as
a yellow solid (55.0 mg, 91%), mp 119e120 ꢀC. 1H NMR (400 MHz,
CDCl3):
d
¼3.86 (s, 3H, OMe), 6.97 (d, J¼8.8 Hz, 2H, 30 and 50-H), 7.28
(dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.34 (s, 1H, 3-H), 7.66 (d, J¼8.8 Hz,
2H, 20 and 60-H), 7.99 (dd, J¼8.0 and 2.0 Hz, 1H, 4-H), 8.49 (br d, 1H,
4.3.10. 2-(Thiophen-3-yl)thieno[2,3-b]pyridine (36). From com-
pound 10 (80.0 mg, 0.370 mmol), compound 36 was obtained as
6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼55.39 (OMe), 114.46 (30

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7091
a yellow solid (66.0 mg, 82%), mp 109e110 ꢀC. 1H NMR (400 MHz,
CDCl3):
solid (63.0 mg, 80%). Recrystallization from ether/petroleum ether
d
¼7.30 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.33 (s, 1H, 3-H),
gave orange crystals, mp 115e117 ꢀC. 1H NMR (400 MHz, CDCl3):
7.41e7.44 (m, 2H), 7.55e7.59 (m, 1H), 8.01 (dd, J¼8.0 and 1.6 Hz, 1H,
d
¼7.22 (dd, J¼8.2 and 4.4 Hz,1H, 6-H), 7.38e7.49 (m, 3H), 7.75e7.77
(m, 3H), 8.13 (m, 1H, 7-H), 8.67 (dd, J¼4.4 and 1.6 Hz, 1H, 5-H) ppm.
13C NMR (100.6 MHz, CDCl3):
4-H), 8.50 (br d, 1H, 6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼116.38 (3-CH), 119.85 (5-CH), 122.32 (CH), 125.77 (CH), 126.92
d
¼118.60 (6-CH), 120.50 (3-CH),
(CH), 130.85 (4-CH), 134.33 (C), 135.16 (C), 139.51 (C), 145.59 (6-CH),
160.48 (C) ppm. MS-EI: m/z (%) 217 (Mþ, 100). HRMS: calcd for
C11H7NS2 [Mþ] 217.0020. Found 227.0023.
126.48 (2ꢂ CH), 129.07 (2ꢂ CH), 129.10 (CH), 130.01 (7-CH), 133.38
(C), 133.63 (C), 147.46 (5-CH), 148.32 (C), 156.86 (C) ppm. MS-EI: m/z
(%) 211 (Mþ, 100). HRMS: calcd for C13H9NS [Mþ] 211.0456. Found
211.0459.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 3-ethynylthiophene (1.1 equiv) and after purifi-
cation by dry flash chromatography using a solvent gradient from
neat petroleum ether to 20% ether/petroleum ether, compound 36
was obtained as a yellow solid (44.0 mg, 60%).
In one-pot, from 2-bromo-3-chloropyridine (70.0 mg, 0.364 mmol)
and phenylacetylene (1.1 equiv) and after recrystallization from ether/
petroleum ether, compound 40 was obtained as an orange solid
(72.0 mg, 94%).
4.3.11. 2-(Pyridin-3-yl)thieno[2,3-b]pyridine (37). From compound
11 (101 mg, 0.471 mmol), compound 37 was obtained as a brown
solid (70.0 mg, 70%). Recrystallization from ether/petroleum ether
gave brown crystals, mp 86e88 ꢀC. 1H NMR (400 MHz, CDCl3):
4.3.15. 4-(Thieno[3,2-b]pyridin-2-yl)aniline (41). From compound
15 (134.0 mg, 0.586 mmol), compound 41 was obtained as a brown
solid (113 mg, 85%). Recrystallization from ether/petroleum ether
gave brown crystals, mp 142e144 ꢀC. 1H NMR (400 MHz, DMSO-
d
¼7.31 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.40e7.44 (m, 1H, 50-H), 7.54
d6):
d
¼5.59 (br s, 2H, NH2), 6.64 (d, J¼8.4 Hz, 2H, 2 and 6-H), 7.22
(s, 1H, 3-H), 8.00e8.03 (m, 1H), 8.06 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H),
(dd, J¼8.2 and 4.8 Hz, 1H, 60-H), 7.52 (d, J¼8.4 Hz, 2H, 3 and 5-H),
8.56 (dd, J¼4.8 and 1.6 Hz,1H, 6-H), 8.61 (br dd, 1H, 60-H), 9.01 (br d,
7.63 (s, 1H, 30-H), 8.29e8.33 (m, 1H, 70-H), 8.53 (dd, J¼4.8 and
1H, 20-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼118.27 (3-CH),
1.6 Hz, 1H, 50-H) ppm. 13C NMR (100.6 MHz, DMSO-d6):
d
¼113.89 (2
120.09 (5-CH), 123.98 (60-CH), 130.24 (C), 131.13 (4-CH), 133.81 (C),
134.29 (40-CH), 140.21 (C), 146.72 (20-CH), 146.96 (6-CH), 148.86 (60-
CH), 161.61 (C) ppm. MS-EI: m/z (%) 212 (Mþ, 100). HRMS: calcd for
C12H8N2S [Mþ] 212.0408. Found 212.0407.
and 6-CH), 116.29 (30-CH), 118.04 (60-CH), 118.51 (C), 120.19 (C),
127.24 (3 and 5-CH), 130.10 (70-CH), 147.10 (50-CH), 149.13 (C),
150.28 (C), 157.18 (C) ppm. MS-EI: m/z (%) 226 (Mþ, 100). HRMS:
calcd for C13H10N2S [Mþ] 226.0565. Found 226.0568.
In one-pot, from 3-bromo-2-chloropyridine (80.0 mg,
0.416 mmol) and 3-ethynylpyridine (1.1 equiv) and after purifica-
tion by dry flash chromatography using neat ether as the solvent,
compound 37 was obtained as an off-white solid (62.0 mg, 70%).
In one-pot, from 2-bromo-3-chloropyridine (96.0 mg,
0.500 mmol) and 4-ethynylaniline (1.1 equiv) and after purification
by dry flash chromatography using neat ether, compound 41 was
obtained as a brown solid (74.0 mg, 65%).
4.3.12. 2-(Pyridin-2-yl)thieno[2,3-b]pyridine (38). From compound
12 (60.0 mg, 0.280 mmol), compound 38 was obtained as a color-
less oil (50.0 mg, 86%). 1H NMR (400 MHz, acetone-d6):
4.3.16. 3-(Thieno[3,2-b]pyridin-2-yl)aniline (42). From compound
16 (67.0 mg, 0.293 mmol), compound 42 was obtained as a yellow
solid (57.0 mg, 86%), mp 145e146 ꢀC. 1H NMR (400 MHz, DMSO-
d
¼7.39e7.41 (m, 1H), 7.44 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.92e7.97
d6):
d
¼5.31 (br s, 2H, NH2), 6.62e6.64 (m, 1H, 6-H), 6.99e7.01 (m,
(m, 1H), 8.08 (s, 1H, 3-H), 8.10e8.13 (m, 1H), 8.26 (dd, J¼8.0 and
1.6 Hz, 1H, 4-H), 8.58 (dd, J¼4.8 and 1.6 Hz, 1H, 6-H), 8.65e8.67 (m,
2H, 2 and 4-H), 7.11e7.15 (m, 1H, 5-H), 7.31 (dd, J¼8.0 and 4.4 Hz,
1H, 60-H), 7.78 (s, 1H, 30-H), 8.41 (dd, J¼8.0 and 1.2 Hz, 1H, 70-H),
8.61 (dd, J¼4.4 and 1.2 Hz, 1H, 50-H) ppm. 13C NMR (100.6 MHz,
1H) ppm. 13C NMR (100.6 MHz, acetone-d6):
d
¼119.81 (3-CH),
120.34 (CH), 120.90 (5-CH), 121.09 (C), 124.25 (CH), 132.36 (4-CH),
134.92 (C), 137.86 (CH), 146.00 (C), 148.06 (6-CH), 150.56 (CH),
163.05 (C) ppm. MS-EI: m/z (%) 212 (Mþ, 100). HRMS: calcd for
C12H8N2S [Mþ] 212.0408. Found 212.0406.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg,
0.338 mmol) and 2-ethynylpyridine (1.1 equiv) and after purifica-
tion by dry flash chromatography using neat ether as the solvent,
compound 38 was obtained as an off-white solid (47.0 mg, 66%).
DMSO-d6):
d
¼111.10 (CH), 113.70 (CH), 114.95 (6-CH), 118.87 (60-
CH), 119.56 (30-CH), 129.77 (5-CH), 130.55 (70-CH), 132.30 (C),
133.44 (C), 147.45 (50-CH), 148.60 (C), 149.36 (C), 156.44 (C) ppm.
MS-EI: m/z (%) 226 (Mþ, 100). HRMS: calcd for C13H10N2S [Mþ]
226.0565. Found 226.0564.
4.3.17. 2-(Thieno[3,2-b]pyridin-2-yl)aniline (43). From compound
17 (50.0 mg, 0.220 mmol), compound 43 was obtained as a brown
oil (47 mg, 94%). 1H NMR (400 MHz, DMSO-d6):
d
¼5.35 (br s, 2H,
4.3.13. 2-(1-Methyl-1H-imidazol-5-yl)thieno[2,3-b]pyridine
(39). From compound 13 (100 mg, 0.466 mmol), compound 39 was
obtained as an off-white solid (70.0 mg, 71%). Recrystallization
from ether/petroleum ether gave off-white crystals, mp 78e80 ꢀC.
NH2), 6.65e6.69 (m,1H, 4-H), 6.83e6-86 (m,1H, 6-H), 7.10e7.15 (m,
1H, 5-H), 7.27e7.30 (m, 1H, 3-H), 7.33 (dd, J¼8.2 and 4.8 Hz, 1H, 60-
H), 7.65 (s, 1H, 30-H), 8.42 (dd, J¼8.2 and 1.6 Hz, 1H, 70-H), 8.63 (dd,
J¼4.8 and 1.6 Hz, 1H, 50-H) ppm. 13C NMR (100.6 MHz, DMSO-d6):
1H NMR (400 MHz, CDCl3):
d¼3.85 (s, 3H, NMe), 7.24 (s, 1H, 3-H),
d
¼116.20 (6-CH), 116.78 (4-CH), 117.41 (C), 118.70 (60-CH), 122.14
7.32 (dd, J¼8.0 and 4.8 Hz, 1H, 5-H), 7.35 (br s, 1H), 7.66 (br s, 1H),
(30-CH), 129.84 (5-CH), 130.09 (3-CH), 130.24 (70-CH), 132.41 (C),
146.00 (C),146.09 (C),147.21 (50-CH),156.42 (C) ppm. MS-EI: m/z (%)
226 (Mþ, 100). HRMS: calcd for C13H10N2S [Mþ] 226.0565. Found
226.0563.
8.03 (dd, J¼8.0 and 1.6 Hz, 1H, 4-H), 8.54 (dd, J¼4.8 and 1.6 Hz, 1H,
6-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d¼33.19 (NMe), 119.14 (3-
CH), 119.96 (5-CH), 126.74 (C), 130.18 (CH), 130.74 (4-CH), 131.29 (C),
133.27 (C), 140.21 (CH), 146.71 (6-CH), 161.45 (C) ppm. MS-EI: m/z
(%) 215 (Mþ, 100). HRMS: calcd for C11H9N3S [Mþ] 215.0517. Found
215.0518.
In one-pot, from 3-bromo-2-chloropyridine (65.0 mg, 0.338 mmol)
and 5-ethynyl-1-methyl-1H-imidazole (1.1 equiv) and after re-
crystallization from ether/petroleum ether, compound 39 was
obtained as an off-white solid (47.0 mg, 66%).
In one-pot, from 2-bromo-3-chloropyridine (65.0 mg, 0.338 mmol)
and 2-ethynylaniline (1.1 equiv) and after purification by dry flash
chromatography using neat ether as the solvent, compound 43 was
obtained as a beige solid (62.0 mg, 80%).
4.3.18. 2-(4-Methoxyphenyl)thieno[3,2-b]pyridine (44). From com-
pound 18 (94.0 mg, 0.380 mmol) compound 44 was obtained as
a yellow solid (90.0 mg, 97%). Recrystallization from ether/petro-
leum ether gave yellow crystals, mp 106e107 ꢀC. 1H NMR
4.3.14. 2-Phenylthieno[3,2-b]pyridine (40). From compound 14
(80.0 mg, 0.374 mmol), compound 40 was obtained as an orange
(400 MHz, acetone-d6):
d
¼3.91 (s, 3H, OMe), 7.10 (d, J¼8.8 Hz, 2H, 30

7092
D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
and 50-H), 7.31 (dd, J¼8.2 and 4.8 Hz, 1H, 6-H), 7.77 (s, 1H, 3-H), 7.83
(d, J¼8.8 Hz, 2H, 20 and 60-H), 8.34 (dd, J¼8.2 and 1.2 Hz, 1H, 7-H),
8.65 (dd, J¼4.8 and 1.2 Hz, 1H, 5-H) ppm. 13C NMR (100.6 MHz,
164.06 (d, J¼224.5 Hz, CeF). MS-EI: m/z (%) 229 (Mþ, 100). HRMS:
calcd for C13H8FNS [Mþ] 229.0361. Found 229.0362.
acetone-d6):
d
¼55.76 (OMe), 115.44 (30 and 50-CH), 119.44 (6-CH),
4.3.23. 2-(Thiophen-3-yl)thieno[3,2-b]pyridine
(49). From
120.05 (3-CH), 123.99 (C), 127.01 (C), 128.51 (20 and 60-CH), 130.73
(7-CH), 148.32 (5-CH), 148.78 (C), 158.24 (C), 161.63 (C) ppm. MS-EI:
m/z (%) 241 (Mþ, 100). HRMS: calcd for C14H11NOS [Mþ] 241.0561.
Found 241.0563.
In one-pot, from 2-bromo-3-chloropyridine (65.0 mg, 0.338 mmol)
and 4-ethynylanisole (1.1 equiv) and after recrystallization from ether/
petroleum ether, compound 44 was obtained as a beige solid (70.0 mg,
86%).
compound 23 (50.0 mg, 0. 230 mmol), compound 49 was obtained
as a yellow solid (40.0 mg, 80%), mp 98e99 ꢀC. 1H NMR (400 MHz,
CDCl3):
7.69 (s, 1H, 3-H), 8.15 (br d, 1H, 7-H), 8.66 (br s, 1H, 5-H) ppm. 13C
NMR (100.6 MHz, CDCl3):
d
¼7.25e7.29 (m, 1H), 7.42e7.46 (m, 2H), 7.63e7.64 (m, 1H),
d¼118.55 (CH), 119.46 (3-CH), 122.74
(CH), 125.97 (CH), 127.09 (CH), 130.82 (7-CH), 133.48 (C), 134.91 (C),
143.96 (C), 146.26 (5-CH), 155.64 (C) ppm. MS-EI: m/z (%) 217
(Mþ, 100). HRMS: calcd for C11H7NS2 [Mþ] 217.0020. Found
217.0021.
4.3.19. 2-(3-Methoxyphenyl)thieno[3,2-b]pyridine (45). From com-
pound 19 (119 mg, 0.480 mmol) compound 45 was obtained as
a yellow solid (110 mg, 95%). Recrystallization from ether/petro-
leum ether gave yellow crystals, mp 85e86 ꢀC. 1H NMR (400 MHz,
In one-pot, from 2-bromo-3-chloropyridine (65.0 mg,
0.338 mmol) and 3-ethynylthiophene (1.1 equiv) and after purifi-
cation by dry flash chromatography using a solvent gradient from
neat petroleum ether to 20% ether/petroleum ether, compound 49
was obtained as a beige solid (54.0 mg, 73%).
CDCl3):
d
¼3.89 (s, 3H, OMe), 6.94e6.97 (m, 1H), 7.25 (dd, J¼8.0 and
4.8 Hz,1H, 6-H), 7.27e7.28 (m,1H), 7.35e7.38 (m, 2H), 7.80 (s,1H, 3-
H), 8.15e8.17 (m, 1H, 7-H), 8.65e8.67 (m, 1H, 5-H) ppm. 13C NMR
4.3.24. 2-(Pyridin-3-yl)thieno[3,2-b]pyridine (50). From compound
24 (60.0 mg, 0.279 mmol), compound 50 was obtained as an orange
solid (41.0 mg, 70%). Recrystallization from ether/petroleum ether
gave orange crystals, mp 153e154 ꢀC. 1H NMR (400 MHz, CDCl3):
(100.6 MHz, CDCl3):
d
¼55.57 (OMe),112.18 (CH), 114.70 (CH), 118.64
(6-CH), 119.07 (CH), 120.23 (3-CH), 130.15 (CH), 130.55 (7-CH),
133.64 (C), 134.76 (C), 146.81 (5-CH), 148.82 (C), 156.08 (C), 160.03
(C) ppm. MS-EI: m/z (%) 241 (Mþ, 100). HRMS: calcd for C14H11NOS
[Mþ] 241.0561. Found 241.0560.
d
¼7.26 (dd, J¼8.2 and 4.6 Hz, 1H, 6-H), 7.39 (dd, J¼8.0 and 4.8 Hz,
1H, 50-H), 7.83 (s, 1H, 3-H), 8.01e8.02 (m, 1H, 40-H), 8.16e8.19 (dd,
J¼8.2 and 1.2 Hz, 1H, 7-H), 8.62 (br d, 1H, 60-H), 8.68 (dd, J¼4.6 and
1.2 Hz, 1H, 5-H), 9.00 (br s, 1H, 20-H) ppm. 13C NMR (100.6 MHz,
In one-pot, from 2-bromo-3-chloropyridine (96.0 mg,
0.500 mmol) and 3-ethynylanisole (1.1 equiv) and after re-
crystallization from ether/petroleum ether, compound 45 was
obtained as a beige solid (101 mg, 84%).
CDCl3):
d
¼119.08 (6-CH), 121.51 (3-CH), 123.80 (50-CH), 129.63 (C),
130.50 (7-CH), 133.63 (40-CH), 133.73 (C), 144.61 (C), 147.29 (CH),
147.35 (CH),149.91 (60-CH),156.00 (C) ppm. MS-EI: m/z (%) 212 (Mþ,
100). HRMS: calcd for C12H8N2S [Mþ] 212.0408. Found 212.0414.
In one-pot, from 2-bromo-3-chloropyridine (65.0 mg, 0.338 mmol)
and 3-ethynylpyridine (1.1 equiv) and after recrystallization from
ether/petroleum ether, compound 50 was obtained as a beige solid
(55.0 mg, 77%).
4.3.20. 2-(Thieno[3,2-b]pyridin-2-yl)phenol (46). From compound
20 (121 mg, 0.490 mmol) compound 46 was obtained as a white
solid, which was washed with CHCl3 (70.0 mg, 64%), mp
136e137 ꢀC. 1H NMR (400 MHz, acetone-d6):
d
¼7.01e7.05 (m, 1H,
4-H), 7.13e7.16 (m, 1H, 6-H), 7.28e7.35 (m, 2H, 60 and 5-H),
7.81e7.83 (m, 1H, 3-H), 8.12 (m, 1H, 30-H), 8.35e8.38 (m, 1H, 70-H),
8.68 (br s, 1H, 50-H), 9.63 (br s, 1H, OH) ppm. 13C NMR (100.6 MHz,
4.3.25. 2-(Pyridin-2-yl)thieno[3,2-b]pyridine (51). From compound
25 (100 mg, 0.466 mmol), compound 51 was obtained as an orange
solid (70.0 mg, 71%). Recrystallization from ether/petroleum ether
gave orange crystals, mp 153e155 ꢀC. 1H NMR (400 MHz, CDCl3):
acetone-d6):
d
¼117.53 (6-CH), 119.37 (60-CH), 121.04 (4-CH), 121.24
(C), 123.51 (30-CH), 129.67 (3-CH), 130.58 (70-CH), 130.92 (5-CH),
133.97 (C), 145.57 (C), 147.96 (50-CH), 155.49 (C), 157.48 (C) ppm.
MS-EI: m/z (%) 227 (Mþ, 100). HRMS: calcd for C13H9NOS [Mþ]
227.0405. Found 227.0405.
d
¼7.28e7.31 (m, 2H), 7.77e7.81 (m, 1H), 7.89e7.91 (m, 1H), 8.06 (s,
1H, 3-H), 8.24 (br d, 1H), 8.65e8.68 (m, 2H) ppm. 13C NMR
(100.6 MHz, CDCl3):
d
¼119.19 (CH), 119.96 (CH), 120.98 (3-CH),
4.3.21. 2-(4-Bromophenyl)thieno[3,2-b]pyridine (47). From com-
pound 21 (50.0 mg, 0.170 mmol), compound 47 was obtained as
a yellow solid (45.0 mg, 94%), mp 104e105 ꢀC. 1H NMR (400 MHz,
123.59 (CH), 131.21 (CH),135.13 (C),136.87 (CH),146.62 (CH),149.75
(CH),149.89 (C),151.49 (C),155.64 (C) ppm. Anal. Calcd for C12H8N2S
(212.27): C, 67.90; H, 3.80; N, 13.20; S, 15.11. Found: C, 67.66; H,
4.01; N, 12.93; S, 14.89.
acetone-d6):
d
¼7.35 (dd, J¼8.0 and 4.4 Hz, 1H, 6-H), 7.54 (d,
J¼8.8 Hz, 2H, 20 and 60-H), 7.90 (d, J¼8.8 Hz, 2H, 30 and 50-H), 7.99 (s,
In one-pot, from 2-bromo-3-chloropyridine (65.0 mg,
0.338 mmol) and 2-ethynylpyridine (1.1 equiv) and after re-
crystallization from ether/petroleum ether, compound 51 was
obtained as a beige solid (56.0 mg, 78%).
1H, 3-H), 8.39 (dd, J¼8.0 and 1.2 Hz, 1H, 7-H), 8.69 (br d, 1H, 5-H)
ppm. 13C NMR (100.6 MHz, acetone-d6):
d¼119.83 (6-CH),121.53 (3-
CH), 127.12 (30 and 50-CH), 130.05 (C), 130.08 (20 and 60-CH), 130.94
(7-CH), 133.94 (C), 134.47 (C), 148.51 (5-CH), 148.69 (C), 157.94 (C)
ppm. MS-EI: m/z (%) 291 (Mþ 81Br, 100), 289 (Mþ 79Br, 100). HRMS:
calcd for C13H789BrNS [Mþ] 288.9561. Found 288.9565. Calcd for
C13H881BrNS [Mþ] 290.9540. Found 290.9549.
4.3.26. 2-(1-Methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridine (52).
From compound 26 (75.0 mg, 0.450 mmol), compound 52 was
obtained as an off-white solid (40.0 mg, 54%). Recrystallization
from ether/petroleum ether gave off-white crystals, mp
4.3.22. 2-(3-Fluorophenyl)thieno[3,2-b]pyridine (48). From com-
pound 22 (30.0 mg, 0.130 mmol), compound 48 was obtained as
a yellow solid (25.0 mg, 85%), mp 122e123 ꢀC. 1H NMR (400 MHz,
110e112 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼3.86 (s, 3H, NMe), 7.24
(dd, J¼8.2 and 4.6 Hz, 1H, 6-H), 7.39 (br s, 1H), 7.52 (s, 1H, 3-H),
7.65 (br s, 1H), 8.23 (dd, J¼8.2 and 1.4 Hz, 1H, 7-H), 8.54 (dd, J¼4.6
acetone-d6):
d
¼7.25e7.28 (m, 1H), 7.32 (dd, J¼8.2 and 4.8 Hz, 1H, 6-
and 1.4 Hz, 1H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼33.25
H), 7.56e7.62 (m, 1H), 7.68e7.74 (m, 2H), 8.00 (s, 1H, 3-H), 8.42 (dd,
J¼8.2 and 1.6 Hz, 1H, 7-H), 8.71 (dd, J¼4.8 and 1.6 Hz, 1H, 5-H) ppm.
(NMe), 118.92 (6-CH), 121.76 (3-CH), 126.51 (C), 129.83 (7-CH),
130.41 (CH), 132.99 (C), 135.29 (C), 140.61 (CH), 147.60 (5-CH),
156.23 (C) ppm. MS-EI: m/z (%) 215 (Mþ, 100). HRMS: calcd for
C11H9N3S [Mþ] 215.0517. Found 215.0519.
13C NMR (100.6 MHz, acetone-d6):
d¼113.79 (d, J¼23.1 Hz, CH),
116.64 (d, J¼21.1 Hz, CH), 120.18 (6-CH), 122.73 (3-CH), 123.18 (d,
J¼3.0 Hz, 60-CH), 131.08 (7-CH), 132.08 (d, J¼8.0 Hz, 50-CH), 134.12
(C), 137.83 (d, J¼8.0 Hz, 10-C) 143.32 (C), 148.75 (5-CH), 157.71 (C),
In one-pot, from 2-bromo-3-chloropyridine (96.0 mg,
0.500 mmol) and 5-ethynyl-1-methyl-1H-imidazole (1.1 equiv) and

D. Peixoto et al. / Tetrahedron 68 (2012) 7082e7094
7093
after recrystallization from ether/petroleum ether, compound 52
was obtained as an off-white solid (74.0 mg, 69%).
(br s, 1H, 20-H). 13C NMR (100.6 MHz, CDCl3):
d
¼120.95 (5-CH),
124.61 (50-CH), 131.71 (4-CH), 131.93 (C), 132.96 (C), 139.40 (40-CH),
142.74 (C), 147.03 (60-CH), 147.25 (20-CH), 148.53 (6-CH), 159.29 (C),
161.59 (C). MS-EI: m/z (%) 292 (Mþ 81Br, 100), 290 (Mþ 79Br, 93).
HRMS: calcd for C12H779BrN2S [Mþ] 289.9513. Found 289.9507. Calcd
for C12H871BrN2S [Mþ] 291.9493. Found 291.9492.
4.4. Synthesis of 1-(4-methoxyphenyl)-3-[2-(thieno[3,2-b]
pyridin-2-yl)phenyl]urea (53)
Thienopyridine
43
(30.0 mg,
0.120 mmol)
and
4-
methoxyphenylisocyanate (1 equiv) were left stirring in 6 mL
THF/CH2Cl2 (1:1) at room temperature for 16 h. A precipitate did
not come out after this time and hexane (3e5 mL) was added to the
mixture and the precipitate formed was filtered under vacuum.
Compound 53 was obtained as a yellow solid (20.0 mg, 90%), mp
4.6. Chlorination of the thieno[2,3-b]pyridine 32
4.6.1. 4-Chloro-2-(3-methoxyphenyl)thieno[2,3-b]pyridine (57). To
compound 32 (60.0 mg, 0.250 mmol) in 6 mL DME/hexane (1:2),
MCPBA (1.2 equiv) was added portionwise at 0 ꢀC and the mixture
was left stirring for 40 h at room temperature, following the re-
action by TLC. After this time the solvents were evaporated and the
resulting solid was put in CHCl3 and POCl3 (19.5 equiv) was added
dropwise at 0 ꢀC. After 3 h the reaction was completed, ice H2O and
Na2CO3 satd were added and the reaction was extracted with CHCl3.
The organic phases were collected, dried with MgSO4, filtered and
evaporated to give a brown oil. This was submitted to PLC ether/
petroleum ether 2:1 and compound 57 was obtained as a yellow
solid (60.0 mg, 86%) mp 95e96 ꢀC. 1H NMR (400 MHz, CDCl3):
199e200 ꢀC. 1H NMR (400 MHz, DMSO-d6):
d
¼3.69 (s, 3H, OMe),
6.83 (d, J¼8.8 Hz, 2H, 30 and 50-H), 7.16e7.21 (m, 1H), 7.31 (d,
J¼8.8 Hz, 2H, 20 and 60-H), 7.36e7.44 (m, 2H), 7.53e7.55 (m, 1H),
7.71 (s, 1H, 3000-H), 7.92e7.95 (m, 1H), 8.02 (br s, 1H, NH), 8.47e8.50
(m, 1H), 8.67e8.68 (m, 1H, 5000-H) 8.84 (br s, 1H, NH) ppm. 13C NMR
(100.6 MHz, DMSO-d6):
d
¼55.12 (OMe), 113.97 (30 and 50-CH),
119.11 (CH), 119.84 (20 and 60-CH), 123.22 (CH), 123.43 (CH), 124.18
(3000-CH), 125.01 (C), 129.49 (CH), 130.36 (CH), 130.58 (CH), 132.63
(C), 133.56 (C), 136.63 (C), 144.26 (C), 147.42 (5000-CH), 152.76 (C),
154.44 (C), 155.91 (C) ppm. MS-ESI: m/z (%) 376 (MþþH, 100).
HRMS: calcd for C21H18N3O2S [Mþ] 376.1114. Found 376.1111.
d
¼3.90 (s, 3H, OMe), 7.35e7.45 (m, 3H), 7.58e7.61 (m, 1H), 7.62 (s,
1H, 3-H), 8.00e8.03 (m, 1H), 8.10e8.11 (m, 1H), 8.50 (br s, 1H, 6-H)
ppm. 13C NMR (100.6 MHz, CDCl3):
d
¼55.45 (OMe), 114.96 (3-CH),
4.5. General conditions for the bromination in position 3
119.28 (CH), 120.26 (C), 128.27 (CH), 129.80 (CH), 130.23 (CH), 131.11
(C), 133.77 (CH), 134.67 (C), 138.65 (C), 160.00 (C), 145.86 (6-CH),
In a dry Schlenk tube, thienopyridines 27, 37 or 40 were put in
dry Et2O or dry CH2Cl2. Then, Br2 (1.1 equiv) was added dropwise at
0 ꢀC and the solution was stirred at this temperature for 30 min to
1 h. Then the mixture was diluted with H2O and extracted with
ethyl acetate. The combined organic layers were dried over
anhydrous MgSO4, filtered, and the solvent was removed
under reduced pressure. The resulting crudes were submitted to
column chromatography or PLC to give the expected 3-bromo-2-
phenylpyridines.
160.11 (30-C) ppm. MS-EI: m/z (%) 277 (Mþ 37Cl, 29), 275 (Mþ 35Cl,
100). HRMS: calcd for C14
H
ClNSO [Mþ] 275.0172. Found 275.0165.
35
10
37
Calcd for C14
H
ClNSO [Mþ] 277.0142. Found 277.0139.
10
Acknowledgements
To the Foundation for the Science and Technology (FCTePortu-
gal) 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).
4.5.1. 3-Bromo-2-phenylthieno[2,3-b]pyridine (54). From com-
pound 27 (60.0 mg, 0.284 mmol), and after purification by PLC
using neat Et2O as eluent, compound 54 was obtained as a yellow
solid (33.0 mg, 40%), mp 54e55 ꢀC. 1H NMR (400 MHz, CDCl3):
d
¼7.44e7.54 (m, 4H), 7.77e7.80 (m, 2H), 8.14 (dd, J¼8.0 and 1.6 Hz,
1H, 4-H), 8.62 (br d, 1H, 6-H). 13C NMR (100.6 MHz, CDCl3):
References and notes
d
¼102.30 (C), 120.51 (CH), 128.73 (2ꢂ CH), 129.28 (CH), 129.64 (2ꢂ
1. (a) Boschelli, D. H.; Wu, B.; Sosa, A. C. B.; Durutlic, H.; Ye, F.; Raifeld, Y.; Golas, J.
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chaelides, M. R. Bioorg. Med. Chem. Lett. 2004, 14, 4505e4509; (d) Hayakawa, I.;
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(b) Ragan, J. A.; Raggon, J. W.; Hill, P. D.; Jones, B. P.; McDermott, R. E.;
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CH), 131.43 (4-CH), 132.38 (C), 133.64 (C), 139.23 (C), 147.06 (6-CH),
158.74 (C). MS-EI: m/z (%) 291 (Mþ 81Br, 99), 289 (Mþ 79Br, 100).
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pound 40 (69.0 mg, 0.328 mmol), and after purification by column
chromatography using 40% ether/petroleum ether, compound 55
was obtained as an off-white solid (40.0 mg, 42%), mp 109e111 ꢀC
(lit3d 110e112 ꢀC). 1H NMR (400 MHz, CDCl3):
d
¼7.36e7.39 (br m,
1H, 6-H), 7.49e7.55 (m, 3H), 7.81e7.83 (m, 2H), 8.20 (br d, 1H, 7-H),
8.85 (br s, 1H, 5-H). 13C NMR (100.6 MHz, CDCl3):
d
¼107.05 (C),
119.90 (6-CH), 128.79 (2ꢂ CH), 129.47 (2ꢂ CH), 129.51 (40CH),
130.75 (7-CH), 132.57 (C), 133.18 (C), 142.77 (C), 147.90 (5-CH),
152.79 (C), 161.46 (C) ppm. MS-EI: m/z (%)¼211 (Mþ, 100).
4.5.3. 3-Bromo-2-pyridin-3-yl-thieno[2,3-b]pyridine
(56). From
compound 37 (30.0 mg, 0.142 mmol), and after purification by re-
crystallization with ether/petroleum ether, compound 56 was
obtained as an ochre solid (27.0 mg, 65%), mp 201e203 ꢀC. 1H NMR
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