Palladium-catalysed direct arylation of heteroaromatics with functionalised bromopyridines

Article abstract of DOI:10.1016/j.tet.2012.06.034

The regioselective 5-arylation of a variety of heteroaromatics with functionalised pyridyl bromides using palladium catalyst gives a simple access to functionalised heteroarylated pyridines. The target products were obtained in moderate to good yields using only 1 mol % PdCl(C₃H ₅)(dppb) as the catalyst. Substituents, such as fluoro, acetyl, nitrile, nitro, methoxy or amino on the pyridyl bromide are tolerated. However, the nature of the substituents has an important influence on the yields. Electron-withdrawing substituent favours the reaction; whereas electron-donating are unfavourable.

Full text of DOI:10.1016/j.tet.2012.06.034

Tetrahedron 68 (2012) 7655e7662
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Palladium-catalysed direct arylation of heteroaromatics with functionalised
bromopyridines
*
Souhila Bensaid, Henri Doucet
ꢀ
Institut Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes 1, “Catalyse et Organometalliques”, Campus de Beaulieu, 35042 Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The regioselective 5-arylation of a variety of heteroaromatics with functionalised pyridyl bromides using
palladium catalyst gives a simple access to functionalised heteroarylated pyridines. The target products
were obtained in moderate to good yields using only 1 mol % PdCl(C3H5)(dppb) as the catalyst. Sub-
stituents, such as fluoro, acetyl, nitrile, nitro, methoxy or amino on the pyridyl bromide are tolerated.
However, the nature of the substituents has an important influence on the yields. Electron-withdrawing
substituent favours the reaction; whereas electron-donating are unfavourable.
Received 1 March 2012
Received in revised form 14 May 2012
Accepted 8 June 2012
Available online 19 June 2012
Keywords:
Palladium
Ó 2012 Elsevier Ltd. All rights reserved.
Catalysis
CeH bond activation
Pyridines
Heteroaromatics
1. Introduction
However, so far, few examples of palladium-catalysed direct
arylation at C5 of thiophenes, furans or pyrroles have been de-
The pyridine motif is a ubiquitous building block found in many
bioactive compounds. Among them, pyridines or quinolines
substituted by furans, pyrroles or imidazoles have display useful
pharmaceutical properties. For example, Methoxatin displays an-
tioxidant properties; Acodazole has antimicrobial and antineo-
plastic properties, whereas Nifuroquine and Telithromycin are
antibacterial agents (Fig. 1).
Suzuki, Stille or Negishi palladium-catalysed cross-coupling
reactions are valuable methods to prepare such compounds.1
However, they require the preliminary preparation of a requisite
organometallic species. Ohta and co-workers reported in 1990 that
the direct 2- or 5-arylation of several heteroaromatics with aryl
halides via a CeH bond activation proceed in moderate to good
yields using Pd(PPh3)4 as the catalyst.2 Since this report, the
palladium-catalysed direct arylation of heteroaryl derivatives with
aryl halides has proven to be a cost-effective and environmentally
attractive method for the synthesis of a wide variety of arylated
heterocycles.3e10 Indeed, the major by-products of the reaction are
a base associated to HX, instead of metallic salts produced under
more classical cross-coupling procedures, such as Suzuki, Negishi
or Stille reactions (Scheme 1). Moreover, the method avoids the
preliminary preparation of an organometallic derivative reducing
the number of steps needed to prepare such compounds.
scribed using functionalised halopyridines.11e13 Moreover, in most
cases large amounts of catalyst (e.g., 5e10 mol %) have been
employed. A few examples using methoxy-substituted pyridines
have been described.11 For example, the reaction of two imidazo
[1,2-b]pyridazines with 3-bromo-5-methoxypyridine using
10 mol % Pd(OAc)2 with 20 mol % PPh3 gives the coupling products
in 75% and 89% yields.11a Daugulis and co-workers reported that
benzothiophene can be arylated with 2-chloro-6-methoxypyridine
using 5 mol % Pd(OAc)2 and 10 mol % nBuAd2P.11b A similar
CO2H
N
HO2C
HN
O
O
NH
N
HN
N
HO2C
O
N
Methoxatin
NO2
Acodazole
R
N
O
N
CO2H
N
O
N
Nifuroquine
Telithromycin
* Corresponding author. Tel.: þ33 2 23 23 63 84; fax: þ33 2 23 23 69 39; e-mail
address: henri.doucet@univ-rennes1.fr (H. Doucet).
Fig. 1. Examples of bioactive compounds.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.034

7656
S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
Table 1
Y
Y
Palladium-catalysed reaction of 3-bromo-5-acetylpyridine with heteroaromatics
R2
Y
X
R1M
[Pd]
[Pd]
Z
Y
R
Z
O
+ R2
Z
Y
+
R2
PdCl(C3H5)(dppb)
1 mol%
R
Z
N
R1MX
R1MX
X
O
R1M
+
Z
DMAc, KOAc,
150 °C, 20 h
N
2-10
N
N
Br
X = I, Br, Cl
Y = C, N
N
Z = O, S, NR
M = Zn, Mg, Sn or B
Entry
1
Heteroarene
Product
Yield (%)
94
Scheme 1.
O
N
S
N
procedure was employed for the reaction of a 3-bromopyridine
bearing a formyl substituent at C5 with an imidazo[1,2-b][1,2,4,5]
tetrazine.12 Using 8 mol % Pd(OAc)2 and 16 mol % PCy3 as the cat-
alyst system, the coupling product was obtained in 82% yield. Fi-
nally, an ‘on water’ reaction of 2-chloro-4-iodopyridine with 2-
phenylindazole using PPh3 (10 mol %), Pd(dppf)Cl2 (5 mol %) as
the catalyst system gave the arylated indazole in high yield.13
To our knowledge, no example of palladium-catalysed direct
arylation using halopyridines substituted by acetyl, nitrile, nitro or
amino group has been reported. Therefore, the discovery of more
effective conditions, for the direct coupling of a wider variety of
functionalised halopyridines with various heteroarenes, could be
a considerable advantage for industrial applications and for sus-
tainable development. Here, we wish to report on the palladium-
catalysed direct arylation at C5 of a set of functionalised bromo-
pyridines using a wide variety of heteroarenes.
S
N
2
O
2
3
91
90
S
S
N
3
O
S
CN
S
N
CN
4
O
4
5
88
93
S
Cl
S
N
Cl
O
5
O
2. Results and discussion
O
S
S
N
For this study, based onpreviousresults,14 DMAc was chosen as the
solvent and KOAc as the base. The reactions were performed at 150 ꢀC
under argon in the presence 1 mol % PdCl(C3H5)(dppb) as the catalyst.
However, using these conditions, the coupling of methyl 5-
bromonicotinate with 2-iso-butylthiazole gave 1 in a low 18% yield
due totheformationofseveralunidentifiedside-products(Scheme2).
O
O
6
Cl
Cl
O
6
90
S
S
N
O
O
7
N
O
N
S
PdCl(C3H5)(dppb)
1 mol%
MeO2C
7
8
89
78
+
O
S
MeO2C
DMAc, KOAc,
150 °C, 20 h
O
N
8
1 18%
N
Br
N
O
CO2Me
CO2Me
Scheme 2.
O
O
N
9
On the other hand, the reaction of 3-bromo-5-acetylpyridine with
2-iso-butylthiazole was found to be very selective and 2 was almost
obtained in quantitative yield (Table 1, entry 1). Then, several
substituted thiophene derivatives were coupled with 3-bromo-5-
acetylpyridine. From 2-methylthiophene, thiophene-2-carbonitrile,
2-chlorothiophene, 2-methyl-2-thiophen-2-yl-[1,3]dioxolane or 4-
chloro-2-acetylthiophene the desired products 3e7 were obtained
in very high yields (Table 1, entries 2e6). It should be noted that no
cleavage of the CeCl bond was observed in the course of the reaction
with 2-chlorothiophene or 4-chloro-2-acetylthiophene allowing
further transformations. Two 2-substituted furan derivatives
were also reacted with 3-bromo-5-acetylpyridine. From 2-n-
butylthiophene, 8 was isolated in 89% yield (Table 1, entry 7). A lower
yield in 9 was obtained with methyl 2-methylfuran-3-carboxylate
due to the formation of side-products (Table 1, entry 8). Finally, the
O
9
76a
N
N
N
10
Conditions: PdCl(C3H5)(dppb) 1 mol %, 3-bromo-5-acetylpyridine (1 equiv), heter-
oaromatic (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 20 h.
a
1-Methylpyrrole: 4 equiv.
useof4equivof1-methylpyrroleallowedtheformationonthemono-
arylated pyrrole 10 in 76% yield (Table 1, entry 9). Using these con-
ditions, only trace amounts of di-arylated pyrrole were detected.
3-Bromo-5-cyanopyridine was also found to be a reactive sub-
strate, and in most cases, almost quantitative yields of coupling
products were obtained (Table 2). For example, from thiophenes

S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
7657
Table 2
substituted at C2 by methyl, nitrile, chloro, acetyl or a protected
Palladium-catalysed reaction of 3-bromo-5-cyanopyridine with heteroaromatics
acetyl, the products 12e17 were obtained in 71e94% yields (Table 2,
entries 2e7). Four furan derivatives were also employed, and in all
cases, the desired products 18e21 were also obtained in high yields
(Table 2, entries 8e11). Pyrroles substituted at C2 by ester, formyl or
acetyl substituents gave selectively the C5 arylated pyrroles 23e25
in 80e85% yields (Table 2, entries 13e15). Finally, 3,5-
dimethylisoxazole was employed, and the C4 arylated product 26
was obtained in 82% yield (Table 2, entry 16).
Y
R
Y
PdCl(C3H5)(dppb)
1 mol%
R
Z
NC
+
Z
NC
DMAc, KOAc,
150 °C, 20 h
11-26
N
Br
N
Our initial attempts to arylate 2-iso-butylthiazole with 3-
bromo-6-nitropyridine were unsuccessful. Full consumption of
pyridyl bromide was observed, but the desired coupling product 27
was not detected by GC/MS analysis and the 1H NMR spectrum of
the crude mixture revealed decomposition of the reactants.
Therefore, we performed the reaction at lower temperatures. At
120 ꢀC, product 27 was detected, but the formation of some side-
products was still observed. On the other hand, at 100 ꢀC a clean
reaction was observed, and 27 was isolated in 76% yield (Scheme 3).
Entry
1
Heteroarene
Product
Yield (%)
92
NC
N
S
N
S
N
11
NC
2
3
94
80
S
S
N
12
N
NC
N
PdCl(C3H5)(dppb)
S
1 mol%
S
+
CN
S
S
N
CN
DMAc, KOAc,
100 °C, 20 h
13
O2N
27 76%
N
O2N
Br
NC
N
4
5
71
91
Scheme 3.
S
Cl
S
N
Cl
14
NC
With 3-bromo-6-fluoropyridine, good yields of products 28e30
were obtained in the presence of 2-iso-butylthiazole, 2-
chlorothiophene or 4-chloro-2-acetylthiophene (Table 3). Again, no
cleavageoftheCeClbondsof thethiophenederivativeswasobserved.
The presence of electron-donating groups on the bromopyr-
idines was also examined. With 3-bromo-6-methoxypyridine and
2-iso-butylthiazole as the coupling partners, a good yield of 68% in
31 was obtained (Table 4, entry 1). On the other hand, the coupling
of this deactivated pyridyl bromide with thiophene-2-carbonitrile,
2-chlorothiophene or 2-methyl-2-thiophen-2-yl-[1,3]dioxolane led
to moderate yields of 32e34 due to a partial consumption of this
reactant (Table 4, entries 2e4). With this catalyst, the oxidative
addition of 3-bromo-6-methoxypyridine to palladium is probably
the rate-limiting step of the reaction.
O
S
O
S
N
O
O
15
NC
6
7
87
71
S
S
N
O
O
16
Cl
S
NC
Cl
S
N
O
O
17
Some examples of direct arylation reactions using hetero-
arenes14,15 or haloanilines16 bearing free-NH2 substituents have been
reported in recent years. On the other hand, to our knowledge, direct
arylations using unprotected haloaminopyridines have not been de-
scribed. The direct use of pyridines bearing unprotected amine sub-
stituents would be useful in organic synthesis since it would allow to
avoid the protection/deprotection sequence. We examined the re-
activity of a bromopyridine substituted at C2 by a free-NH2 (Table 5).
Again, moderate yields in 35e37 were obtained due to a partial con-
sumption of the pyridyl bromide. However, it should be noted that no
amination products were produced in the course of these reactions.
In summary, we have demonstrated that the direct arylation of
heteroaromatics can be performed with a variety of functionalised
pyridyl bromides using 1 mol % PdCl(C3H5)(dppb) as the catalyst.
Electron-withdrawing substituent on the pyridyl moiety, such as
acetyl or nitrile favours the reaction; whereas electron-donating
substituents are unfavourable. However, a bromopyridine bearing
a free-NH2 substituent led to the desired coupling products, with-
out formation of amination products, in the presence of the most
reactive heteroarenes. It should be noted that, despite their in-
terest, most of the products prepared by this method are new, in-
dicating a relatively limited access to such compounds using more
traditional cross-coupling procedures. This procedure employs
a relatively low loading (1 mol %) of commercially available and air
NC
NC
8
9
74
81
O
O
N
N
18
19
O
O
O
O
NC
10
11
12
84
80
OAc
O
O
OAc
O
N
20
NC
CO2Me
CO2Me
O
N
21
NC
81a
N
N
N
22
(continued on next page)

7658
S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
Table 2 (continued )
Table 4
Palladium-catalysed reaction of 3-bromo-6-methoxypyridine with heteroaromatics
Entry
Heteroarene
Product
Yield (%)
84
Y
R
NC
Y
PdCl(C3H5)(dppb)
1 mol%
R
S
+
13
N
CO2Me
S
N
N
DMAc, KOAc,
150 °C, 20 h
CO2Me
MeO
23
31-34
N
MeO
Br
N
NC
14
15
16
85
80
82
Entry
1
Heteroarene
Product
Yield (%)
68
O
N
O
N
N
N
N
24
MeO
N
S
S
N
NC
31
O
N
O
N
MeO
MeO
25
2
3
4
58
55
58
S
S
N
CN
CN
32
NC
N
O
N
O
N
26
S
S
N
Cl
O
Cl
33
Conditions: PdCl(C3H5)(dppb) 1 mol %, 3-bromo-5-cyanopyridine (1 equiv), heter-
oaromatic (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 20 h.
MeO
S
N
O
a
S
1-Methylpyrrole: 4 equiv.
O
O
34
stable phosphine ligand and palladium source. There is no need to
prepare organometallic derivatives of heteroarenes or of func-
tionalised pyridyl derivatives, which is sometimes tricky. Moreover,
a wide variety of pyridyl bromides and heteroarenes are commer-
cially available. These are the practical advantages of this reaction.
Conditions: PdCl(C3H5)(dppb) 1 mol %, 3-bromo-6-acetylpyridine (1 equiv), heter-
oaromatic (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 20 h.
Commercial bromopyridines and heteroarenes were used without
purification. The reactions were followed by GC and NMR spec-
troscopic analysis. 1H and 13C spectra were recorded with Bruker
400 and 500 MHz spectrometers. Chemical shifts are reported in
3. Experimental
3.1. General remarks
parts per million relative to CDCl3 (7.25 for 1H NMR and 77.0 for 13
C
All reactions were run under argon in Schlenk tubes using
vacuum lines. DMAc (analytical grade) and KOAc (99%) were used.
NMR). Flash chromatography was performed on silica gel
Table 3
Table 5
Palladium-catalysed reaction of 3-bromo-6-fluoropyridine with heteroaromatics
Palladium-catalysed reaction of 2-amino-5-bromopyridine with heteroaromatics
Y
R
Y
R
Y
PdCl(C3H5)(dppb)
1 mol%
R
S
+
Y
PdCl(C3H5)(dppb)
1 mol%
R
S
+
S
DMAc, KOAc,
150 °C, 20 h
S
DMAc, KOAc,
150 °C, 20 h
F
28-30
N
H2N
F
Br
35-37
N
H2N
Br
N
N
Entry
1
Heteroarene
Product
Yield (%)
Entry
1
Heteroarene
Product
Yield (%)
65
N
S
N
S
F
77
68
75
N
S
N
N
H2N
H2N
28
S
N
N
35
F
2
3
S
S
N
Cl
Cl
2
3
60
62
29
S
S
36
Cl
Cl
Cl
Cl
F
O
S
O
S
N
H2N
O
S
O
N
S
30
37
Conditions: PdCl(C3H5)(dppb) 1 mol %, 3-bromo-6-fluoropyridine (1 equiv), heter-
oaromatic (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 20 h.
Conditions: PdCl(C3H5)(dppb) 1 mol %, 2-amino-5-bromopyridine (1 equiv), het-
eroaromatic (2 equiv), KOAc (2 equiv), DMAc, 150 ꢀC, 20 h.

S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
7659
(230e400 mesh). Yields quoted are isolated yields following flash
chlorothiophene (0.238 g, 2 mmol), product 5 was obtained in
chromatography.
88% (0.209 g) yield.
1H NMR (400 MHz, CDCl3)
d 8.98 (s, 1H), 8.86 (s, 1H), 8.21 (s, 1H),
3.2. Preparation of the PdCl(C3H5)(dppb) catalyst17
7.15 (d, J¼3.8 Hz, 1H), 6.89 (d, J¼3.8 Hz, 1H), 2.61 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d 196.2, 150.0, 148.5, 137.6, 132.3, 131.6, 131.5,
An oven-dried 40 mL Schlenk tube equipped with a magnetic
stirring bar under argon atmosphere, was charged with [Pd(C3H5)
Cl]2 (182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). 10 mL of
anhydrous dichloromethane were added, then, the solution was
stirred at room temperature for 20 min. The solvent was removed
in vacuo. The yellow powder was used without purification. 31P
130.0, 127.5, 124.4, 26.8. Elemental analysis: calcd (%) for
C11H8ClNOS (237.71): C 55.58, H 3.39; found: C 55.51, H 3.28.
3.3.6. 1-{5-[5-(2-Methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-pyridin-
3-yl}-ethanone (6). From 3-bromo-5-acetylpyridine (0.200 g,
1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g,
2 mmol), product 5 was obtained in 93% (0.269 g) yield.
NMR (81 MHz, CDCl3)
d
¼19.3 (s).
1H NMR (400 MHz, CDCl3)
d
8.99 (s, 1H), 8.94 (s, 1H), 8.30 (s, 1H),
7.22(s,1H), 7.03 (s,1H), 4.06e3.95(m, 4H), 2.63(s, 3H),1.76 (s, 3H).13C
NMR (100 MHz, CDCl3) 196.4, 150.3, 149.3, 148.3, 138.6, 132.2, 131.8,
3.3. General procedure
d
In a typical experiment, the bromopyridine (1 mmol), hetero-
aromatic derivative (2 mmol), KOAc (0.196 g, 2 mmol) and
PdCl(C3H5)(dppb) (6.8 mg, 0.01 mmol), were dissolved in DMAc
(4 mL) under an argon atmosphere. The reaction mixture was
stirred at 100 ꢀC or 150 ꢀC (see schemes) for 20 h. After evaporation
of the solvent, the product was purified by silica gel column
chromatography.
130.7,125.4,124.9,107.0, 65.1, 27.4, 26.9. Elemental analysis: calcd (%)
for C15H15NO3S (289.35): C 62.26, H 5.23; found: C 62.14, H 5.17.
3.3.7. 1-[5-(5-Acetylpyridin-3-yl)-4-chlorothiophen-2-yl]-ethanone
(7). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and 4-
chloro-2-acetylthiophene (0.321 g,
obtained in 90% (0.251 g) yield.
2 mmol), product 7 was
1H NMR (400 MHz, CDCl3)
d
9.12 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H),
7.56 (s, 1H), 2.63 (s, 3H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3)
195.9, 189.5, 152.6, 149.8, 142.7, 139.3, 135.3, 133.5, 132.0, 128.0,
3.3.1. Methyl 5-(2-isobutylthiazol-5-yl)-nicotinate (1). From methyl
5-bromonicotinate (0.216 g, 1 mmol) and 2-iso-butylthiazole
(0.282 g, 2 mmol), product 1 was obtained in 18% (0.050 g) yield.
d
123.8, 26.9, 26.4. Elemental analysis: calcd (%) for C13H10ClNO2S
(279.74): C 55.82, H 3.60; found: C 55.99, H 3.51.
1H NMR (400 MHz, CDCl3)
d 9.12 (s, 1H), 8.94 (s, 1H), 8.39 (s, 1H),
7.94 (s, 1H), 3.98 (s, 3H), 2.91 (d, J¼7.5 Hz, 2H), 2.16 (m, 1H), 1.02 (d,
J¼7.5 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
171.6, 166.8, 150.8, 149.7,
3.3.8. 1-[5-(5-Butylfuran-2-yl)-pyridin-3-yl]-ethanone (8). From 3-
bromo-5-acetylpyridine (0.200 g, 1 mmol) and 2-n-butylfuran
(0.248 g, 2 mmol), product 8 was obtained in 89% (0.216 g) yield.
139.4, 134.4, 132.5, 127.9, 126.2, 52.6, 42.6, 29.8, 22.3. Elemental
analysis: calcd (%) for C14H16N2O2S (276.36): C 60.85, H 5.84; found:
C 60.97, H 5.74.
1H NMR (400 MHz, CDCl3)
d 9.01 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H),
6.72 (s, 1H), 6.11 (s, 1H), 2.69 (t, J¼7.6 Hz, 2H), 2.65 (s, 3H), 1.67 (m,
3.3.2. 1-[5-(2-Isobutylthiazol-5-yl)-pyridin-3-yl]-ethanone
(2). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and 2-iso-
butylthiazole (0.282 g, 2 mmol), product 2 was obtained in 94%
(0.244 g) yield.
2H), 1.41 (m, 2H), 0.94 (t, J¼7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
196.8, 158.3, 148.4, 148.1, 147.3, 132.1, 129.2, 127.4, 108.4, 107.4,
30.1, 27.8, 26.9, 22.3, 13.8. Elemental analysis: calcd (%) for
C15H17NO2 (243.30): C 74.05, H 7.04; found: C 74.15, H 7.00.
1H NMR (400 MHz, CDCl3)
d 9.00 (s, 1H), 8.89 (s, 1H), 8.25 (s, 1H),
7.89 (d, J¼3.6 Hz, 1H), 2.85 (d, J¼7.6 Hz, 2H), 2.61 (s, 3H), 2.10 (m,
3.3.9. Methyl 5-(5-acetylpyridin-3-yl)-2-methylfuran-3-carboxylate
(9). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and
methyl 2-methylfuran-3-carboxylate (0.280 g, 2 mmol), product 9
1H), 0.96 (d, J¼7.6 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
195.2, 170.6,
149.9, 147.8, 138.5, 132.5, 131.7, 131.3, 127.3, 41.6, 28.8, 25.8, 21.2.
Elemental analysis: calcd (%) for C14H16N2OS (260.36): C 64.58, H
6.19; found: C 64.41, H 6.27.
was obtained in 78% (0.202 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.97 (s, 2H), 8.35 (s, 1H), 7.01 (s, 1H),
3.80 (s, 3H), 2.62 (s, 6H). 13C NMR (100 MHz, CDCl3)
d
196.4, 163.9,
3.3.3. 1-[5-(5-Methylthiophen-2-yl)-pyridin-3-yl]-ethanone
(3). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and 2-
methylthiophene (0.196 g, 2 mmol), product 3 was obtained in
91% (0.197 g) yield.
160.2, 148.6, 148.3, 147.8, 132.1, 129.8, 126.3, 115.6, 108.1, 51.6, 26.8,
13.9. Elemental analysis: calcd (%) for C14H13NO4 (259.26): C 64.86,
H 5.05; found: C 65.02, H 5.17.
1H NMR (400 MHz, CDCl3)
d
8.97 (s, 1H), 8.94 (s, 1H), 8.29 (s, 1H),
7.22 (d, J¼3.8 Hz, 1H), 6.78 (d, J¼3.8 Hz, 1H), 2.65 (s, 3H), 2.52 (s,
3H). 13C NMR (100 MHz, CDCl3)
196.6, 150.1, 147.8, 141.8, 136.6,
3.3.10. 1-[5-(1-Methylpyrrol-2-yl)-pyridin-3-yl]-ethanone
(10). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and 1-
methylpyrrole (0.324 g, 4 mmol), product 10 was obtained in 76%
(0.152 g) yield.
d
132.2, 131.3, 130.9, 126.7, 125.0, 26.8, 15.4. Elemental analysis: calcd
(%) for C12H11NOS (217.29): C 66.33, H 5.10; found: C 66.50, H 5.01.
1H NMR (400 MHz, CDCl3)
d
8.99 (s, 1H), 8.78 (s, 1H), 8.16 (s, 1H),
6.73 (s, 1H), 6.30 (s, 1H), 6.18 (s, 1H), 3.64 (s, 3H), 2.60 (s, 3H). 13C
NMR (100 MHz, CDCl3) 196.6, 152.7, 147.5, 134.2, 131.9, 129.7,
3.3.4. 5-(5-Acetylpyridin-3-yl)-thiophene-2-carbonitrile (4). From
3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and thiophene-2-
carbonitrile (0.218 g, 2 mmol), product 4 was obtained in 90%
(0.205 g) yield.
d
129.4,125.5,110.5,108.5, 35.2, 26.8. Elemental analysis: calcd (%) for
C12H12N2O (200.24): C 71.98, H 6.04; found: C 72.19, H 5.84.
1H NMR (400 MHz, CDCl3)
d
9.08 (s, 1H), 8.97 (s, 1H), 8.33 (s, 1H),
3.3.11. 5-(2-Isobutylthiazol-5-yl)-nicotinonitrile
(11). From
3-
7.60 (d, J¼3.8 Hz, 1H), 7.38 (d, J¼3.8 Hz, 1H), 2.63 (s, 3H). 13C NMR
bromo-5-cyanopyridine (0.183 g, 1 mmol) and 2-iso-butylthiazole
(0.282 g, 2 mmol), product 11 was obtained in 92% (0.224 g) yield.
(100 MHz, CDCl3)
d 194.8, 149.6, 149.0, 145.2, 137.5, 131.7, 131.4,
127.7, 124.2, 112.6, 109.5, 25.9. Elemental analysis: calcd (%) for
C12H8N2OS (228.27): C 63.14, H 3.53; found: C 63.22, H 3.67.
1H NMR (400 MHz, CDCl3)
d
8.91 (s, 1H), 8.72 (s, 1H), 7.99 (s, 1H),
7.89 (s, 1H), 2.88 (d, J¼7.5 Hz, 2H), 2.10 (m, 1H), 1.01 (d, J¼7.6 Hz,
6H). 13C NMR (100 MHz, CDCl3)
172.5, 150.8, 150.3, 140.1, 136.1,
d
3.3.5. 1-[5-(5-Chlorothiophen-2-yl)-pyridin-3-yl]-ethanone
(5). From 3-bromo-5-acetylpyridine (0.200 g, 1 mmol) and 2-
132.1, 128.5, 116.0, 110.4, 42.6, 29.8, 22.3. Elemental analysis: calcd
(%) for C13H13N3S (243.33): C 64.17, H 5.38; found: C 64.25, H 5.24.

7660
S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
3.3.12. 5-(5-Methylthiophen-2-yl)-nicotinonitrile (12). From 3-
bromo-5-cyanopyridine (0.183 g, 1 mmol) and 2-methylthiophene
(0.196 g, 2 mmol), product 12 was obtained in 94% (0.188 g) yield.
3.3.19. 5-(5-Butyrylfuran-2-yl)-nicotinonitrile (19). From 3-bromo-
5-cyanopyridine (0.183 g, 1 mmol) and 1-(furan-2-yl)butan-1-one
(0.276 g, 2 mmol), product 19 was obtained in 81% (0.195 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.89 (s, 1H), 8.62 (s, 1H), 7.94 (s, 1H),
1H NMR (400 MHz, CDCl3)
d 9.12 (s, 1H), 8.76 (s, 1H), 8.26 (s, 1H),
7.16 (d, J¼3.6 Hz, 1H), 6.74 (d, J¼3.6 Hz, 1H), 2.47 (s, 3H). 13C NMR
7.22 (d, J¼3.3 Hz, 1H), 6.93 (d, J¼3.3 Hz, 1H), 2.81 (t, J¼7.5 Hz, 2H),
(100 MHz, CDCl3)
d 150.0, 149.7, 143.2, 135.3, 135.0, 131.2, 127.2,
1.73 (m, 2H), 0.96 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
126.0, 116.7, 110.3, 15.7. Elemental analysis: calcd (%) for C11H8N2S
(200.26): C 65.97, H 4.03; found: C 66.17, H 4.18.
d 189.1, 153.2, 151.5, 151.4, 148.9, 134.4, 125.8, 118.3, 115.9, 110.3,
110.2, 40.4, 17.6, 13.7. Elemental analysis: calcd (%) for C14H12N2O2
(240.26): C 69.99, H 5.03; found: C 69.89, H 5.14.
3.3.13. 5-(5-Cyanothiophen-2-yl)-nicotinonitrile (13). From 3-bromo-
5-cyanopyridine (0.183 g, 1 mmol) and thiophene-2-carbonitrile
(0.218 g, 2 mmol), product 13 was obtained in 80% (0.169 g) yield.
3.3.20. Acetic acid 5-(5-cyanopyridin-3-yl)-furan-2-ylmethyl ester
(20). From 3-bromo-5-cyanopyridine (0.183 g, 1 mmol) and fur-
furyl acetate (0.280 g, 2 mmol), product 20 was obtained in 84%
(0.203 g) yield.
1H NMR (400 MHz, CDCl3)
d 8.98 (s, 1H), 8.82 (s, 1H), 8.06 (s, 1H),
7.62 (d, J¼3.6 Hz, 1H), 7.35 (d, J¼3.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3)
d
152.2, 150.2, 144.4, 138.6, 136.3, 128.8, 125.8, 115.7, 113.2,
1H NMR (400 MHz, CDCl3)
d
9.01 (s, 1H), 8.76 (s, 1H), 8.13 (s, 1H),
6.77 (s, 1H), 6.50 (s, 1H), 5.05 (s, 2H), 2.05 (s, 3H). 13C NMR
(100 MHz, CDCl3) 170.5, 151.5, 150.3, 149.1, 148.2, 133.5, 126.7,
111.5, 110.7. Elemental analysis: calcd (%) for C11H5N3S (211.24): C
62.54, H 2.39; found: C 62.67, H 2.30.
d
116.3, 113.0, 110.2, 109.3, 57.8, 20.8. Elemental analysis: calcd (%) for
C13H10N2O3 (242.23): C 64.46, H 4.16; found: C 64.28, H 4.29.
3.3.14. 5-(5-Chlorothiophen-2-yl)-nicotinonitrile
(14). From 3-
bromo-5-cyanopyridine (0.183 g, 1 mmol) and 2-chlorothiophene
(0.238 g, 2 mmol), product 14 was obtained in 71% (0.157 g) yield.
3.3.21. Methyl 5-(5-cyanopyridin-3-yl)-2-methylfuran-3-carboxylate
(21). From 3-bromo-5-cyanopyridine (0.183 g, 1 mmol) and methyl
2-methylfuran-3-carboxylate (0.280 g, 2 mmol), product 21 was
obtained in 80% (0.193 g) yield.
1H NMR (400 MHz, CDCl3)
d 8.94 (s, 1H), 8.76 (s, 1H), 8.00 (s, 1H),
7.19 (d, J¼3.6 Hz, 1H), 6.98 (d, J¼3.6 Hz, 1H). 13C NMR (100 MHz,
CDCl3)
d 150.6, 149.5, 136.0, 135.1, 132.6, 130.1, 127.8, 125.2, 116.1,
110.3. Elemental analysis: calcd (%) for C10H5ClN2S (220.68): C
54.43, H 2.28; found: C 54.51, H 2.10.
1H NMR (400 MHz, CDCl3)
d
9.04 (s, 1H), 8.73 (s, 1H), 8.13 (s, 1H),
7.09 (s, 1H), 3.85 (s, 3H), 2.66 (s, 3H). 13C NMR (100 MHz, CDCl3)
163.6, 160.8, 150.2, 147.9, 146.4, 133.2, 126.4, 116.2, 115.8, 110.2,
d
3.3.15. 5-[5-(2-Methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-nic-
otinonitrile (15). From 3-bromo-5-cyanopyridine (0.183 g, 1 mmol)
and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g, 2 mmol),
product 15 was obtained in 91% (0.248 g) yield.
109.2, 51.7, 13.9. Elemental analysis: calcd (%) for C13H10N2O3
(242.23): C 64.46, H 4.16; found: C 64.53, H 4.10.
3.3.22. 5-(1-Methylpyrrol-2-yl)-nicotinonitrile (22). From 3-bromo-
5-cyanopyridine (0.183 g, 1 mmol) and 1-methylpyrrole (0.324 g,
4 mmol), product 22 was obtained in 81% (0.148 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.93 (s, 1H), 8.68 (s, 1H), 8.00 (s, 1H),
7.20 (d, J¼3.6 Hz, 1H), 7.02 (d, J¼3.6 Hz, 1H), 3.98 (m, 4H), 1.73 (s,
3H). 13C NMR (100 MHz, CDCl3)
150.0, 149.9, 149.4, 136.6, 134.9,
d
1H NMR (400 MHz, CDCl3)
d
8.79 (s, 1H), 8.69 (s, 1H), 7.88 (s, 1H),
6.75 (s,1H), 6.30 (s,1H), 6.18 (s,1H), 3.64 (s, 3H). 13C NMR (100 MHz,
CDCl3) 152.0, 149.6, 137.5, 129.6, 128.4, 126.3, 116.5, 111.4, 109.8,
130.5, 125.3, 125.2, 115.9, 109.9, 106.5, 64.8, 27.1. Elemental analysis:
calcd (%) for C14H12N2O2S (272.32): C 61.75, H 4.44; found: C 61.89,
H 4.67.
d
108.9, 35.3. Elemental analysis: calcd (%) for C11H9N3 (183.21): C
72.11, H 4.95; found: C 72.34, H 5.14.
3.3.16. 5-(5-Acetylthiophen-2-yl)-nicotinonitrile
(16). From
3-
bromo-5-cyanopyridine (0.183 g, 1 mmol) and 2-acetylthiophene
3.3.23. Methyl 5-(5-cyanopyridin-3-yl)-1-methylpyrrole-2-
carboxylate (23). From 3-bromo-5-cyanopyridine (0.183 g,
1 mmol) and methyl 1-methyl-2-pyrrolecarboxylate (0.278 g,
2 mmol) product 23 was obtained in 84% (0.202 g) yield.
(0.252 g, 2 mmol), product 16 was obtained in 87% (0.198 g) yield.
1H NMR (400 MHz, CDCl3)
d 9.02 (s, 1H), 8.78 (s, 1H), 8.10 (s, 1H),
7.65 (d, J¼3.6 Hz, 1H), 7.37 (d, J¼3.6 Hz, 1H), 2.53 (s, 3H). 13C NMR
(100 MHz, CDCl3)
d
190.3, 151.6, 150.1, 145.9, 145.0, 136.0, 133.2,
1H NMR (400 MHz, CDCl3)
d 8.86 (s, 2H), 7.97 (s, 1H), 7.03 (d,
129.9, 126.4, 115.9, 110.5, 26.7. Elemental analysis: calcd (%) for
C12H8N2OS (228.27): C 63.14, H 3.53; found: C 63.01, H 3.41.
J¼3.7 Hz, 1H), 6.31 (d, J¼3.7 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H). 13C
NMR (100 MHz, CDCl3)
d 161.6, 152.8, 151.0, 138.9, 134.9, 128.6,
125.5, 117.9, 116.1, 111.0, 110.0, 51.4, 34.4. Elemental analysis: calcd
(%) for C13H11N3O2 (241.25): C 64.72, H 4.60; found: C 64.89, H 4.51.
3.3.17. 5-(5-Acetyl-3-chlorothiophen-2-yl)-nicotinonitrile
(17). From 3-bromo-5-cyanopyridine (0.183 g, 1 mmol) and 4-
chloro-2-acetylthiophene (0.321 g,
obtained in 71% (0.186 g) yield.
2
mmol), product
7
was
3.3.24. 5-(5-Formyl-1-methylpyrrol-2-yl)-nicotinonitrile (24). From
3-bromo-5-cyanopyridine (0.183 g, 1 mmol) and 1-methyl-2-
formylpyrrole (0.219 g, 2 mmol), product 24 was obtained in 85%
(0.179 g) yield.
1H NMR (400 MHz, CDCl3)
d
9.02 (s, 1H), 8.85 (s, 1H), 8.23 (s, 1H),
7.56 (s, 1H), 2.52 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
189.3, 152.2,
152.1, 143.4, 138.6, 137.4, 133.4, 128.2, 124.4, 115.8, 110.3, 26.4. Ele-
mental analysis: calcd (%) for C12H7ClN2OS (262.72): C 54.86, H
2.69; found: C 54.93, H 2.47.
1H NMR (400 MHz, CDCl3)
d
9.64 (s, 1H), 8.89 (s, 2H), 8.01 (s, 1H),
7.01 (s, 1H), 6.41 (s, 1H), 3.94 (s, 3H). 13C NMR (100 MHz, CDCl3)
180.2, 152.7, 151.6, 139.0, 137.3, 134.2, 127.8, 124.2, 115.9, 112.2,
d
110.2, 34.9. Elemental analysis: calcd (%) for C12H9N3O (211.22): C
68.24, H 4.29; found: C 68.11, H 4.13.
3.3.18. 5-(5-Butylfuran-2-yl)-nicotinonitrile (18). From 3-bromo-5-
cyanopyridine (0.183 g, 1 mmol) and 2-n-butylfuran (0.248 g,
2 mmol), product 18 was obtained in 74% (0.167 g) yield.
3.3.25. 5-(5-Acetyl-1-methylpyrrol-2-yl)-nicotinonitrile (25). From
3-bromo-5-cyanopyridine (0.183 g, 1 mmol) and 1-methyl-2-
acetylpyrrole (0.246 g, 2 mmol), product 25 was obtained in 80%
(0.180 g) yield.
1H NMR (400 MHz, CDCl3)
d 9.01 (s, 1H), 8.65 (s, 1H), 8.10 (s, 1H),
6.75 (s, 1H), 6.13 (s, 1H), 2.70 (d, J¼7.5 Hz, 3H), 1.70e1.65 (m, 2H),
1.45e1.35 (m, 2H), 0.95 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d
159.1, 149.3, 147.7, 146.7, 132.6, 127.3, 116.5, 110.0, 109.4, 107.7, 30.0,
1H NMR (400 MHz, CDCl3)
d 8.81 (s, 2H), 7.92 (s, 1H), 6.99 (d,
27.8, 22.2, 13.7. Elemental analysis: calcd (%) for C14H14N2O
(226.27): C 74.31, H 6.24; found: C 74.50, H 6.32.
J¼3.7 Hz, 1H), 6.26 (d, J¼3.7 Hz, 1H), 3.84 (s, 3H), 2.43 (s, 3H). 13C
NMR (100 MHz, CDCl3)
d 189.1, 152.8, 151.3, 139.0, 136.0, 133.3,

S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
7661
128.4, 119.6, 116.0, 111.0, 110.1, 35.2, 27.6. Elemental analysis: calcd
(%) for C13H11N3O (225.25): C 69.32, H 4.92; found: C 69.47, H 4.40.
3.3.32. 5-(6-Methoxypyridin-3-yl)-thiophene-2-carbonitrile
(32). From 3-bromo-6-methoxypyridine (0.188 g, 1 mmol) and
thiophene-2-carbonitrile (0.218 g, 2 mmol), product 32 was
obtained in 58% (0.125 g) yield.
3.3.26. 5-(3,5-Dimethylisoxazol-4-yl)-nicotinonitrile (26). From 3-
bromo-5-cyanopyridine (0.183 g,
1
mmol) and 3,5-dimethy
1H NMR (500 MHz, CDCl3)
d
8.45 (d, J¼2.5 Hz, 1H), 7.78 (dd,
lisoxazole (0.194 g, 2 mmol), product 26 was obtained in 82%
J¼8.4, 2.5 Hz, 1H), 7.61 (d, J¼3.8 Hz, 1H), 7.21 (d, J¼3.8 Hz, 1H), 6.83
(0.163 g) yield.
(d, J¼8.4 Hz, 1H), 4.00 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 164.7,
1H NMR (400 MHz, CDCl3)
d
8.87 (s, 1H), 8.73 (s, 1H), 7.85 (s, 1H),
148.3, 144.7, 138.4, 136.6, 123.0, 122.0, 114.2, 111.5, 108.1, 53.8. Ele-
mental analysis: calcd (%) for C11H8N2OS (216.26): C 61.09, H 3.73;
found: C 61.30, H 3.57.
2.45 (s, 3H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3)
d
166.9, 158.0,
152.9, 151.1, 138.9, 127.3, 116.1, 111.8, 110.4, 11.7, 10.7. Elemental
analysis: calcd (%) for C11H9N3O (199.21): C 66.32, H 4.55; found: C
66.21, H 4.50.
3.3.33. 5-(5-Chlorothiophen-2-yl)-2-methoxypyridine (33). From 3-
bromo-6-methoxypyridine (0.188 g,
1
mmol) and 2-
3.3.27. 1-Methyl-5-(6-nitropyridin-3-yl)-pyrrole-2-carbaldehyde
chlorothiophene (0.238 g, 2 mmol), product 33 was obtained in
(27). From 3-bromo-6-nitropyridine (0.203 g, 1 mmol) and 1-
55% (0.124 g) yield.
methyl-2-formylpyrrole (0.219 g,
obtained in 58% (0.134 g) yield.
2
mmol), product 27 was
1H NMR (400 MHz, CDCl3)
d
8.24 (s, 1H), 7.60 (d, J¼8.4 Hz,
1H), 6.89 (d, J¼3.8 Hz, 1H), 6.80 (d, J¼3.8 Hz, 1H), 6.69 (d,
1H NMR (400 MHz, CDCl3)
d
9.61 (s, 1H), 8.67 (s, 1H), 8.30 (d,
J¼8.4 Hz,1H), 8.02 (d, J¼8.4 Hz,1H), 6.98 (s,1H), 6.44 (s, 1H), 3.93 (s,
3H). 13C NMR (100 MHz, CDCl3)
180.3, 155.7, 148.5, 139.5, 137.3,
J¼8.4 Hz, 1H), 3.88 (s, 3H). 13C NMR (100 MHz, CDCl3)
d 163.7,
143.7, 139.3, 136.1, 128.9, 127.1, 123.4, 122.1, 111.1, 53.7. Elemental
analysis: calcd (%) for C10H8ClNOS (225.70): C 53.22, H 3.57;
found: C 53.40, H 3.68.
d
134.7, 133.0, 124.2, 118.0, 112.7, 34.6. Elemental analysis: calcd (%)
for C11H9N3O3 (231.21): C 57.14, H 3.92; found: C 57.23, H 3.99.
3.3.34. 2-Methoxy-5-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-
yl]-pyridine (34). From 3-bromo-6-methoxypyridine (0.188 g,
1 mmol) and 2-methyl-2-thiophen-2-yl-[1,3]dioxolane (0.340 g,
2 mmol), product 34 was obtained in 58% (0.161 g) yield.
3.3.28. 2-Fluoro-5-(2-isobutylthiazol-5-yl)-pyridine (28). From 3-
bromo-6-fluoropyridine (0.176 g, 1 mmol) and 2-iso-butylthiazole
(0.282 g, 2 mmol), product 28 was obtained in 77% (0.182 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.31 (s, 1H), 7.86 (t, J¼7.5 Hz, 1H),
1H NMR (400 MHz, CDCl3)
d
8.37 (s, 1H), 7.72 (d, J¼8.4 Hz,
7.75 (s, 1H), 6.91 (d, J¼8.4 Hz, 1H), 2.83 (d, J¼7.6 Hz, 2H), 2.07 (m,
1H), 7.03 (d, J¼3.8 Hz, 1H), 7.00 (d, J¼3.8 Hz, 1H), 6.74 72 (d,
1H), 0.96 (d, J¼7.6 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 170.9, 163.1
J¼8.4 Hz, 1H), 4.00 (m, 4H), 3.94 (s, 3H), 1.78 (s, 3H). 13C NMR
(d, J¼240.8 Hz), 145.2 (d, J¼15.1 Hz), 139.0 (d, J¼7.9 Hz), 138.7, 133.2,
126.0 (d, J¼4.8 Hz), 109.8 (d, J¼38.1 Hz), 42.5, 29.8, 22.2. Elemental
analysis: calcd (%) for C12H13FN2S (236.31): C 60.99, H 5.54; found:
C 61.12, H 5.68.
(100 MHz, CDCl3) d 163.2, 146.3, 143.4, 139.9, 135.9, 124.9, 123.7,
122.2, 110.6, 106.7, 64.6, 53.2, 27.1. Elemental analysis:
calcd (%) for C14H15NO3S (277.34): C 60.63, H 5.45; found: C
60.78, H 5.37.
3.3.29. 5-(5-Chlorothiophen-2-yl)-2-fluoropyridine (29). From 3-
bromo-6-fluoropyridine (0.176 g, 1 mmol) and 2-chlorothiophene
(0.238 g, 2 mmol), product 29 was obtained in 68% (0.145 g) yield.
3.3.35. 5-(4-Ethyl-2-methylthiazol-5-yl)-pyridin-2-ylamine
(35). From 2-amino-5-bromopyridine (0.173 g, 1 mmol) and 4-
ethyl-2-methylthiazole (0.254 g,
obtained in 65% (0.142 g) yield.
2 mmol), product 35 was
1H NMR (400 MHz, CDCl3)
d
8.34 (s, 1H), 7.85 (t, J¼7.5 Hz,
1H), 7.04 (d, J¼3.6 Hz, 1H), 6.94 (d, J¼8.4 Hz, 1H), 6.91 (d,
1H NMR (400 MHz, CDCl3)
d
8.06 (s, 1H), 7.40 (d, J¼8.2 Hz, 1H),
J¼3.6 Hz, 1H). 13C NMR (75 MHz, CDCl3)
d
162.9 (d, J¼240.8 Hz),
6.47 (d, J¼8.2 Hz, 1H), 4.49 (br s, 2H), 2.92 (q, J¼7.5 Hz, 2H), 2.34 (s,
144.3 (d, J¼15.1 Hz), 138.1 (d, J¼8.9 Hz), 137.5, 130.5, 127.9 (d,
J¼4.8 Hz), 127.3, 123.6, 109.8 (d, J¼38.2 Hz). Elemental analysis:
calcd (%) for C9H5ClFNS (213.66): C 50.59, H 2.36; found: C 50.41,
H 2.14.
3H), 1.32 (t, J¼7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 168.9, 156.6,
147.2, 146.0, 137.5, 126.7, 117.7, 107.1, 25.9, 14.8, 13.3. Elemental
analysis: calcd (%) for C11H13N3S (219.31): C 60.24, H 5.97; found: C
60.04, H 5.99.
3.3.30. 1-[4-Chloro-5-(6-fluoropyridin-3-yl)-thiophen-2-yl]-etha-
none (30). From 3-bromo-6-fluoropyridine (0.176 g, 1 mmol) and
4-chloro-2-acetylthiophene (0.321 g, 2 mmol), product 30 was
obtained in 75% (0.191 g) yield.
3.3.36. 5-(5-Methylthiophen-2-yl)-pyridin-2-ylamine (36). From 2-
amino-5-bromopyridine (0.173 g,
1 mmol) and 2-methylthi
ophene (0.196 g, 2 mmol), product 36 was obtained in 60%
(0.114 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.50 (s, 1H), 8.08 (t, J¼7.5 Hz, 1H),
1H NMR (400 MHz, CDCl3)
d
8.26 (s, 1H), 7.57 (d, J¼8.2 Hz, 1H),
6.93 (d, J¼3.0 Hz, 1H), 6.69 (d, J¼3.0 Hz, 1H), 6.50 (d, J¼8.2 Hz, 1H),
4.52 (br s, 2H), 2.48 (s, 3H). 13C NMR (100 MHz, CDCl3)
157.3,144.9,
139.0, 138.6, 135.4, 126.0, 121.8, 108.5, 15.3. Elemental analysis:
7.58 (s, 1H), 7.04 (d, J¼8.4 Hz, 1H), 2.55 (s, 3H). 13C NMR (100 MHz,
CDCl3)
d
189.5, 164.0 (d, J¼243.2 Hz), 147.5 (d, J¼16.0 Hz), 142.1,
d
141.2 (d, J¼8.8 Hz), 139.3, 133.4, 125.7 (d, J¼4.8 Hz), 123.2, 109.8 (d,
J¼38.2 Hz), 26.3. Elemental analysis: calcd (%) for C11H7ClFNOS
(255.70): C 51.67, H 2.76; found: C 51.60, H 2.79.
calcd (%) for C10H10N2S (190.27):
C 63.08, H 5.18.
C 63.13, H 5.30; found:
3.3.31. 5-(2-Isobutylthiazol-5-yl)-2-methoxypyridine (31). From 3-
bromo-6-methoxypyridine (0.188 g, 1 mmol) and 2-iso-butylth-
iazole (0.282 g, 2 mmol), product 31 was obtained in 68% (0.169 g)
yield.
3.3.37. 1-[5-(6-Aminopyridin-3-yl)-4-chlorothiophen-2-yl]-etha-
none (37). From 2-amino-5-bromopyridine (0.173 g, 1 mmol) and
4-chloro-2-acetylthiophene (0.321 g, 2 mmol), product 37 was
obtained in 62% (0.156 g) yield.
1H NMR (400 MHz, CDCl3)
d
8.25 (s, 1H), 7.65 (s, 1H), 7.64 (d,
1H NMR (400 MHz, CDCl3)
d
8.40 (s, 1H), 7.76 (d, J¼8.2 Hz,
1H), 7.54 (s, 1H), 6.55 (d, J¼8.2 Hz, 1H), 4.73 (br s, 2H), 2.52 (s,
3H). 13C NMR (100 MHz, CDCl3)
191.6, 160.0, 147.4, 142.7, 139.6,
137.9, 135.5, 120.8, 115.9, 108.9, 26.3. Elemental analysis: calcd
J¼8.4 Hz, 1H), 6.70 (d, J¼8.4 Hz, 1H), 3.88 (s, 3H), 2.80 (d, J¼7.6 Hz,
2H), 2.10 (m, 1H), 0.95 (d, J¼7.6 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d
d
169.6, 163.8, 139.4, 137.4, 136.8, 134.8, 121.3, 111.1, 53.6, 42.5, 29.8,
22.3. Elemental analysis: calcd (%) for C13H16N2OS (248.35): C 62.87,
H 6.49; found: C 62.86, H 6.69.
(%) for C11H9ClN2OS (252.72):
52.18, H 3.71.
C 52.28, H 3.59; found: C

7662
S. Bensaid, H. Doucet / Tetrahedron 68 (2012) 7655e7662
7. For recent examples of direct arylations of thiazoles: (a) Gottumukkala, A. L.;
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