Selective C-N bond-forming reaction of 2,6-dibromopyridine with amines

Article abstract of DOI:10.1002/ejoc.201402619

A practical and efficient protocol for the syntheses of 6-substituted 2-bromopyridine compounds has been developed by using a selective copper-catalyzed C-N bond-forming reaction between 2,6-dibromopyridine and a range of amines. The major advantage of this protocol is the complete control of selectivity of the pyridine bromine atom for the C-N cross-coupling reaction. There are few reported syntheses of unsymmetrical 2,6-disubstituted pyridine-bridged compounds because of their complicated preparations. Although this is the case, a new series of these unsymmetrical compounds have been successfully prepared in two steps by using this copper-catalyzed coupling approach. A practical protocol for the syntheses of 6-substituted 2-bromopyridine compounds has been developed by using a selective copper-catalyzed coupling reaction of 2,6-dibromopyridine with a range of amines.

Full text of DOI:10.1002/ejoc.201402619

FULL PAPER
DOI: 10.1002/ejoc.201402619
Selective C–N Bond-Forming Reaction of 2,6-Dibromopyridine with Amines
[a]
[a]
[a]
[a]
Lei Wang, Ning Liu,* Bin Dai,* and Hengcai Hu
Keywords: Synthetic methods / Nitrogen heterocycles / Cross-coupling / Copper / Amines
A practical and efficient protocol for the syntheses of 6-sub-
stituted 2-bromopyridine compounds has been developed by
coupling reaction. There are few reported syntheses of un-
symmetrical 2,6-disubstituted pyridine-bridged compounds
using a selective copper-catalyzed C–N bond-forming reac- because of their complicated preparations. Although this is
tion between 2,6-dibromopyridine and a range of amines.
The major advantage of this protocol is the complete control
of selectivity of the pyridine bromine atom for the C–N cross-
the case, a new series of these unsymmetrical compounds
have been successfully prepared in two steps by using this
copper-catalyzed coupling approach.
Introduction
organometallic catalysis, and advanced materials synthesis,
unsymmetrical 2,6-disubstituted pyridine-bridged com-
2,6-Disubstituted pyridine-bridged compounds have at- pounds are much less studied.
tracted much attention because of their widespread applica-
Recent research has shown that unsymmetrical 2,6-di-
[1]
tions in pharmaceutical synthesis, organometallic cataly- substituted pyridine-bridged compounds exhibit remark-
sis,[ and the field of advanced materials.[3] Generally, sym- able performance in pharmaceutical synthesis and orga-
2]
[6]
[
7]
metrical 2,6-disubstituted pyridine-bridged compounds are nometallic catalysis. Yu and co-workers reported the first
prepared by a classical copper-catalyzed C–N bond-form- example of a selective C–N bond-forming reaction for the
[
4]
ing reaction, but unsymmetrical compounds are difficult preparation of 2-bromo-6-(pyrazol-1-yl)pyridines by em-
to obtain (see Scheme 1). Consequently, it is no surprise ploying a palladium-catalyzed coupling reaction of 2,6-di-
[
8]
that copper-catalyzed coupling reactions with 2,6-dibromo- bromopyridine and pyrazoles. This method has been em-
pyridine have been developed to give symmetrical 2,6-di- ployed to construct a class of unsymmetrical pyridine-
[5]
substituted pyridine-bridged compounds. Despite the pre- bridged pyrazolyl-imidazolyl ligands that exhibit exception-
[
9]
valence of these compounds in pharmaceutical synthesis, ally high catalytic activity in the Suzuki reaction and the
Scheme 1. The C–N coupling of 2,6-dibromopyridine.
transfer hydrogenation of ketones.[10] Recently, Frech’s
[
a] School of Chemistry and Chemical Engineering,
Key Laboratory for Green Processing of Chemical Engineering group also developed a transition-metal-free approach for
of Xinjiang Bingtuan, Shihezi University,
North 4th Road, Shihezi, Xinjiang 832003, China
E-mail: ninglau@163.com;
[11]
the preparation of 6-bromopyridine-2-amines.
Buckley
and co-workers synthesized a series of imidazo[1,2-a]pyr-
idines, which are highly potent interleukin-1 receptor asso-
ciated kinase-4 (IRAK-4) inhibitors with good drug-like
dbinly@126.com
http://hglsgc.shzu.edu.cn/www/hgxy/index.shtml
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402619.
[
12]
properties.
However, these unsymmetrical 2,6-disubsti-
Eur. J. Org. Chem. 2014, 6493–6500
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6493

L. Wang, N. Liu, B. Dai, H. Hu
FULL PAPER
tuted pyridine-bridged compounds are typically prepared uct yield increased as the temperature increased from 70 to
by using a stoichiometric method or an expensive palla- 90 °C (see Table 1, Entries 1 and 2). However, with a tem-
dium catalyst, and, thus, these approaches result in low perature of 110 °C, the monosubstituted product rapidly
atom economy and high cost. Because unsymmetrical 2,6- converted into the disubstituted one (see Table 1, Entry 3).
disubstituted pyridine-bridged compounds are important At the higher temperature, the monosubstituted product
building blocks in pharmaceutical synthesis and organome- was prone to undergo a further C–N coupling to give 72%
tallic catalysis, there is an urgent need to seek an efficient, yield of the disubstituted product (see Table 1, Entry 3).
atom-economic, and inexpensive synthetic protocol to ob- The effect of using different solvents was also examined,
tain these compounds.
and DMSO was determined to be the optimal solvent (see
The copper-catalyzed cross-coupling reaction has more Table 1, Entries 4 vs. 5, 6, and 7).
than one hundred year history, and it is still actively em-
ployed in the field of organic synthesis as an efficient and
[
13]
versatile method.
2,6-Dibromopyridine contains two
bromo groups, and, therefore, some control in the selectivity
of the C–N cross-coupling reactions of this compound is
unavoidable. In classical synthetic methods, complete con-
trol of the selectivity of C–N bond formation with 2,6-di-
bromopyridine is a challenge (see Scheme 1). To the best
of our knowledge, there is no report of a copper-catalyzed
selective C–N cross-coupling reaction of 2,6-dibromopyr-
idine and amines to synthesize 6-substituted 2-bromo-
pyridines.
Table 1. Optimization of copper-catalyzed N-arylation.[a]
The presence of a ligand is important to the efficiency
and selectivity of a reaction. We have a long-standing inter-
est in the development of an efficient catalytic system to
resolve the problems of the selective C–N cross-coupling
reaction of 2,6-dibromopyridine. Inspired by Buchwald’s re-
[
14]
Entry Solvent Copper
L
Base
% Yield[b]
search, we tried a Cu-catalyzed C–N coupling reaction of
,6-dibromopyridine with amines. We found that the ligand 1[
c]
DMSO CuI
DMSO CuI
DMSO CuI
L
L
L
L
L
K
K
K
K
K
69 (8)
2
3
3
3
3
3
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
[
[
d]
e]
2
3
4
5
6
7
8
9
1
1
81 (13)
20 (72)
68 (9)
34 (trace)
37 (trace)
55 (6)
61 (17)
65 (13)
49 (8)
37 (11)
53 (13)
45 (15)
47 (28)
32 (12)
15 (trace)
27 (trace)
73 (12)
50 (26)
37 (47)
47 (8)
played an important role in the control of the selectivity
with regard to 2,6-dibromopyridine. When 1,2-ethanedi-
amine derivatives (L) were used as the ligand, the CuI/L/
dimethyl sulfoxide (DMSO) catalytic system showed high
selectivity in the coupling reaction of 2,6-dibromopyridine
to produce 6-substituted 2-bromopyridine compounds as
the major product. Therefore, in a copper-catalyzed cou-
pling reaction, the selectivity for the formation of a mono-
or disubstituted pyridine product depends on the appropri- 12
ate choice of a ligand.
Herein, we report an efficient protocol for the selective
construction of 6-substituted 2-bromopyridine compounds
by using a copper-catalyzed coupling approach. The gener- 17
DMSO CuI
[f]
DMF[
CuI
CuI
CuI
f]
f]
DMA[
L3
2
K CO
NMP
L
L
L
L
L
L
L
L
3
3
3
3
3
3
3
3
K
K
K
K
K
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
2
CO
DMSO CuCl
DMSO Cu
DMSO CuSO
DMSO Cu(OAc)
2
O
0
1
4
2
)
3 2
DMSO Cu(NO
DMSO CuO
DMSO Cu
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
DMSO CuI
1
1
1
1
3
4
5
6
none
L
L2
1
2
K CO
1
1
2
2
2
8
9
0
1
2
L
L
L
L
L
L
4
5
6
7
3
3
K
K
K
K
K
2
2
2
2
3
CO
CO
CO
CO
ation of these compounds provides access to a variety of
subsequent transformations. We envisage that the 6-substi-
tuted 2-bromopyridine compounds may be useful interme-
[
15]
diates in organic synthesis, such as in a Suzuki coupling,
PO
CO
4
44 (7)
[16]
a Heck coupling, a Sonogashira coupling,
an Ullmann- 23
Na
2
3
42 (trace)
38 (trace)
9 (53)
trace (41)
6 (47)
trace (17)
7 (trace)
[
17]
24
L3
NaHCO3
KOH
NaOH
type reaction, and an N-alkylation.
2
2
2
2
2
5
6
7
8
9
L
L
L
L
L
3
3
3
3
3
Cs
KOtBu
Et
2
CO
3
Results and Discussion
3
N
The cross-coupling reaction of 2,6-dibromopyridine and [a] Reagents and conditions: 2,6-dibromopyridine (0.5 mmol),
benzimidazole was selected as a model to optimize the reac- benzimidazole (1.0 mmol), Cu (20 mol-%), ligand (40 mol-%), and
base (1.5 mmol) in DMSO (2 mL), 90 °C, 12 h. [b] Isolated yield.
tion conditions, in which a diverse range of temperatures,
Data in parentheses correspond to yield of 2,6-bis(benzimidazol-1-
solvents, copper sources, ligands, and bases were evaluated.
yl)pyridine. [c] 70 °C, 24 h. [d] 90 °C, 24 h. [e] 110 °C, 24 h. [f] DMF
Initially, the effect of temperature on the cross-coupling re-
=
N,N-dimethylformamide, DMA = N,N-dimethylacetamide, NMP
action was investigated, and the results show that the prod- = N-methyl-2-pyrrolidone.
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Selective of 6-Substituted 2-Bromopyridines
A range of different copper sources (Cu , Cu , and Cu ) Table 2. Synthesis of 6-substituted 2-bromopyridine compounds.[a]
were subsequently evaluated. The results show that the cop-
I
II
0
per(I) compounds were more catalytically active than the
other copper sources, and CuI provided the best results (see
Table 1, Entry 4). A control experiment revealed that a
lower product yield was obtained in the presence of CuI
but in the absence of a ligand (see Table 1, Entry 15). By
using CuI as the copper source, we investigated the poten-
tial catalytic efficiency of different ligands, such as 1,2-eth-
anediamine (L ), N,NЈ-dimethyl-1,2-ethanediamine (L ),
1
2
and N,N-dimethylethylenediamine (L ). Among the three li-
3
gands, L efficiently assisted in the catalysis of the cross-
3
coupling reaction (see Table 1, Entry 4), and the reactivity
decreased when L was replaced with either L or L (see
3
1
2
Table 1, Entries 4 vs. 16 and 17). Encouraged by these re-
sults, we employed N,N,NЈ,NЈ-tetramethylethane-1,2-di-
amine (L ) as a ligand in the reaction. Interestingly, L was
4
4
superior to the other ligands, and the reaction proceeded
slightly faster than it did with L (see Table 1, Entries 18 vs.
3
4
). Inspired by the structure–activity relationship of L and
1
L , the activities of trans-1,2-diaminocyclohexane (L ) and
2
5
N,NЈ-dimethyl-trans-cyclohexane-1,2-diamine (L6) were
also investigated. As expected, L exhibited a higher activity
6
than L (see Table 1, Entries 20 vs. 19), however there was
5
an obvious increase in the disubstituted product formation.
The l-proline (L ) ligand provided moderate conversion
7
(see Table 1, Entry 21).
Generally, the nature of the base is an important factor
to determine the efficiency of a copper-catalyzed C–N
bond-forming reaction. Among the examined inorganic
bases, the weaker ones afforded better results than the
stronger ones (see Table 1, Entries 4, 22, 23, and 24 vs. 25,
26, 27, and 28). It is noteworthy that cesium carbonate and
potassium tert-butoxide, which are stronger bases, gave
poor conversion (see Table 1, Entries 27 and 28). The
stronger bases promoted the formation of the disubstituted
product. Among the potassium bases, potassium carbonate
was superior to the others, with potassium phosphate, hy-
droxide, and tert-butoxide giving a lower conversion (see
Table 1, Entries 4 vs. 22, 25, and 28). The organic base tri-
ethylamine was also examined in the cross-coupling reac-
tion and followed the same trend as the stronger bases (see
Table 1, Entry 29).
This method for the selective C–N bond formation to
give a monosubstituted pyridine is important because of
6-substituted 2-bromopyridine compounds are difficult to
synthesize through other methods. Therefore, the scope of
the catalytic system was explored by using a range of
amines under the optimized reaction conditions (see
Table 2). The copper-catalyzed cross-coupling products
were obtained in moderate to good yields through the N-
arylation of 2,6-dibromopyridine with various amines. The
coupling of 2,6-dibromopyridine with benzimidazole, imid-
azole, pyrrole, and pyrazole afforded the corresponding
product in 81, 72, 76, and 60% yield, respectively (see
Table 2, Entries 1, 2, 3 and 4). Nitrogen heterocycles such
as indazole, indole and benzotriazole gave products in rela-
[
a] Reagents and conditions: 2,6-dibromopyridine (0.5 mmol),
amines (1.0 mmol), CuI (20 mol-%), L (40 mol-%), and K CO
1.5 mmol) in DMSO (2 mL), 90 °C, 24 h. [b] Isolated yield. Data
4
2
3
(
tively lower yields than the those obtained from the other in parentheses correspond to the yield of 2,6-disubstituted pyridine.
Eur. J. Org. Chem. 2014, 6493–6500
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FULL PAPER
N-heterocyclic compounds (see Table 2, Entries 5, 6, and 7 Table 3. Synthesis of unsymmetrical 2,6-disubstituted pyridine-
bridged compounds.[
a]
vs. 1, 2, 3, and 4). The reason for these poorer results was
that the monosubstituted products were prone to further
C–N coupling to give the corresponding disubstituted prod-
uct. The optimized reaction conditions were also applied in
the N-arylation of sterically hindered 2-methyl-1H-imid-
azole and 2-methyl-1H-benzimidazole. The effect of this
steric hindrance on the coupling reaction was obvious, and
the desired cross-coupling products were only afforded in
moderate yields (see Table 2, Entries 8 and 9). In general,
the N-arylation was not affected by the nature of the sub-
stituent on either the imidazole or indole substrate, and,
thus, these reactions provided the corresponding product
with either an electron-donating or -withdrawing substitu-
ent such as a methyl, methoxy, or nitro group (see Table 2,
Entries 10, 11, and 12). To extend the scope of the N-aryl-
ation, the copper-catalyzed C–N bond-forming reactions
between 2,6-dibromopyridine and an alkyl or arylamine
were examined. For example, n-pentylamine underwent a
moderate conversion to give the desired product in 61%
yield (see Table 2, Entry 13), whereas the coupling of aniline
failed to furnish the desired product (see Table 2, Entry 14).
Because 2,6-dichloropyridine is less expensive and more
readily available than 2,6-dibromopyridine, we examined its
coupling reaction with benzimidazole under the optimized
conditions, and a moderate yield of the product was ob-
tained (see Table 2, Entry 15).
Symmetrical 2,6-disubstituted pyridine-bridged com-
[
18]
pounds have been extensively investigated and explored,
but little attention has been paid to the synthesis and appli-
cation of unsymmetrical 2,6-disubstituted pyridine-bridged
compounds because of their complicated synthetic prepara-
tion. We became interested in the synthesis of the unsym-
metrical compounds that contain different nitrogen hetero-
cycles, as they exhibit some hemilability to transition metals
to produce an efficient transition-metal catalyst. Inspired
by the effect of temperature on the coupling reaction (see
Table 1) and that the higher temperature could favorably
generate the disubstituted product, we examined the cop-
per-catalyzed C–N coupling reaction between the 6-substi-
tuted 2-bromopyridine compounds and a range of amines
by using L and K CO at a higher reaction temperature
3
2
3
(
see Table 3). The results show that these C–N coupling re-
actions with imidazole, pyrazole, indazole, pyrrole, and
benzotriazole took place smoothly to give good to excellent imidazole (0.5 mmol), amines (0.5 mmol), CuI (20 mol-%), L3
CO (1.0 mmol) in DMSO (2 mL), 110 °C,
[
a] Reagents and conditions: 1-(6-bromopyridin-2-yl)-1H-benzo[d]-
yields of the unsymmetrical compounds (see Table 3, En- (40 mol-%), and K
2
3
48 h. [b] Isolated yield. [c] 72 h.
tries 1–5). However, 5-methoxyindole was slightly less reac-
tive, and the coupling reaction proceeded with moderate
conversion (see Table 3, Entry 6). Encouraged by the suc-
cess of the heteroarylamines, alkyl and arylamines were also
The 6-substituted 2-bromopyridine compounds are of
evaluated. n-Pentylamine was employed under the same re- great use and versatility in organic synthesis, as they can be
action conditions to give the desired product in 40% yield converted into useful pharmaceuticals, organocatalysts, and
(see Table 3, Entry 7). Aniline was then submitted to the advanced material intermediates through transition-metal-
reaction, and no product formation was observed, despite catalyzed Suzuki couplings, Ullmann-type reactions, and
the extended reaction times (see Table 3, Entry 8). These Sonogashira couplings as well as through simple N-alkyl-
findings are important as unsymmetrical 2,6-disubstituted ation reactions. As illustrated in Figure 1, all these reactions
pyridine-bridged compounds are difficult to synthesize by proceeded smoothly to give four new unsymmetrical 2,6-
others methods.
disubstituted pyridine-bridged compounds in good yields.
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Eur. J. Org. Chem. 2014, 6493–6500

Selective of 6-Substituted 2-Bromopyridines
Figure 1. Functionalization of 6-substituted 2-bromopyridine compounds [tBu-Amphos = 2-(di-tert-butylphosphino)ethyltrimethylammo-
nium chloride].
temperature for 30 min and then heated to 90 °C for 24 h. The reac-
tion mixture was then added to brine (15 mL), and the resulting
Conclusions
In summary, the valuable and cost-effective copper-cata- solution was extracted with dichloromethane (3ϫ 15 mL). The
lyzed selective C–N coupling of 2,6-dibromopyridine and combined extracts were concentrated under vacuum, and the crude
amines was developed for the preparation of 6-substituted product was isolated by short chromatography on a silica gel (300–
400 mesh) column.
2-bromopyridine compounds, which are common core
structures for a number of pharmaceuticals, organocata- 1-(6-Bromopyridin-2-yl)-1H-benzo[d]imidazole (1a): Purification by
lysts, and advanced material intermediates. Furthermore, a flash chromatography (petroleum ether/EtOAc, 2:1) afforded 1a
1
series of the unsymmetrical 2,6-disubstituted pyridine- (111 mg, 81%) as a white solid; m.p. 145–148 °C. H NMR
(
7
8
3
400 MHz, CDCl ): δ = 8.60 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H),
bridged compounds were obtained in good yields. We pre-
dict that the new methods developed herein will have wide
synthetic utility in medicinal chemistry, organometallic ca-
talysis, and materials science.
.87 (d, J = 8.0 Hz, 1 H), 7.76 (t, J = 8.0 Hz, 1 H), 7.56 (d, J =
.0 Hz, 1 H), 7.49 (dd, J = 8.0 Hz, J = 4.0 Hz, 1 H), 7.45–7.37 (m, 2
1
3
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 149.60, 144.66, 141.15,
1
1
2
40.92, 140.84, 131.79, 125.75, 124.63, 123.72, 120.79, 112.88,
+
12.14 ppm. HRMS (MALDI): calcd. for C12
73.9974; found 273.9977.
8 3
H BrN [M + H]
Experimental Section
2
-Bromo-6-(1H-imidazol-1-yl)pyridine (1b): Purification by flash
General Methods: All reactions were carried out in Schlenk tubes
under nitrogen. DMSO was distilled from molecular sieves (4 Å).
All solvents and reagents were purchased from Alfa Aesar, Acros,
and Adamas-beta. The NMR spectroscopic were recorded with a
Varian Inova-400 spectrometer by using TMS as internal standard
chromatography (petroleum ether/EtOAc, 2:1) afforded 1b (80 mg,
72%) as a white solid; m.p. 92–94 °C. H NMR (400 MHz, CDCl ):
3
1
δ = 8.32 (s, 1 H), 7.67 (t, J = 8.0 Hz, 1 H), 7.61 (s, 1 H), 7.41 (dd,
J = 8.0 Hz, 1 H), 7.31 (dd, J = 8.0 Hz, 1 H), 7.19 (s, 1 H) ppm.
1
3
C NMR (100 MHz, CDCl
3
): δ = 148.81, 141.01, 140.91, 134.99,
1
13
(400 MHz for H NMR and 100 MHz for C NMR). Mass spec-
131.01, 126.04, 116.12, 110.60 ppm. HRMS (EI): calcd. for
+
trometry data were collected with a Bruker ultrafleXtreme mass
spectrometer. All products were isolated by short chromatography
on a silica gel (300–400 mesh) column.
C
8
H
6
BrN
-Bromo-6-(1H-pyrrol-1-yl)pyridine (1c): Purification by flash
chromatography (petroleum ether) afforded 1c (85 mg, 76%) as a
3
[M] 222.9740; found 222.9737.
2
1
Typical Procedure for the Synthesis of 6-Substituted 2-Bromopyr-
idine Compounds: A mixture of 2,6-dibromopyridine (0.5 mmol),
the amine (1.0 mmol), the Cu compound (0.1 mmol), the ligand
white solid; m.p. 72–74 °C. H NMR (400 MHz, CDCl
3
): δ = 7.56
(t, J = 8.0 Hz, 1 H), 7.47–7.46 (m, 2 H), 7.25 (dd, J = 12.0 Hz, J
1
3
3
= 8.0 Hz, 2 H), 6.35 (s, 2 H) ppm. C NMR (100 MHz, CDCl ):
(
0.2 mmol), and K
2 3
CO (1.5 mmol) in DMSO (2 mL) was com- δ = 140.58, 140.39, 127.03, 123.87, 118.21, 111.90, 109.40 ppm.
+
bined under nitrogen. The reaction mixture was stirred at room
HRMS (EI): calcd. for C
9
H
7
BrN
2
[M] 221.9787; found 221.9789.
Eur. J. Org. Chem. 2014, 6493–6500
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L. Wang, N. Liu, B. Dai, H. Hu
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2
-Bromo-6-(1H-pyrazol-1-yl)pyridine (1d):[19] Purification by flash
chromatography (petroleum ether/EtOAc, 20:1) afforded 1d (66 mg,
140.27, 134.24, 125.54, 112.34, 110.19, 13.74 ppm. HRMS
(MALDI): calcd. for C
237.9980.
9 8 3
H BrN
[M + H]+ 237.9974; found
1
60%) as a white solid; m.p. 55–58 °C. H NMR (400 MHz, CDCl
3
):
δ = 8.53 (s, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.65 (t,
1
-(6-Bromopyridin-2-yl)-5-methoxy-1H-indole (1k): Purification by
1
3
J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 6.46 (s, 1 H) ppm.
NMR (100 MHz, CDCl ): δ = 151.39, 142.66, 140.68, 139.86,
27.52, 125.19, 110.83, 108.19 ppm. HRMS (EI): calcd. for
C
flash chromatography (petroleum ether/EtOAc, 20:1) afforded 1k
3
1
(
(
4
7
8
70 mg, 46%) as a pale brown solid; m.p. 59–60 °C. H NMR
400 MHz, CDCl ): δ = 8.23 (d, J = 8.0 Hz, 1 H), 7.64 (d, J =
.0 Hz, 1 H), 7.61 (t, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H),
.28 (d, J = 8.0 Hz, 1 H), 7.09 (d, J = 4.0 Hz, 1 H), 6.96 (dd, J =
.0 Hz, J = 4.0 Hz, 1 H), 6.64 (d, J = 4.0 Hz, 1 H), 3.87 (s, 3
1
C
3
+
8 6 3
H BrN [M] 222.9740; found 222.9737.
1
-(6-Bromopyridin-2-yl)-1H-indazole (1e): Purification by flash
chromatography (petroleum ether/EtOAc, 20:1) afforded 1e (56 mg,
1%) as a white solid; m.p. 102–105 °C. 1H NMR (400 MHz,
CDCl ): δ = 8.76 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 4.0 Hz, 1 H),
.98 (dd, J = 8.0 Hz, J = 4.0 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H),
.63 (t, J = 8.0 Hz, 1 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.31–7.27 (m, 2
1
3
H) ppm. C NMR (100 MHz, CDCl ): δ = 155.31, 152.18, 140.38,
3
4
1
1
40.25, 131.34, 130.02, 125.69, 123.14, 114.67, 112.98, 111.35,
06.45, 103.13, 55.72 ppm. HRMS (MALDI): calcd. for
3
7
7
C
14
H
11BrN
2
O [M]+ 302.0049; found 302.0054.
13
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 153.69, 140.25, 139.29,
1-(6-Bromopyridin-2-yl)-5-nitro-1H-benzo[d]imidazole (1l): Purifica-
tion by flash chromatography (petroleum ether/EtOAc, 2:1) af-
1
1
38.75, 137.64, 128.42, 126.10, 123.40, 122.98, 120.79, 115.33,
11.52 ppm. HRMS (EI): calcd. for C12H BrN [M] 272.9896; forded 1l (113 mg, 70%) as a pale yellow solid; m.p. 201–202 °C.
8 3
+
found 272.9890.
-(6-Bromopyridin-2-yl)-1H-indole (1f): Purification by flash
chromatography (petroleum ether/EtOAc, 20:1) afforded 1f (58 mg,
1
3
H NMR (400 MHz, CDCl ): δ = 8.77 (d, J = 2.0 Hz, 1 H), 8.68
(
s, 1 H), 8.36 (dd, J = 2.0 Hz, J = 8.0 Hz, 1 H), 8.28 (d, J = 8.0 Hz,
1
1
3
1
H), 7.84 (t, J = 8.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 2 H) ppm.
): δ = 148.79, 144.58, 144.17, 143.72,
41.50, 141.24, 135.93, 126.94, 120.23, 117.19, 113.62, 112.46 ppm.
C
1
NMR (100 MHz, CDCl
3
1
4
8
8
7
3
2%) as a white viscous solid. H NMR (400 MHz, CDCl ): δ =
.27 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 4.0 Hz, 1 H), 7.64 (t, J =
.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 2 H),
.22 (t, J = 8.0 Hz, 1 H), 6.71 (d, J = 4.0 Hz, 1 H) ppm. 13C NMR
7 4 2
H BrN O
[M + H]+ 318.9825;
HRMS (MALDI): calcd. for C12
found 318.9830.
(100 MHz, CDCl
3
): δ = 152.18, 140.47, 140.32, 134.97, 130.60,
6-Bromo-N-pentylpyridin-2-amine (1m): Purification by flash
1
25.44, 123.63, 123.55, 121.82, 121.15, 113.50, 112.04, 106.58 ppm.
chromatography (petroleum ether/EtOAc, 20:1) afforded 1m
+
1
HRMS (EI): calcd. for C13
-(6-Bromopyridin-2-yl)-1H-benzo[d][1,2,3]triazole (1g):[20] Purifica-
tion by flash chromatography (petroleum ether/EtOAc, 20:1) af-
H
9
BrN
2
[M] 271.9944; found 271.9939.
(75 mg, 61%) as a pale brown oil. H NMR (400 MHz, CDCl
3
): δ
=
7.24 (t, J = 8.0 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.26 (d, J =
1
8
.0 Hz, 1 H), 4.72 (br., 1 H), 3.19 (t, J = 8.0 Hz, 2 H), 1.63–1.56
1
3
(
m, 2 H), 1.38–1.32 (m, 4 H), 0.92–0.89 (m, 3 H) ppm. C NMR
100 MHz, CDCl ): δ = 159.02, 140.24, 139.50, 115.43, 103.89,
2.26, 29.09, 28.95, 22.39, 14.00 ppm. HRMS (MALDI): calcd. for
15BrN
[M + H]+ 243.0491; found 243.0490.
-(6-Chloropyridin-2-yl)-1H-benzo[d]imidazole (1o): Purification by
1
forded 1g (66 mg, 48%) as a white solid; m.p. 114–116 °C.
NMR (400 MHz, CDCl ): δ = 8.59 (d, J = 8.0 Hz, 1 H), 8.27 (d,
J = 8.0 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.78 (t, J = 8.0 Hz, 1
H), 7.64 (t, J = 8.0 Hz, 1 H), 7.51–7.46 (m, 2 H) ppm. 13C NMR
H
(
4
C
3
3
10
H
2
1
(100 MHz, CDCl
3
): δ = 151.08, 146.74, 140.83, 140.02, 131.24,
flash chromatography (petroleum ether/EtOAc, 2:1) afforded 1o
129.28, 126.14, 125.25, 119.91, 114.70, 112.58 ppm. HRMS (EI):
1
+
(61 mg, 53%) as a white solid; m.p. 122–124 °C. H NMR
calcd. for C11
H
7
4
BrN [M] 273.9849; found 273.9841.
(
400 MHz, CDCl
3
): δ = 8.57 (s, 1 H), 8.10–8.08 (m, 1 H), 7.86 (t,
2
-Bromo-6-(2-methyl-1H-imidazol-1-yl)pyridine (1h): Purification
J = 8.0 Hz, 2 H), 7.51 (dd, J = 8.0 Hz, J = 0.8 Hz, 1 H), 7.44–7.35
by flash chromatography (EtOAc): afforded 1h (69 mg, 58%) as a
white solid; m.p. 98–101 °C. H NMR (400 MHz, CDCl
13
(
(
1
m, 2 H), 7.32 (dd, J = 8.0 Hz, J = 0.8 Hz, 1 H) ppm. C NMR
100 MHz, CDCl ): δ = 150.89, 149.53, 144.67, 141.20, 140.96,
31.80, 124.59, 123.69, 121.90, 120.79, 112.89, 111.83 ppm.
1
3
): δ = 7.70
3
(t, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8.0 Hz, J = 0.8 Hz, 1 H), 7.30–
1
3
7
.28 (m, 2 H), 7.01 (d, J = 1.6 Hz, 1 H), 2.63 (s, 3 H) ppm.
): δ = 150.30, 145.12, 140.69, 140.62,
28.23, 126.36, 118.68, 115.07, 15.67 ppm. HRMS (MALDI):
C
Typical Procedure for the Synthesis of Unsymmetrical 2,6-Disubsti-
tuted Pyridine-Bridged Compounds: A mixture of 1-(6-bromopyr-
idin-2-yl)-1H-benzo[d]imidazole (0.5 mmol), the amine (0.5 mmol),
NMR (100 MHz, CDCl
1
calcd. for C H BrN [M + H] 237.9974; found 237.9973.
9 8 3
3
+
CuI (0.1 mmol), L
3 2 3
(0.2 mmol), and K CO (1.0 mmol) in DMSO
1
-(6-Bromopyridin-2-yl)-2-methyl-1H-benzo[d]imidazole (1i): Purifi-
(
2 mL) was combined under nitrogen. The reaction mixture was
cation by flash chromatography (petroleum ether/EtOAc, 1:1) af-
forded 1i (69 mg, 48%) as a white solid; m.p. 102–104 °C. H NMR
stirred at room temperature for 30 min and then heated to 110 °C
for 48 h. The mixture was then added to brine (15 mL), and the
resulting solution was extracted with dichloromethane (3ϫ 15 mL).
The combined extracts were concentrated under vacuum, and the
product was isolated by short chromatography on a silica gel (300–
1
(
400 MHz, CDCl
3
): δ = 7.80 (t, J = 8.0 Hz, 1 H), 7.73 (d, J =
.0 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H),
.40 (d, J = 8.0 Hz, 1 H), 7.31–7.23 (m, 2 H), 2.71 (s, 3 H) ppm.
8
7
1
3
C NMR (100 MHz, CDCl
3
): δ = 151.35, 149.46, 142.67, 141.33,
400 mesh) column.
1
1
2
40.69, 134.48, 127.18, 123.23, 123.12, 119.39, 118.05, 110.15,
1-[6-(1H-Imidazol-1-yl)pyridin-2-yl]-1H-benzo[d]imidazole (2a): Pu-
5.54 ppm. HRMS (MALDI): calcd. for C13
88.0131; found 288.0140.
H10BrN
3
[M + H]+
rification by flash chromatography (EtOAc) afforded 2a (108 mg,
1
8
3%) as a white solid; m.p. 144–146 °C. H NMR (400 MHz,
CDCl ): δ = 8.59 (s, 1 H), 8.44 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H),
8.04 (t, J = 8.0 Hz, 1 H), 7.89 (d, J = 8.0 Hz, 1 H), 7.71 (s, 1 H),
74 mg, 63%) as a white solid; m.p. 72–74 °C. H NMR (400 MHz, 7.50 (d, J = 8.0 Hz, 1 H), 7.45–7.38 (m, 2 H), 7.34 (d, J = 8.0 Hz,
2
-Bromo-6-(4-methyl-1H-imidazol-1-yl)pyridine (1j): Purification by
3
flash chromatography (petroleum ether/EtOAc, 1:1) afforded 1j
(
1
1
3
3 3
CDCl ): δ = 8.23 (d, J = 1.6 Hz, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 1 H), 7.27 (s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 149.30,
7
7
.37 (dd, J = 8.0 Hz, J = 0.8 Hz, 1 H), 7.31 (t, J = 1.2 Hz, 1 H),
.24 (dd, J = 8.0 Hz, J = 0.4 Hz, 1 H), 2.28 (d, J = 4.0 Hz, 3
148.58, 144.72, 142.04, 140.99, 135.07, 131.86, 131.21, 124.68,
123.77, 120.92, 116.19, 112.81, 111.37, 109.36 ppm. HRMS (EI):
13
+
H) ppm. C NMR (100 MHz, CDCl
3
): δ = 148.85, 140.92, 140.80,
calcd. for C15
H
11
N
5
[M] 261.1009; found 261.1014.
6498
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6493–6500

Selective of 6-Substituted 2-Bromopyridines
1-[6-(1H-Pyrazol-1-yl)pyridin-2-yl]-1H-benzo[d]imidazole (2b): Puri-
158.60, 148.61, 144.54, 141.59, 139.64, 132.26, 123.73, 122.87,
fication by flash chromatography (petroleum ether/EtOAc, 2:1) af-
120.41, 112.90, 104.55, 101.87, 42.15, 29.25, 29.23, 22.45,
1
+
forded 2b (124 mg, 95%) as a white solid; m.p. 116–119 °C.
NMR (400 MHz, CDCl ): δ = 8.60 (s, 2 H), 8.08 (d, J = 8.0 Hz, 1
H), 8.02 (t, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.90 (d, J
8.0 Hz, 1 H), 7.80 (d, J = 4.0 Hz, 1 H), 7.45–7.37 (m, 3 H), 6.54
H
14.02 ppm. HRMS (MALDI): calcd. for C17
281.1761; found 281.1755.
20 4
H N [M + H]
3
1-(6-Phenylpyridin-2-yl)-1H-benzo[d]imidazole (2i): Purification by
=
flash chromatography (petroleum ether/EtOAc, 2:1) afforded 2i
1
3
(
1
1
d, J = 4.0 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ =
51.06, 148.36, 144.70, 142.75, 141.69, 141.24, 132.02, 127.28,
24.44, 123.54, 120.88, 112.57, 111.01, 109.97, 108.47 ppm. HRMS
121 mg, 89 %) as a white solid; m.p. 138–140 °C. 1H NMR
(
(
400 MHz, CDCl
3
): δ = 8.67 (s, 1 H), 8.16 (d, J = 8.0 Hz, 1 H),
8
8
.10 (d, J = 8.0 Hz, 2 H), 7.92 (t, J = 8.0 Hz, 2 H), 7.72 (d, J =
+
(EI): calcd. for C15
H
11
N
5
[M] 261.1009; found 261.1005.
13
.0 Hz, 1 H), 7.54–7.45 (m, 4 H), 7.41–7.37 (m, 2 H) ppm.
C
1-[6-(1H-Benzo[d]imidazol-1-yl)pyridin-2-yl]-1H-indazole (2c): Puri-
NMR (100 MHz, CDCl ): δ = 157.26, 149.59, 144.46, 141.34,
3
fication by flash chromatography (petroleum ether/EtOAc, 2:1) af-
139.75, 137.99, 132.20, 129.76, 128.95, 126.95, 124.31, 123.37,
1
forded 2c (118 mg, 76%) as a white solid; m.p. 129–132 °C.
NMR (400 MHz, CDCl ): δ = 8.70 (d, J = 8.0 Hz, 1 H), 8.64 (s, 1
H), 8.21 (s, 1 H), 8.04–7.91 (m, 4 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.47
H
120.63, 118.09, 112.97, 112.33 ppm. HRMS (EI): calcd. for
+
3
C H N [M] 271.1104; found 271.1100.
1
8
13
3
1
-[6-(Phenylethynyl)pyridin-2-yl]-1H-benzo[d]imidazole (2j): Purifi-
1
3
(
t, J = 8.0 Hz, 1 H), 7.39–7.25 (m, 4 H) ppm. C NMR (100 MHz,
CDCl ): δ = 153.67, 147.75, 144.72, 141.55, 141.00, 138.65, 137.71,
32.09, 128.43, 126.20, 124.25, 123.39, 122.99, 120.97, 120.83,
15.09, 112.31, 111.21, 109.92 ppm. HRMS (EI): calcd. for
cation by flash chromatography (petroleum ether/EtOAc, 2:1) af-
3
1
forded 2j (94 mg, 64%) as a yellow solid; m.p. 91–94 °C. H NMR
1
1
C
(
400 MHz, CDCl
3
): δ = 8.63 (s, 1 H), 8.09 (d, J = 8.0 Hz, 1 H),
7
2
.89 (t, J = 8.0 Hz, 2 H), 7.66–7.63 (m, 2 H), 7.53 (t, J = 8.0 Hz,
H), 7.43–7.35 (m, 5 H) ppm. C NMR (100 MHz, CDCl ): δ =
3
+
19
H
13
N
5
[M] 311.1165; found 311.1167.
-[6-(1H-Pyrrol-1-yl)pyridin-2-yl]-1H-benzo[d]imidazole (2d): Puri-
fication by flash chromatography (petroleum ether/EtOAc, 2:1) af-
forded 2d (103 mg, 79%) as a white solid; m.p. 119–120 °C.
NMR (400 MHz, CDCl ): δ = 8.58 (s, 1 H), 8.11 (d, J = 8.0 Hz, 1
H), 7.90 (q, J = 8.0 Hz, 2 H), 7.57 (s, 2 H), 7.43–7.35 (m, 2 H),
.32 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 6.41 (s, 2
): δ = 150.87, 148.85, 144.72,
41.36, 141.20, 132.03, 124.38, 123.45, 120.76, 118.22, 112.87,
12.07, 109.44, 108.45 ppm. HRMS (EI): calcd. for C16H N
12 4
13
1
149.83, 144.69, 143.21, 141.36, 139.13, 132.16, 132.03, 129.36,
128.48, 125.23, 124.35, 123.42, 121.81, 120.71, 113.47, 112.66,
90.51, 87.88 ppm. HRMS (MALDI): calcd. for C H N [M +
1
H
2
0
13
3
+
3
H] 296.1182; found 296.1189.
-(6-Bromopyridin-2-yl)-3-methyl-1H-benzo[d]imidazol-3-ium Iodide
2k): Purification by flash chromatography (petroleum ether/
EtOAc, 2:1) afforded 2k (168 mg, 81%) as a white solid; m.p. 230–
1
(
7
13
H) ppm. C NMR (100 MHz, CDCl
1
1
3
1
2
32 °C. H NMR (400 MHz, [D
6
]DMSO): δ = 10.53 (s, 1 H), 8.43–
8.40 (m, 1 H), 8.25 (t, J = 8.0 Hz, 1 H), 8.18–8.15 (m, 1 H), 8.10
+
[M] 260.1056; found 260.1053.
(
d, J = 8.0 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.84–7.81 (m, 2 H),
1
3
1
-[6-(1H-Benzo[d]imidazol-1-yl)pyridin-2-yl]-1H-benzo[d][1,2,3]tri- 4.21 (s, 3 H) ppm. C NMR (100 MHz, [D ]DMSO): δ = 147.16,
6
azole (2e): Purification by flash chromatography (petroleum ether/
EtOAc, 2:1) afforded 2e (128 mg, 82%) as a white solid; m.p. 156– 116.16, 115.60, 114.31, 34.07 ppm. HRMS (ESI): calcd. for
143.51, 143.24, 140.03, 132.43, 129.29, 129.25, 128.14, 127.43,
1
+
1
3
13 11 3
58 °C. H NMR (400 MHz, CDCl ): δ = 8.67 (s, 1 H), 8.55 (d, J C H BrIN [M – I] 288.0131; found 288.0132.
=
8.0 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1 H), 8.18 (t, J = 8.0 Hz, 2 H),
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H NMR and C NMR spectra of all compounds.
8.03–8.01 (m, 1 H), 7.95–7.93 (m, 1 H), 7.62–7.58 (m, 2 H), 7.49
1
13
13
(
t, J = 8.0 Hz, 1 H), 7.43–7.41 (m, 2 H) ppm. C NMR (100 MHz,
CDCl ): δ = 151.08, 148.46, 146.86, 144.79, 141.93, 141.32, 131.98,
31.25, 129.41, 125.31, 124.58, 123.73, 121.05, 120.18, 114.34,
12.44, 112.25, 112.14 ppm. HRMS (EI): calcd. for C18
3
1
1
Acknowledgments
12 6
H N
+
[M] 312.1118; found 312.1115.
The authors thank the Start-Up Foundation for Young Scientists
of Shihezi University (grant number RCZX201207) and the Pro-
gram for Excellent Talents of Shihezi University (grant number
1
-[6-(5-Methoxy-1H-indol-1-yl)pyridin-2-yl]-1H-benzo[d]imidazole
(
2f): Purification by flash chromatography (petroleum ether/
2012ZRKXYQ03) for their financial support.
EtOAc, 2:1) afforded 2f (85 mg, 50%) as a brown solid; m.p. 167–
1
168 °C. H NMR (400 MHz, CDCl
3
): δ = 8.70 (s, 1 H), 8.25 (d, J
=
8.0 Hz, 1 H), 8.14–8.11 (m, 1 H), 8.01 (t, J = 8.0 Hz, 1 H), 7.93–
[
1] a) S. Dey, S. Sarkar, H. Paul, E. Zangrando, P. Chattopadhyay,
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.91 (m, 1 H), 7.77 (d, J = 4.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H),
.42–7.39 (m, 3 H), 7.14 (d, J = 2.8 Hz, 1 H), 6.94 (dd, J = 9.2 Hz,
J = 2.4 Hz, 1 H), 6.71 (dd, J = 3.6 Hz, J = 0.8 Hz, 1 H), 3.89 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl
3
): δ = 155.41, 152.17, 148.79,
44.51, 141.36, 141.26, 132.07, 131.49, 130.08, 126.00, 124.53,
23.62, 120.74, 114.79, 113.08, 113.01, 110.82, 109.12, 106.62,
03.31, 55.77 ppm. HRMS (MALDI): calcd. for C21 O [M +
1
1
1
3
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A. P. Higueruelo, L. A. James, K. Jenkins, S. R. Mack, T. Mor-
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H] 341.1397; found 341.1397.
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mez-Benitez, D. Morales-Morales, T. Pape, Organometallics
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-(1H-Benzo[d]imidazol-1-yl)-N-pentylpyridin-2-amine (2g): Purifi-
cation by flash chromatography (petroleum ether/EtOAc, 1:1) af-
forded 2g (56 mg, 40%) as a white solid; m.p. 91–93 °C. H NMR
1
(400 MHz, CDCl
3
): δ = 8.55 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H),
7
2
1
0
.85 (d, J = 8.0 Hz, 1 H), 7.58 (t, J = 8.0 Hz, 1 H), 7.37–7.31 (m,
H), 6.78 (d, J = 8.0 Hz, 1 H), 6.34 (d, J = 8.0 Hz, 1 H), 4.70 (br.,
H), 3.39–3.34 (m, 2 H), 1,71–1.64 (m, 2 H), 1.43–1.36 (m, 4 H),
2005, 24, 6458–6463.
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45, 126–132; b) H. Y. Gong, B. M. Rambo, E. Karnas, V. M.
.93 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl
): δ =
3
Eur. J. Org. Chem. 2014, 6493–6500
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6499

L. Wang, N. Liu, B. Dai, H. Hu
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Published Online: September 1, 2014
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Eur. J. Org. Chem. 2014, 6493–6500