A facile synthesis of 4-Ar-2-bromopyridine and its 2,2′-bipyridine derivatives

Article abstract of DOI:10.1081/SCC-200028631

By means of selective cross-coupling of ArMgBr with 2-bromo-4-iodopyridine in the presence of a catalytic amount of Pd(PPh₃)₄, 4-Ar-2-bromopyridines were facilely one-step synthesized. These pyridine compounds were smoothly transform

Full text of DOI:10.1081/SCC-200028631

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A Facile Synthesis of
4‐Ar‐2‐bromopyridine and Its
2,2′‐Bipyridine Derivatives
Xin‐Fang Duan a , Xiang‐Hong Li a , Fu‐You Li b &
Chun‐Hui Huang b
a Department of Chemistry , Beijing Normal
University , Beijing, 100875, China
b Institute of Advanced Materials , Fudan
University , Shanghai, China
Published online: 10 Jan 2011.
To cite this article: Xin‐Fang Duan , Xiang‐Hong Li , Fu‐You Li & Chun‐Hui
Huang (2004) A Facile Synthesis of 4‐Ar‐2‐bromopyridine and Its 2,2′‐Bipyridine
Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:17, 3227-3233, DOI: 10.1081/
SCC-200028631
To link to this article: http://dx.doi.org/10.1081/SCC-200028631
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 17, pp. 3227–3233, 2004
A Facile Synthesis of 4-Ar-2-bromopyridine
and Its 2,20-Bipyridine Derivatives
1
2
Xin-Fang Duan,1, Xiang-Hong Li, Fu-You Li, and
*
Chun-Hui Huang2
1Department of Chemistry, Beijing Normal University,
Beijing, China
2Institute of Advanced Materials, Fudan University,
Shanghai, China
ABSTRACT
By means of selective cross-coupling of ArMgBr with 2-bromo-4-iodo-
pyridine in the presence of a catalytic amount of Pd(PPh3)4, 4-Ar-2-bro-
mopyridines were facilely one-step synthesized. These pyridine
compounds were smoothly transformed into their 2,20-bipyridine deriva-
tives via Stille-type cross-couplings.
Key Words: 4-Ar-2-bromopyridine; 2,2-Bipyridine; 2-Bromo-4-iodo-
pyridine; Stille-coupling.
2,20-Bipyridines have been extensively used in supermolecular chemistry,
molecular biology, and photochemistry.[1,2] As a result, the efficient syntheses
*
Correspondence: Xin-Fang Duan, Department of Chemistry, Beijing Normal Univer-
sity, Beijing, 100875, China; E-mail: xinfangduan@vip.163.com.
3227
DOI: 10.1081/SCC-200028631
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3228
Duan et al.
of these compounds have always attracted the attention of researchers. Among
various synthetic approaches to these compounds,[3,4] modern palladium(0)-
catalyzed Suzuki,[5] Negishi,[6], and Stille[7]-type cross-couplings provide
the most effective methods.
As part of our investigations, we wished to prepare a series of 4-Ar-2,20-
bipyridines or 4-Ar-40-Ar0-2,20-bipyridines. Obviously 4-Ar-2-bromopyridines
are the key building blocks for these bipyridine compounds because they can be
conveniently and flexibly built up into the required bipyridines via the above-
mentioned cross-couplings. For instance, transformations of 4-Ar-2-bromo-
pyridines into symmetrical bipyridines can be easily achieved by homo-coup-
lings,[8] while unsymmetrical bipyridines can be achieved in the following two
ways: (1) directly coupled with 2-pyridyl organometallics; (2) transformed into
the corresponding organometallics, then coupled with 2-pyridyl halides.
4-Ar-2-bromopyridines can be synthesized by reported procedures[9]
involving: (a) preparation of 4-Ar-pyridines;[8] (b) 2-amination via the Chichi-
babin reaction; (c) Sandermeyer substitution of bromide. As a linear route
with three steps, this synthetic strategy seems unattractive and inconvenient
for a variety of 4-Ar-2-bromopyridines. Very recently Bouillon[10] reported
a general synthetic approach to 4-Ar-2-bromopyridines based on the Suzuki
couplings of 2-halopyridin-4-yl-boronic acids with aryl halides. Obviously
these syntheses suffer from inconvenience of preparing boronic acids.
Recently we developed an efficient and convenient synthesis of 2-bromo-4-
iodopyridine via halogen-dance from 2-bromopyridine.[11] Therefore, we con-
sidered that a variety of 4-Ar-2-bromo-pyridines can be facilely one-step pre-
pared by selective substitutions of 2-bromo-4-iodopyridine (at 4-position)
through cross-couplings of ArMgX and 2-bromo-4-iodopyridine.
Cross-couplings of ArMgx to halopyridines performed under the catalysis
of Ni(PPh3)2Cl2 and PdCl2(dppb)2 have been reported.[9,12] During the selec-
tive cross-couplings of ArMgX to 2-bromo-4-iodopyridine (at 4-position) we
selected three readily available catalysts to promote the couplings: (a) CuI; (b)
Ni(PPh3)2Cl2; (c) Pd(PPh3)4. Experiment results revealed that the best catalyst
was Pd(PPh3)4 and the optimal temperature was 2408C. When Ni(PPh3)2Cl2
was used, the reaction consumed 2-bromo-4-iodopyridine almost completely
at 2408C in tetrahydrofuran (THF); however, the substitutions of bromine (by
ArMgX or homo-coupling) also occurred. On the other hand, in the presence
of CuI, the coupling was sluggish and incomplete with excess ArMgX at
2108C, and its optimized yield was only approximately 40%. We their pre-
pared a series of 4-Ar-2-bromopyridines in 54%–70% using Pd(PPh3)4, as
summarized in Table 1.
Having efficiently prepared 4-Ar-2-bromopyridines, we next synthesized
2,20-bipyridines through homo-couplings and the Stille-type couplings,
respectively. According to reported procedures[8] we found that the yields

Facile Synthesis of 4-Ar-2-bromopyridine
3229
of homo-couplings of 2a did not exceed 30%.[11] We found debromination
occurred seriously during the couplings. The preparations via the Stille coup-
lings were accomplished in two ways, as illustrated in Sch. 1: (1) 2a cross-
coupled with 4-RC5H3N-2-SnBu3; (2) the tributylstannyl derivative of 2a
cross-coupled with 2-Br-4-R-pyridine. These couplings were carried out accor-
ding standard procedures,[7] and the yields were moderate (as summarized in
Table 1).
In summary, by virtue of the selective cross-couplings of ArMgBr with
2-bromo-4-iodopyridine, this synthetic strategy furnishes us with an efficient
preparation of 2,2-bipyridine derivatives with only two or three steps.
EXPERIMENTAL
Melting points were measured using a RY-1 capillary melting point appar-
atus and uncorrected (China). 1H and 13CNMR spectra were recorded in CDCl3
on a 500 MHz Brucker instrument (Germany) using tetramethylsilane (TMS)
as the internal standard. Infrared (IR) spectra were recorded on a 60 FT-IR
Vaatar3 spectrometer (Italy).
General Procedure for the Syntheses of
2-Bromo-4-Ar-pyridines
A solution of 2-bromo-4-iodopyridine (2.0 g, 7 mmol), Pd(PPh3)4
(400 mg, 0.35 mmol) in 50 mL THF was cooled to 2408C. A solution of
Scheme 1.

3230
Duan et al.
d
d

Facile Synthesis of 4-Ar-2-bromopyridine
3231

3232
Duan et al.
ArMgBr (0.74 mmol) in THF was added and kept at that temperature. After
completion of the coupling [monitored by thin layer chromatography
(TLC)], the reaction was quenched by a saturated NH4Cl aqueous solution
and extracted with CH2Cl2. After dried over anhyd K2CO3, CH2Cl2 was evap-
orated and the resulting crude product was purified by flash chromatography
(petroleum-ethyl acetate-triethylamine; 180 : 10 : 1).
General Procedure for the Syntheses of 4-Ar-40-R-2,20-
pyridines via Stille-Coupling
To a solution of 2-tributylstannyl-4-R-pyridine[7] [or 4-(4-MeC6H4)-2-
tributylstannyl-pyridine] (12 mmol), Pd(PPh3)4 (500 mg, 0.44 mmol) in
50 mL xylene was added 2-bromo-4-(4-MeC6H4)pyridine (or 4-R-pyridine)
(10 mmol). The reaction mixture was stirred at 1208C–1308C under an Ar
atmosphere. After completion of the coupling (monitored by TLC), the reac-
tion was quenched by a saturated NH4Cl aqueous solution and extracted with
CH2Cl2. After being dried over anhyd K2CO3, CH2Cl2 was evaporated and the
resulting crude product was purified by flash chromatography (petroleum-
ethyl acetate-triethylamine; 180 : 10 : 1).
ACKNOWLEDGMENTS
The authors thank NHTRDP (863 Program No. 2002AA322403),
National Science Foundation of China (20221101), Shanghai Sci. Tech.
Comm. (03QB14006), and Shanghai Nanotech Promotion (0216nm040) for
financial support.
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Received in Japan January 19, 2004.