Synthesis of 2,4-dibromopyridine and 4,4'-dibromo-2,2'-bipyridine. Efficient usage in selective bromine-substitution under palladium-catalysis

Article abstract of DOI:10.3987/COM-07-11170

We report an efficient method for preparing 2,4-dibromopyridine and 4,4'-dibromo-2,2'-bipyridine from the corresponding nitroazine N-oxide in one step via a tandem nucleophilic substitution-N-oxide reduction process. The one step preparation of 4,4'-dihalo-2,2'-bipyridines from dihalopyridines via a Stille reaction is also described. 4,4'-Dibromo-2,2'-bipyridine undergoes selective mono- or disubstitution processes under palladium catalysis. This short synthetic procedure is an efficient and reliable process for preparing conjugated pyridine and 2,2'-bipyridine building blocks for applications in coordination chemistry and materials science.

Full text of DOI:10.3987/COM-07-11170

HETEROCYCLES, Vol. 75, No. 1, 2008
57
HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 57 - 64. © The Japan Institute of Heterocyclic Chemistry
Received, 11th July, 2007, Accepted, 14th September, 2007, Published online, 20th September, 2007. COM-07-11170
SYNTHESIS
OF
2,4-DIBROMOPYRIDINE
AND
4,4’-DIBROMO-2,2’-BIPYRIDINE. EFFICIENT USAGE IN SELECTIVE
BROMINE-SUBSTITUTION UNDER PALLADIUM-CATALYSIS
Ramón García-Lago, José-Lorenzo Alonso-Gómez, Cristina Sicre, and
María-Magdalena Cid*
Organic Chemistry Department, University of Vigo, Lagoas-Marcosende, 36310
Vigo, Spain; mcid@uvigo.es
Abstract−We report an efficient method for preparing 2,4-dibromopyridine and
4,4’-dibromo-2,2’-bipyridine from the corresponding nitroazine N-oxide in one
step via a tandem nucleophilic substitution–N-oxide reduction process. The one
step preparation of 4,4’-dihalo-2,2’-bipyridines from dihalopyridines via a Stille
reaction is also described. 4,4'-Dibromo-2,2’-bipyridine undergoes selective
mono- or disubstitution processes under palladium catalysis. This short synthetic
procedure is an efficient and reliable process for preparing conjugated pyridine
and 2,2’-bipyridine building blocks for applications in coordination chemistry and
materials science.
INTRODUCTION
There has been an extensive effort to develop synthetic methods for azines, specially pyridines and
2,2’-bipyridines, due to their presence as substructures in many natural products and pharmaceuticals, and
also as ligands for transition metals.1 The renewed interest in this chemistry has been driven, to a great
extent, by their ability to act as chelating agents for almost all kinds of metal ions and the wide range of
applications rising from their involvement in supramolecular chemistry2 and in materials science.3
However, synthetic access to functionalized derivatives is still difficult, and reliable preparative protocols
are therefore highly desirable. Disubstituted 2,2’-bipyridines have been prepared by connecting two
pyridine precursors at C-2 with the help of palladium or nickel transition metal complexes and some
protocols have proven to be quite successful for the preparation of symmetrically and non–symmetrically
substituted derivatives. 4, 5
However, most of the reported disubstituted pyridine building blocks are 2,6- or 2,5-derivatives, whereas
2,4-derivatives are scarce, because 2,4-dihalopyridines are not readily available.6
The growing interest in this field and our interest in the synthesis of complex pyridine-containing

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HETEROCYCLES, Vol. 75, No. 1, 2008
molecules7 led us to focus on the development of expeditious methods for the preparation of suitable
pyridine precursors for use in transition-metal catalyzed-processes, namely 2,4-dibromopyridine (1)8 and
4,4’-dihalo-2,2’-bipyridine (2).9
Br
X
X
N
Br
N
N
1
2a X = Br
2b X = Cl
Figure 1
RESULTS AND DISCUSSION
For the synthesis of 2,4-dibromopyridine two commercially available starting materials appeared to be the
most appropriate, 2,4-dihydroxypyridine (3) and 2-bromopyridine (4) (Scheme 1)
OH
Br
POBr3, 125 ºC
90%
OH
N
N
Br
3
1
Br2, HBr,
NaNO2
60%
AcBr, 130 ºC
71 %
NO2
NH2
a) MCPBA, CHCl3,
25 ºC
Fe, AcOH
100 ºC
b) HNO3, H2SO4
Br
N
Br
100%
N
Br
N
77%
O
4
5
6
Scheme 1
Firstly, we optimized the method reported by den Hertog and prepared 2,4-dibromopyridine (1) in 90 %
yield by treatment of 2,4-dihydroxypyridine with phosphorus oxybromide at 125 ºC.8a, 10 Alternatively,
diazotation of amine 6 followed by bromine substitution provided 2,4-dibromopyridine in 46 % yield in
four steps from easily accessible starting material 2-bromopyridine.6b Although these protocols gave quite
satisfactory results, more practical and scalable routes to 2,4-dibromopyridine (1) would be very
advantageous.
We have developed an alternative procedure for preparing larger quantities of dibromopyridine
derivatives 1 and 2 starting from the appropriate pyridine N-oxide. Treatment of 2-bromo-4-nitropyridine
N-oxide (5) with acetyl bromide yielded different products depending on the reaction temperature, either
2,4-dibromopyridine N-oxide (7) or 2,4-dibromopyridine (1). Thus, when the reaction between pyridine

HETEROCYCLES, Vol. 75, No. 1, 2008
59
N-oxide 5 and acetyl bromide was run at 80 ºC dibromopyridine N-oxide 7 was obtained in 85% yield.
Most conveniently, keeping the temperature at 130 ºC throughout the reaction, the target
2,4-dibromopyridine (1) was prepared in 55% yield from 2-bromopyridine in three steps (Scheme 2).
2,4-Dibromopyridine (1) undergoes efficient regioselective palladium-catalyzed cross-coupling reactions
affording 4-bromo-2-carbon-susbstituted pyridines, which have proven to be quite difficult to prepare
using other methods.7c
NO2
Br
Br
AcBr, AcOH, 80 ºC
for 5: 85%
for 8: 76%
AcBr, AcOH, 130 ºC
for 7: 80%
for 9: 60%
N
O
X
N
O
X
N
X
1 X = Br
2a X = 4-bromopyrid-2-yl
5 X = Br
8 X = 4-nitropyrid-2-yl
7 X = Br
9 X = 4-bromopyrid-2-yl
AcBr, AcOH, 130 ºC
for 5: 71%
for 8: 70%
Scheme 2
These results prompted us to apply the same strategy to the synthesis of 4,4’-dibromo-2,2’-bipyridine (2),
an important building block in supramolecular chemistry and coordination chemistry. Treatment of
dinitro compound 8 with acetyl bromide in glacial acetic acid at 130 ºC led to dibromobipyridine 2a in
good yield in one-pot with the subsequent waste reduction. This global transformation can also be carried
out stepwise in a 46% overall yield (Scheme 2).11
The efficiency of metal-catalyzed cross-coupling reactions for connecting unsaturated and saturated
fragments is well documented, particularly for (aza)biaryl bond formation.12 The Stille reaction has
already proven to be a very attractive procedure to synthesize oligopyridines.13 We therefore conceived an
alternative approach to dihalobipyridines by position-selective Stille coupling of 2-bromo-4-halopyridines
with 4-halo-2-stannylpyridines. The latter could in turn be prepared in situ by Pd-assisted cross-coupling
of the same 2-bromo-4-halopyridine with hexaalkyldistannanes14 (Scheme 3).
X
X
X
N
(Me3Sn)2, Pd(PPh3)4
100 ºC; 65% (for 1)
1, Pd(PPh3)4, CuI
100 ºC; 57% (for 11)
N
N
Br
N
SnMe3
X
1 X = Br
10 X = Cl
11 X = Br
12 X = Cl
2a X = Br
2b X = Cl
(Me3Sn)2, Pd(PPh3)4
for 1: CuI, 100 ºC, 35-45%
for 10: 130 ºC, 70%
Scheme 3
Treatment of 2-bromo-4-chloropyridine (10) with hexamethyldistannane (60 mol%) and Pd(PPh3)4 (10

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HETEROCYCLES, Vol. 75, No. 1, 2008
mol%) in xylene at 130 °C for 20 h, afforded 4,4’-dichloro-2,2’-bipyridine (2b) in 70 % yield. The
reaction was highly halogen-selective, since only traces of a side product, identified as
4,4”-dichloro-2,2’:4’,2”-terpyridine, were detected by 1H-NMR analysis of the reaction mixture. However,
under these conditions bipyridine 2a was obtained in lower yield. Although position 2 should react faster
as expected for a SN2-like process, probably the temperature is too high to discriminate fully between
both C—Br bonds and the preparation of the intermediate stannylpyridine 11 was required. Thus,
position-selective reaction of 2,4-dibromopyridine with hexamethylbistannane (110 mol %) involved
heating at 90ºC in toluene for 16 h in the presence of Pd(PPh3)2Cl2 (10 mol%) and LiCl (30 mol%). The
desired 2-stannylpyridine 11 was obtained in 62 % yield and the regioselectivity (C2:C4 coupling) was
10:0.5. The use of Pd(PPh3)4 in dioxane at 100 ºC for 8 h afforded the target compound 11 in 65% yield
with a similar regioselectivity (10:0.7). Finally, the cross-coupling of pyridylstannane 11 and
2,4-dibromopyridine (1) using Pd(PPh3)4 (10 mol%) in the presence of CuI in dioxane at 100 ºC for 90 h
gave 4,4’-dibromo-2,2’-bipyridine (2a) in 56% yield, along with small amounts of
2,4’-dibromo-4,2’-bipyridine and 4,4”-dibromo-2,4’:2’,2”-terpyridine.
Bipyridine 2a turned out to be a useful starting material for producing highly conjugated systems under
palladium-catalyzed cross-coupling reaction conditions. Under Suzuki (or Stille) conditions the
monocoupled compound 13 was the major product (85% corrected yield), while under Sonogashira
conditions the dicoupled product 14 was obtained in good yield (78% yield). (Scheme 4).
This methodology represents a useful procedure for preparing, symmetrically and non-symmetrically
substituted bipyridines from 4,4’-dibromo-2,2’-bipyridine (2a).
OH
N
(HO)2B
OH
Pd(PdPh3)4, TlOH
THF, 25 ºC, 53%
N
N
Br
Br
N
13
OH
N
Br
2a
OH
N
Pd(PdPh3)2Cl2, CuI
i-Pr2NH, THF, 40 ºC
78%
14
HO
Scheme 4
In summary, we have developed a practical synthetic route to 2,4-dibromopyridine and
4,4’-dibromo-2,2’-bipyridine from the corresponding nitroazine N-oxides via a tandem two-step sequence.
The Stille coupling of 2-bromo-4-bromo(chloro)pyridine, either in one or two steps, constitutes a direct

HETEROCYCLES, Vol. 75, No. 1, 2008
61
route to 4,4’-dibromo(dichloro)-2,2’-bipyridine. Both azines proved to be valuable compounds in
palladium-catalyzed cross-coupling processes to produce highly conjugated pyridines and bipyridines,
architectural motifs with potential uses in coordination and materials chemistry.
EXPERIMENTAL
General: Reagents and solvents were purchased as reagent-grade and used without further purification
unless otherwise stated. Solvents were dried according to published methods15 and distilled before use.
All reactions were performed in oven-dried or flame-dried glassware under an inert atmosphere of Ar
unless otherwise stated. NMR spectra were recorded in a Bruker AMX400 (400.13 MHz and 100.61 MHz
for proton and carbon respectively) spectrometer at 298 K with residual solvent peaks as internal
reference and the chemical shifts are reported in δ [ppm], coupling constants J are given in [Hz] and
13
expressed as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. C-multiplicities
assigned with DEPT experiments and COSY, HMBC and HSQC methods were used to establish atom
connectivities. Electronic impact ionization (EI) and fast atom bombardment (FAB) mass spectra were
recorded on a VG-Autospec M instrument. Melting points (mp) were taken on a Stuart Scientific
apparatus.
2,4-Dibromopyridine (1). Method a: 2,4-Dihydroxypyridine (3) (2.7 g, 24.3 mmol) and POBr3 (23 g,
80.22 mmol) were heated in a Schlenk flask to 125 ºC for 4.5 h. After cooling to 25 ºC, the reaction
mixture was carefully poured into water, neutralized with Na2CO3 and extracted with CH2Cl2. The
combined extracts were dried and the solvent removed in vacuo. The residue was purified by flash
chromatography (40:60, CH2Cl2/hexane) to give 5.24 g (90 % yield) of 2,4-dibromopyridine (1) as a
white solid, mp 35-36 ºC (EtOH), (lit.,8a 38.0-38.5 ºC) and 698 mg (9%) of 2,3,4-tribromopyridine, mp 86
ºC (EtOH), (lit.,8a 84-85 ºC). 1H NMR (400.16 MHz, CDCl3): δ 7.43 (dd, J = 5.3, 1.4 Hz, 1H), 7.71 (d, J =
1.4 Hz, 1H), 8.21 (d, J = 5.3 Hz, 1H). 13C NMR (100.63 MHz, CDCl3): δ 126.2 (CH, C5), 130.9 (CH, C3),
133.9 (C, C4), 142.5 (C, C2), 150.5 (CH, C6). MS: m/z (%) 237 (M+ 81[Br]79[Br], 75), 158 (97), 156 (100).
Method b: Acetyl bromide (2.4 mL, 31.96 mmol) was added to a solution of 2-bromo-4-nitropyridine
N-Oxide (5)16 (0.5 g, 2.3 mmol) in AcOH (4 mL) and the reaction mixture was heated to 130 ºC for 16 h.
Then, it was carefully poured into ice, basified with Na2CO3 to pH=9 and extracted with CH2Cl2. The
combined organic phase was separated, dried and the solvent removed under reduced pressure. The
residue was purified to give 2,4-dibromopyridine (1) (0.39 g, 71 % yield).
4,4’-Dibromo-2,2’-bipyridine (2a). Method a: following method b for the preparation of
2,4-dibromopyridine (1), acetyl bromide (6.4 mL, 86 mmol) and 4,4’-dinitro-2,2’-bipyridine N,N’-dioxide
(10)9a (0.43 g, 1.55 mmol) in AcOH (11 mL) at 130 ºC for 10 h gave 4,4’-dibromo-2,2’-bipyridine (2a)
(0.34 g, 70%) as a white solid after purification by silica gel column chromatography (96:4,

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HETEROCYCLES, Vol. 75, No. 1, 2008
hexane/EtOAc). Mp 139-140 ºC (lit.,9a 141-142 ºC) (hexane). 1H NMR (400.16 MHz, CDCl3): δ 7.49 (dd,
J = 5.2, 1.8 Hz, 2H), 8.46 (d, J = 5.2 Hz, 2H), 8.60 (d, J = 1.8 Hz, 2H). 13C NMR (100.62 MHz, CDCl3): δ
124.8 (CH), 127.4 (CH), 134.0 (C), 149.8 (CH), 156.0 (C).
Method b: 4-bromo-2-trimethylstannylpyridine (11): In a dry Schlenk flask, Pd(PPh3)2Cl2 (0.075 g,
0.105 mmol), LiCl (0.015 g, 0.3 mmol) and toluene (5 mL) were placed and purged with argon. Then
Me6Sn2 (1.2 mL of a solution 0.97 M in toluene, 1.15 mmol) was added followed by 2,4-dibromopyridine
(1a) (0.250 g, 1.05 mmol). The reaction mixture was stirred at 90 ºC for 16 h, then washed with aqueous
saturated KF and extracted with CH2Cl2. The combined organic layer was separated, dried over Na2SO4
and the solvent removed under reduced pressure. Purification by distillation afforded
4-bromo-2-trimethylstannylpyridine (12a) (220 mg, 65%) along with a compound identified as
1
2-bromo-4-trimethylstannylpyridine in a 20:1 ratio. H NMR (400.16 MHz, CDCl3): δ 0.36 (s, J119Sn-H
2
=
2
3
56.2 Hz, J117Sn-H = 53.7 Hz, 9H), 7.33 (dd, J = 5.4, 2.1 Hz, 1H), 7.61 (d, J =2.0 Hz, J119Sn-H = 22.3 Hz,
3J117Sn-H = 18.4 Hz, 1H), 8.53 (d, J = 5.4 Hz, 1H). 13C NMR (100.61 MHz, CDCl3): δ -9.8 (CH3), 89.8 (C),
125.3 (CH), 131.8 (C), 134.0 (CH), 150.8 (CH). MS (FAB+) m/z (%): 322 ([M+1]+, 6). HRMS (FAB+)
1
calcd. for C8H13NBrSn 319.9244, found 319.9247. 2-Bromo-4-trimethylstannylpyridine: H-NMR
(400.16 MHz, CDCl3): δ 0.35 (s, 2JSn-H = 55.4 Hz, 9H), 7.32 (d, J = 4.5 Hz, 3JSn-H = 37.8 Hz, 1H), 7.56 (bs,
3JSn-H = 39.6 Hz, 1H), 8.26 (d, J = 4.5 Hz, 1H). MS (FAB+) m/z (%): 322 ([M+1]+, 43).
Stille coupling: Pd(PPh3)4 (0.4 g, 0.035 mmol), CuI (135 mg, 705 mmol),
4-bromo-2-trimethylstannylpyridine (12a) (0.11 g, 0.35 mmol) and 2,4-dibromopyridine (1a) (90 mg, 0.4
mmol) were heated in degassed THF (4 mL) at 100 ºC for 96 h under argon. The reaction mixture was
allowed to cool to 25 ºC, the solvent evaporated and the residue was taken up in CH2Cl2. Then a 30%
NH4OH (1 mL) and EDTA (0.18 g) were added and the mixture stirred at 40 ºC for 1 h. The organic
phase was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were
dried, the solvent removed and the residue purified by chromatography in alumina grade III (10:90
CH2Cl2/hexane) to give 4,4’-dibromo-2,2’-bipyridine (2a) (63 mg, 57 %). 2,4’-Dibromo-4,2’-bipyridine:
1H-NMR (400.16 MHz, CDCl3): δ 7.55 (dd, J = 5.2, 1.2 Hz, 1H), 7.83 (dd, J = 5.2, 1.6 Hz, 1H), 7.94 (d, J
= 1.6 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H). 13C NMR
(100.61 MHz, CDCl3): δ 120.1 (CH), 124.5 (CH), 125.6 (CH), 127.5 (CH), 134.0 (C), 143.2 (C), 147.8
(C), 150.7 (C), 150.8 (C), 154.3 (C). MS (EI+) m/z (%): 317 ([M+1]+ 81[Br], 6), 316 ([M]+ 81[Br], 53), 315
([M+1]+ 79[Br] [Br], 13), 314 ([M]+ 79[Br] 81[Br], 96), 313 ([M+1]+ 79[Br], 7), 312 ([M]+ 79[Br], 54).
81
HRMS (EI+) calcd. for C10H6N2Br2 311.8898, found 311.8891. 4,4”-Dibromo-2,4’:2’,2”-terpyridine:
1H-NMR (400.16 MHz, CDCl3): δ 7.52 (dd, J = 5.1, 1.6 Hz, 1H), 7.54 (dd, J = 5.2, 1.8 Hz, 1H), 8.01 (dd,
J = 5.1, 1.4 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.54 (d, J = 5.1 Hz, 1H), 8.59 (d, J = 5.2 Hz, 1H), 8.70 (d, J
13
= 1.6 Hz, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.94 (d, J = 1.4 Hz, 1H). C NMR (100.61 MHz, CDCl3):

HETEROCYCLES, Vol. 75, No. 1, 2008
63
δ 118.6 (C), 121.8 (C), 124.5 (CH), 124.8 (CH), 127.1 (CH), 133.9 (C), 134.1 (C), 146.3 (C), 149.8 (CH),
150.0 (CH), 150.7 (CH), 156.0 (C). MS (EI+) m/z (%): 392 ([M+1]+ 81[Br], 8), 393 ([M]+ 81[Br], 51), 392
([M+1]+ 79[Br] [Br], 19), 391 ([M]+ 79[Br] 81[Br], 100), 389 ([M+1]+ 79[Br], 10), 389 ([M]+ 79[Br], 49).
81
HRMS (EI+) calcd. for C15H9N3Br2 388.9163, found 388.9156.
4,4’-Dichloro-2,2’-bipyridine (2b). To a mixture of Pd(PPh3)4 (0.320 g, 0.25 mmol),
2-bromo-4-chloropyridine (1b)17 (0.480 g, 2.5 mmol) in xylene (12.5 mL) under argon, Me6Sn2 (276 µL,
1.3 mmol) was added. The reaction mixture was stirred at 130 ºC for 20 h. Then the solvent was removed
under reduced pressure and the residue purified by flash chromatography (silica gel, 96:4 hexane/EtOAc)
to give 4,4’-dichloro-2,2’-bipyridine (2b) (196 mg, 70 % yield) as a white solid. Mp 132 ºC (hexane)
(lit.,9b 129 ºC).
ACKNOWLEDGEMENTS
We thank Xunta de Galicia and Ministerio de Educación y Ciencia (Spain) for financial support. J.-L.
A.-G. and C. S. thank Ministerio de Educación y Ciencia for a FPI and FPU fellowship, respectively. R.
G.-L. was a recipient of a stipendium from Xunta de Galicia. We also thank Fernando Martínez for
preliminary experiments and Dr. Tony J. Wigglesworth for editing the manuscript.
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