International Journal of Organic Chemistry, 2011, 1, 33-36
doi:10.4236/ijoc.2011.12006 Published Online June 2011 (
Copyright © 2011 SciRes. IJOC
A Facile and Inexpensive Synthesis of 6-Ethynylbipyridine
Jianqiang Huo, John O. Hoberg
Department of C hemi st ry , University of Wyoming, Laramie, USA
Received April 6, 2011; revised May 16, 2011; accepted May 21, 2011
An inexpensive synthesis of 6-ethynylbipyridine has been accomplished using Sonogashira coupling of
2-bromo-6-iodopyridine with 2-methyl-3-butyn-2-ol. Subsequent Stille coupling with 2-(trimethylstannanyl)
pyridine and hydrolysis provided the target compound in an overall high yield.
Keywords: 6-Ethynylbipyridine, 2-Bromo-6-Iodopyridine, 2-Methyl-3-Butyne-2-ol, Palladium Coupling
1. Introduction
Bipyridines are widely used structures that are found in a
large range of functions. These include ligands in coor-
dination chemistry, photocatalysts, functionalized poly-
mers, sensors, supramolecular assemblies and met-
allo-DNA conjugates. Thus, their importance in inor-
ganic, organic and medicinal chemistry cannot be over-
stated. The syntheses of functionalized 2,2’-bipyridines
for the above areas are therefore needed and although
numerous methods exist in the literature inexpensive and
facile procedures are desirable. One such bipyridine is
6-ethynylbipyridine (1), which has the ability to undergo
Sonogashira coupling to a host of other materials and has
therefore been used in the synthesis of metallo-DNA
conjugates [1], nucleosides bearing metal complexes for
antiviral activity [2-4] and photoactive materials [5-8].
The reported synthesis [1] (Scheme 1) relies on a Stille
reaction in the first step for the formation of 6-bromo-
2,2’-bipyridine (a Suzuki coupling has also been reported
in 54% yield [9]), which, in a second step, undergoes
further coupling of the resulting bromobipyridine prod-
uct with the expensive trimethylacetylene (TMSA). We
recently required large amounts of this material and en-
visioned that both these issues could easily be resolved
by the use of alternative reagents.
2. Results
Our strategy for an alternative synthesis involved the use
of 2-bromo-6-iodopyridine and 2-methyl-3-butyn-2-ol as
replacement reagents (Scheme 2). The synthesis of
2-bromo-6-iodopyridine has been reported in which a
bromine-magnesium exchange using iPrMgCl in THF is
employed [10], however we found this procedure diffi-
cult to reproduce. Therefore, we adapted Peterson’s [11]
procedure, in which the formation of 2-bromo-6-lithio-
pyridine is accomplished using n-butyllithium in di-
chloromethane. Treatment of this with iodine provided 2
in high yield. Sonogashira coupling of 2 with 2-methyl-
3-butyn-2-ol proceeded in excellent yield as expected,
and overcomes the use of expensive TMSA as the cost of
2-methyl-3-butyn-2-ol is inconsequential. We did at-
tempt to couple 2-methyl-3-butyn-2-ol with 2,6-dibro-
mopyridine, however unacceptable yields and complex
mixtures resulted.
Stille coupling of 3 with 2-(trimethylstannyl)pyridine
[12] gave 4 in excellent yield, which was easily hydrolized
to give target bipyridine 1 in an overall very good yield.
In conclusion, we have developed an inexpensive and
facile synthesis of 6-ethynylbipyridine. In particular, a ro-
bust synthesis of 2-bromo-6-iodopyridine (2) has been ac-
complished, which is critical to this chemistry and is a
compound used in a variety of other reported couplings
NBr Br
Scheme 1
86% 93%
Scheme 2. Reagents and conditions: (i) n-BuLi then I2,
CH2Cl2, 78˚C, 3 h; (ii) 2-methyl-3-butyn-2-ol, Pd(PPh3)4,
CuI, Et2NH, r.t., 20 h; (iii) 2-(trimethylstannyl)pyridine,
Pd(PPh3)4, toluene, 110˚C, 12 h; (iv) NaOH, toluene, 90˚C -
100˚C, then H+40 min.
[13-17]. Furthermore, the use 2-methyl-3-butyn-2-ol in
replacement of TMSA has been shown to be successful
in bipyridine chemistry.
3. Experimental
1H and 13C NMR spectra were recorded at 400 and 100
MHz, respectively in the indicated solvent. Chemical
shifts are reported in δ units, J in Hz relative to CDCl3
(7.24 ppm for 1H NMR and 77.0 ppm for 13C NMR).
Infrared spectra were determined on a Perkin Elmer
Paragon 500 FT-IR spectrophotometer. Et2O was distilled
from NaK; toluene and CH2Cl2 were distilled from cal-
cium hydride. Flash chromatography was performed us-
ing Silicycle ultra pure silica gel 60 Å (230 - 400 Mesh).
Standard syringe techniques were employed for handling
air-sensitive reagents and all reactions were carried out
under argon.
3.1. 2-Bromo-6-iodopyridine (2)
To a flame-dried flask containing 2,6-dibromopyridine
(1.00 g, 4.22 mmol), dry CH2Cl2 (100 mL) and cooled to
–78˚C was slowly added n-BuLi (3.3 mL, 4.6 mmol of a
1.4 M hexanes solution). The reaction was stirred for 20
minutes at –78˚C then a solution of I2 (1.06 g, 4.2 mmol,
dissolved in 20 mL of CH2Cl2) was added via cannula.
The resulting mixture was stirred at –78˚C for 3 h, the
cold bath removed, and the mixture stirred for 30 minutes
at room temperature. The mixture was quenched with
saturated NaHCO3 solution, the layers were separated and
the aqueous layer extracted twice with CH2Cl2. The
combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. Gradient flash chromatogra-
phy on silica gel (cyclohexane then 15:1 cyclohex-
ane/EtOAc) afforded 1.13 g (3.63 mmol, 86%) 2 as a light
yellow solid. 1H NMR and 13C NMR spectra were con-
sistent with published data [10].
3.2. 4-(6-Bromopyridin-2-yl)-2-methyl-3-butyn-
2-ol (3)
In an oven-dried flask, 2-bromo-6-iodopyridine (2) (470
mg, 1.65 mmol), 2-methyl-3-butyn-2-ol (152 μL, 1.57
mmol), Pd(PPh3)4 (10 mg, 0.008 mmol) and copper(I)
iodide (10 mg, 0.069 mmol) were dissolved in Et2NH (50
mL) and stirred for 20 h at room temperature. The mixture
was concentrated in vacuo, and quenched with water (20
mL), extracted with Et2O (2 × 20 mL). The combined
organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. Flash chromatography on silica gel, (1:1
cyclohexane/EtOAc) afforded 370 mg (93%) of 3 as a
yellow oil. 1H NMR (CDCl3): δ1.62 (s, 6H, (CH3)2C),
2.70 (s, 1H, OH), 7.34 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 7.8
Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H); 13C NMR (CDCl3): δ
30.9, 65.2, 80.2, 95.5, 125.9, 127.4, 138.3, 141.4, 143.3.
IR (neat): 3450, 2910, 2231, 1550, 1420, 1300 cm–1.
3.3. 2-(Trimethylstannyl)pyridine [12]
2-Bromopyridine (4.25 g, 27.0 mmol) was dissolved in
dry Et2O (100 mL) cooled to –78˚C and then n-BuLi (38.0
mL, 1.4M hexanes solution) was added dropwise fol-
lowed by stirring at –78˚C for 2 h. Me3SnCl (5.75 g, 28.8
mmol) dissolved in Et2O (20 mL) was added dropwise
from a syringe, and the reaction mixture stirred 3 h at
–78˚C followed by slowly warming to room temperature
over 12 h. The reaction flask was concentrated in vacuo
and dry hexanes (30 mL) were added from a syringe and
the slurry was stirred for 10 minutes. Filtration under
argon, concentration in vacuo gave the crude product that
can be stored in a freezer and is used in the next step
without further purification.
3.4. 2-Methyl-4-(6-(2,2-bipyridin)3-butyn-2-ol (4)
The 2-(trimethylstannyl)pyridine obtained above (1.20 g,
4.96 mmol) was dissolved in dry toluene (30 mL), can-
nulated into a flask equiped with condensor and side-arm
containing 3 (770 mg, 3.21 mmol) and the mixture de-
gassed with argon for 1 h. Pd(PPh3)4 (10 mg, 0.008 mmol)
was added and the reaction mixture was heated under
reflux while stirring for 12 h. The mixture was cooled and
poured into 2M NaOH (20 mL) and extracted with toluene
(2 × 30 mL). The combined organic phases were dried
(Na2SO4), filtered and concentrated. Flash chromatogra-
phy on silica gel (10:1 cyclohexane/ EtOAc) afforded 710
mg (92%) of 4 as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ 1.67 (s, 6H, (CH3)2C), 2.97 (s, 1H, OH), 7.31
Copyright © 2011 SciRes. IJOC
J. Q. HUO ET AL.35
(dq, J = 7.5,1.2 Hz, 1H), 7.41 (dd, J = 7.6,1.0 Hz, 1H),
7.77 (t, J = 7.7 Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H),
8.34 (d, J = 7.9 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.68 (d,
J = 5.1 Hz, 1H); 13C NMR (CDCl3): δ 31.2, 65.4, 81.8,
93.5, 120.4, 121.6, 124.0, 127.2, 137.0, 142.3, 149.0,
155.4, 156.3. IR (neat) 3455, 2228, 1685, 1265, 1250,
1150, 1125 cm–1.
3.5. 2-Ethynyl-6-2,2-bipyridine (1)
NaOH (1.61 g, 40.18 mmol) and 4 (450 mg, 2.0 mmol),
were dissolved in toluene (50 mL) and then brought to a
boil for 40 minutes. The resulting golden-brown solution
was concentrated and the residues were quenched with
H2O (20 mL), with CH2Cl2 (30 mL) being added at the
same time. The pH of the mixture was adjusted to 7 by
adding 2M HCl dropwise then the layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 20
mL). The combined organic extractions were dried
MgSO4, filtered and concentrated. Flash chromatography
on silica gel (5:1 cyclohexane/EtOAc) afforded 301 mg
(83%) of 1 as a white solid. 1H NMR and 13C NMR
spectra were consistent with published data [11].
4. Acknowledgements
This work was supported by a grant from the School of
Energy Research, University of Wyoming, which is
gratefully acknowledged.
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