One-pot synthesis of 5,5′-dibromo-2,2′-dipyridylacetylene and its boronic acid derivative

Article abstract of DOI:10.1016/j.tetlet.2010.09.062

5,5′-Dibromo-2,2′-dipyridylacetylene was prepared from 2,5-dibromopyridine and (trimethylsilyl)acetylene via the new one-pot synthesis approach using a regioselective palladium-catalyzed coupling reaction with a 60% yield. Several protocols of lithium-hal

Full text of DOI:10.1016/j.tetlet.2010.09.062

Tetrahedron Letters 51 (2010) 6243–6245
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of 5,50-dibromo-2,20-dipyridylacetylene and its boronic
acid derivative
⇑
Hyung Joon Jeon, Jung Hoon Choi, Jeung Ku Kang
NanoCentury KAIST Institute, Graduate School of EEWS (WCU) and Department of Materials Science & Engineering, KAIST, Daejeon 305-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
5,50-Dibromo-2,20-dipyridylacetylene was prepared from 2,5-dibromopyridine and (trimethylsilyl)acety-
lene via the new one-pot synthesis approach using a regioselective palladium-catalyzed coupling reac-
Article history:
Received 21 July 2010
Revised 14 September 2010
Accepted 17 September 2010
Available online 1 October 2010
tion with
a 60% yield. Several protocols of lithium–halogen exchange were then attempted to
synthesize 6,60-(1,2-ethynediyl)bis[3-pyridylboronic acid] from 5,50-dibromo-2,20-dipyridylacetylene.
The former was successfully obtained with a 54% yield by a reverse addition method using toluene
and THF and it showed potential as a useful building block for cross-coupling reactions in the formation
of carbon–carbon bonds.
Keywords:
2,5-Dibromopyridine
5,50-Dibromo-2,20-dipyridylacetylene
6,60-(1,2-Ethynediyl)bis[3-pyridylboronic
acid]
Ó 2010 Elsevier Ltd. All rights reserved.
Diarylacetylenes are important components in polymers, oligo-
mers, and dendrimers, because their conjugated systems exhibit
unique optical and electronic properties, as well as environmental
stabilities.1 Furthermore, compounds such as diarylacetylenes that
bear carbon–carbon triple bonds are extensively employed in phar-
maceuticals and fine chemicals.2 Among them, 2,20-dipyridylacety-
have not been reported. The effective synthesis of a boronic acid
derivative could give versatile applications in various fields of
chemistry. Therefore, we report the new method for a facile one-
pot preparation of 5,50-dibromo-2,20-dipyridylacetylene and its
boronic acid derivative using the lithium–halogen exchange.
The most commonly employed method for formation of bonds
between acetylene and heterocycle is a palladium-catalyzed cou-
pling in the presence of cuprous iodide and an alkylamine solvent.9
Recently, Tilley and Zawoiski successfully synthesized 5-bromo-2-
[2-(trimethylsilyl)ethynyl]pyridine 2 from commercially available
2,5-dibromopyridine 1 and (trimethylsilyl)acetylene by the con-
ventional palladium-catalyzed coupling.10 In this letter we report
that, 1 reacted regioselectively with (trimethylsilyl)acetylene at
the 2-position of pyridine, and 2 was obtained with a 74%
yield. We focused on the aspect that 1 has the regioselective reac-
tivity in the palladium-catalyzed coupling. For the preparation of
lene, a linear and rigid molecule with an extended p-conjugation,
has won great attention for a proton transfer-mediated electron
transfer in organic materials and its molecular complexes with or-
ganic proton donors or inorganic compounds showed DA-type
intermolecular interactions.3 In addition, recently, new methods
for the preparation of 2,20-dipyridylacetylene have been reported.4
However, to our knowledge there have been no report on the syn-
thesis of their derivatives and the further progress in research
areas using 2,20-dipyridylacetylene.
Meanwhile, boronic acids have been used for cross-coupling
reactions in formation of carbon–carbon bonds.5 While arylboronic
acids are typically prepared through the lithium–halogen exchange
of the corresponding aryl halides,6 the preparation of a boronic
acid of aromatic heterocycle mediated heteroaryllithium has some
problems due to the intrinsic instability of heteroaryllithium.7
Among aromatic heterocyclic compounds, substituted pyridines
have a great potential to be used as important components to drug
candidates. In particular, 3-bromopyridine has been successfully
used to prepare 3-pyridylboronic acid with a good yield.8 However,
so far, the methods for the preparation of a boronic acid of com-
pounds containing two pyridines such as 2,20-dipyridylacetylene
a
Br
Br
Br
TMS
N
N
1
2
1. a
2. d or e
b
1,
c
Br
H
Br
Br
N
N
N
3
4
Scheme 1. Synthesis of 5,50-dibromo-2,20-dipyridylacetylene 4 and reagents: (a)
TMSA, CuI, Pd(PPh3)2Cl2, NEt3; (b) NaOH, MeOH; (c) CuI, Pd(PPh3)2Cl2, NEt3; (d)
TBAF; (e) NH4F, KOH, i-PrOH.
⇑
Corresponding author. Tel.: +82 42 350 3338; fax: +82 42 350 3310.
E-mail address: jeungku@kaist.ac.kr (J.K. Kang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.062

6244
H. J. Jeon et al. / Tetrahedron Letters 51 (2010) 6243–6245
1. n-BuLi
Br
Br
(HO)2B
B(OH)2
N
N
N
N
2. Triisopropyl borate
3. HCl
4
5
Scheme 2. Synthesis of 6,60-(1,2-ethynediyl)bis[3-pyridylboronic acid] 5 and reagents.
5,50-dibromo-2,20-dipyridylacetylene 4, we reacted 1 with 5-bro-
mo-2-ethynylpyridine 3 (Scheme 1). As a result of the reaction,
we obtained 4 with a 72% yield, which was determined through
1H and 13C NMR, GC–MS, and elemental analyzes for its identifica-
tion. Although we successfully obtained 4, this method is not very
efficient as it was carried out in stepwise procedures and the
expensive catalyst palladium was used in two different steps. Also,
the purification of products 2 and 4 from the reaction mixture is
not so easy due to the formation of byproducts and residues of
catalysts. To overcome these shortcomings, we developed one-
pot synthesis methods in which different reagents were used and
obtained 4 in 60% yields.12 The omission of just one reagent from
the mixture of NH4F, KOH, and i-PrOH resulted in no formation
of products. The one-pot synthesis methods also exploit the char-
acteristic that bromine ion attached at the 2-position of pyridine
is only reactive with the palladium catalyst regioselectively. Fur-
thermore, excessive 1 and additional reagents did not disturb the
palladium-catalyzed coupling reaction. The yields by two different
one-pot synthesis methods (60%) were higher than the overall
yield (53%), which is mediated by 2 and 3, and we could obtain 4
easily in gram quantities in these new methods. Also, these results
demonstrate that the important step for one-pot synthesis method
of 4 is how much 2 is generated, because the overall yields deviate
a little from the yield of 2.
lithium generally requires a coordinating solvent to disassociate
aggregations of n-butyllithium, it has been reported that toluene
is suitable for the exchange of some pyridine derivates.8b In gen-
eral, higher yields were obtained when THF was used as a solvent.
The reaction time with n-butyllithium did not affect the yields and
the excessive use of n-butyllithium resulted in no product (entries
5, 6). The use of 2.2 equiv of n-butyllithium and one hour reaction
time were found to be appropriate for this reaction. Therefore, it
appears that the primary difference of yields originated from the
solubility of 4. For the lithiation of 4, the concentration of dissolved
4, which can react with n-butyllithium, is important; a low concen-
tration gives rise to the limited lithiation. While the solubility of 4
was low in THF at ꢀ78 °C, 4 shows a very low solubility in toluene
and diethyl ether even at room temperature and the lithiation
reaction did not occur. Therefore, with the sequential addition, a
stabilizing effect of heteroaryllithium by toluene or diethyl ether
is not anticipated, because heteroaryllithium is not generated. It
is also assumed that the successful lithiation of chemicals contain-
ing one pyridine, such as 3-bromopyridine and 2,5-dibromopyri-
dine, in toluene or diethyl ether stemmed from their good
solubility and the stabilizing effect of the solvent. In cases where
high amounts of THF were used, higher yields were obtained (entry
2). However, further addition of solvent makes this reaction
unpractical.
We next considered the conversion of bromine to boronic acid,
6,60-(1,2-ethynediyl)bis[3-pyridylboronic acid] 5 (Scheme 2). Cur-
rently, there is no report found for the lithiation of chemicals con-
taining two pyridines such as 4. Magnesium- or lithium-halogen
exchanges are generally used for the conversion. However, in the
cases of chemicals containing one pyridine, improved lithium–
halogen exchange methods are mainly used, because then magne-
sium–halogen exchange has some problems in yields and opera-
tion.8 Therefore, we also evaluated different reaction conditions
for the lithium–halogen exchange (Table 1).
The lithium–halogen exchange of bromopyridine resulting in
THF is hindered by de-protonation occurring as a result of the rel-
ative acidity of bromopyridines and this problem causes low
yields.11 The order of addition of the reagents is the key to over-
coming the de-protonation. In this regard, the ‘in situ quench’
method, the ‘reverse addition’ method, and the use of a non-coor-
dinating solvent in conjunction with these methods were carried
out and found to give good yields.8a,b We also applied these meth-
ods to our lithiation procedures with some modifications.
In the ‘in situ quench’ method, n-butyllithium is added to a mix-
ture of pyridyl halide and triisopropyl borate followed by an acid
quench.8a For the efficient preparation of boronic acid by this
method, the lithium–halogen exchange on pyridyl halide should
be faster than the reaction between n-butyllithium and triisopro-
pyl borate; the generated lithiopyridine intermediate then reacts
quickly with the borate to prevent undesired side reactions. How-
ever, we obtained 5 with very low yield at ꢀ40 °C and significant
amounts of 4 were recovered (entry 7). From these results, it was
assumed that n-butyllithium was relatively more reactive with tri-
isopropyl borate than 4 or the generated pyridyllithium was very
labile. In addition, from the result of entry 8, we consider that
the dissolved concentration of 4 was very critical, because we
could not obtain 5 at ꢀ78 °C, a temperature, that is, more appropri-
ate for the prevention of de-protonation at ꢀ40 °C, but most of 4
was recovered. Compared with the sequential addition method,
the yields were not improved. Therefore, we focused on the reverse
addition method.
First, we carried out a conventional method known as the
‘sequential addition’ (entries 1–6). In this method, 4 was treated
with n-butyllithium followed by the addition of a triisopropyl bo-
rate. At entry 6, we used mixed toluene and THF: although n-butyl-
Table 1
Reaction methods and conditions for preparation of 6,60-(1,2-ethynediyl)bis[3-
pyridylboronic acid] 5
Entry Method
Solvent
Temperature Isolated
(°C)
yield (%)
1
Sequential addition THF
Sequential addition THF
Sequential addition THF
Sequential addition THF
Sequential addition Diethyl ether
Sequential addition Toluene + THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ40
ꢀ78
ꢀ78
28
37
30
0
10
15
15
0
2a
3b
4c
5
6d
7d
8d
9
In situ quench
In situ quench
Reverse addition
Reverse addition
Reverse addition
Toluene + THF
Toluene + THF
THF
THF + diethyl ether ꢀ78
THF + toluene
ꢀ78
In the ‘reverse addition’ method, pyridyl halide solution is
added to a solution of n-butyllithium followed by the addition of
triisopropyl borate.8b,11,13 In our experiments, THF was used as a
solvent for the preparation of the pyridyl halide solution due to
the solubility of 4. THF, diethyl ether, and toluene were used as sol-
vents for n-butyllithium and they showed yields of 40%, 21%, and
54%, respectively (entries 9–11). When toluene was used as a sol-
vent in the other methods (entries 6–8), low yields were obtained;
40
21
54
10e
11e
a
b
c
The volume of THF used here is twofold greater than for entry 1.
Reaction time between n-butyllithium and 4 is 2.5 h.
In this entry, 4.4 equiv of n-butyllithium was used.
Toluene and THF were in a ratio of 4:1.
d
e
Diethyl ether or toluene was used as a solvent for n-butyllithium.

H. J. Jeon et al. / Tetrahedron Letters 51 (2010) 6243–6245
6245
Iodobenzene
Na2CO3, Pd(PPh3)4
B(OH)2
(HO)2B
N
N
N
N
1,4-dioxane, H2O, reflux
5
6
Scheme 3. Synthesis of 5,50-diphenyl-2,20-dipyridylacetylene 6 and reagents.
5. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (b) Littke, A. F.; Dai,
C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020–4028.
6. Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631–2634.
7. Gilman, H.; Spatz, S. M. J. Org. Chem. 1951, 16, 1485–1494.
however, in the reverse addition method, toluene gave the highest
yields. It is thought that the reverse addition method prevented the
de-protonation of pyridyllithium and toluene activated the halo-
gen–lithium exchange. Although this method required a large
quantity of THF for the preparation of solution of 4, we could ob-
tain 5 with reproducibility and the best yield. To evaluate its po-
8. (a) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.;
Reider, P. J. J. Org. Chem. 2002, 67, 5394–5397; (b) Cai, D.; Larsen, R. D.; Reider,
P. J. Tetrahedron Lett. 2002, 43, 4285–4287; (c) Bouillon, A.; Lancelot, J.-C.;
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2002, 58, 2885–2890; (d) Parry,
P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002, 67,
7541–7543; (e) Bouillon, A.; Lancelot, J.-C.; Santos, J. S. O.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2003, 59, 10043–10049; (f) Thompson, A. E.; Hughes, G.;
Batsanov, A. S.; Bryce, M. R.; Parry, P. R.; Tarbit, B. J. Org. Chem. 2005, 70,
388–390; (g) Alessi, M.; Larkin, A. L.; Ogilvie, K. A.; Green, L. A.; Lai, S.;
Lopez, S.; Snieckus, V. J. Org. Chem. 2007, 72, 1588–1594; (h) Smith, A. E.;
Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. Eur. J. Org. Chem. 2008,
1458–1463.
tential as
a building block for cross-coupling reactions in
formation of carbon–carbon bonds, 5 was reacted with iodoben-
zene (Scheme 3).14 As a result of the reaction, we obtained 5,50-di-
phenyl-2,20-dipyridylacetylene 6 in 35% yield and it showed that 5
is useful in cross-coupling reaction.
In conclusion, we synthesized 5,50-dibromo-2,20-dipyridylacet-
ylene 4 from 2,5-dibromopyridine 1 with two different one-pot
synthesis methods. For the preparation of boronic acid of 4, we
evaluated several reaction conditions and successfully synthesized
6,60-(1,2-ethynediyl)bis[3-pyridylboronic acid] 5 by a reverse addi-
tion method using toluene and THF. The 5 showed potential as a
building block for cross-coupling reactions and further researches
are in progress in our laboratory.
9. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467–
4470.
10. Tilley, J. W.; Zawoiski, S. J. Org. Chem. 1988, 53, 386–390.
11. Cai, D.; Hughes, D. L.; Verhoeven, T. R. Tetrahedron Lett. 1996, 37, 2537–2540.
12. Preparation
of
5,50-dibromo-2,20-dipyridylacetylene
(4).
(Trimethylsilyl)acetylene (1.47 g, 15 mmol) was added to a solution of 2,5-
dibromopyridine (7 g, 29.7 mmol) in triethylamine (80 mL), cooled to 0 °C in an
ice bath. The solution was purged using argon gas for 10 min and cuprous
iodide (126 mg, 653
lmol) and bis(triphenylphosphinyl)palladium dichloride
(466 mg, 653 mol) were added. The mixture was stirred for 1 h at 0 °C and
l
then removed from the ice bath. The reaction mixture was allowed to warm to
room temperature and stirred for an additional 2.5 h. Tetrabutylammonium
fluoride (1 M in THF, 15 mL, 15 mmol) or a mixture of ammonium fluoride
(560 mg, 15 mmol), KOH (841 mg, 15 mmol), and isopropyl alcohol (30 mL)
was then added to the mixture, which was left under stirring at room
temperature for 24 h. The mixture was diluted with water (60 mL), extracted
with dichloromethane (75 mL ꢁ 4), washed with brine (100 mL), dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure. This
Acknowledgments
This work was mainly supported by the Korea Center for Artifi-
cial Photosynthesis (KCAP) funded by the Ministry of Education,
Science and Technology (NRF-2009-C1AAA001-2009-0093879),
by the Hydrogen Energy R&D Center from one of the 21st Century
Frontier R&D Program, and by the WCU (World Class University)
program (R-31-2008-000-10055-0). The fellowship for Dr. H. J.
Jeon was supported by the Priority Research Centers Program
(NRF-2009-0094041). Also, the works of Prof. J. K. Kang and Mr. J.
H. Choi were supported in parts by the grants from National Re-
search Foundation (NRF-R0A-2007-000-20029-0) and the Center
for Inorganic Photovoltaic materials (NRF-2010-0007692).
material was passed through
a silica gel column, eluted with 2:1
dichloromethane–ether, and crystallized from chloroform to give a pale gray
solid of 4 (2.99 g, 60%); mp: 240–242 °C; MS (EI): m/z 338 (M+); 1H NMR
(500 MHz, CDCl3) d 7.50 (d, 2H, J = 8 Hz), 7.85 (dd, 2H, J = 8 Hz, J = 2 Hz), 8.70 (d,
2H, J = 2 Hz); 13C NMR (125 MHz, CDCl3) d 88.3, 121.3, 128.9, 139.2, 141.0,
151.7; Anal. Calcd for C12H6Br2N2: C, 42.64; H, 1.79; N, 8.29. Found: C, 42.51; H,
1.45; N, 8.30.
13. Reverse addition procedure for the preparation of 6,60-(1,2-ethynediyl)bis[3-
pyridylboronic acid] (5). A solution of 4 (500 mg, 1.48 mmol) in anhydrous THF
(50 mL) was added dropwise to a solution of n-butyllithium (2.5 M in hexane,
1.4 mL, 3.5 mmol) in anhydrous toluene (30 mL), cooled to ꢀ78 °C. The mixture
was stirred for an additional 1 h while the temperature was held at ꢀ78 °C, and
triisopropylborate (1 mL, 4.3 mmol) was added. The mixture was kept to reach
room temperature for an additional hour. Then, the mixture was quenched by
the slow addition of 2 N HCl solution (15 mL) and concentrated under reduced
pressure. The residue was dissolved with an aqueous NaOH solution and
washed with diethyl ether (30 mL ꢁ 3). The resulting aqueous layer was
collected and acidified to pH 4 by the dropwise addition of HCl solution to
precipitate a yellow solid of 5 (212 mg, 54%); 1H NMR (500 MHz, DMSO-d6) d
7.68 (d, 2H, J = 8 Hz), 8.17 (d, 2H, J = 8 Hz), 8.50 (s, 4H), 8.93 (s, 2H); 13C NMR
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.062.
References and notes
1. (a) Marsella, M. J.; Piao, G.; Tham, F. S. Synthesis 2002, 1133–1135; (b)
Pappenfus, T. M.; Mann, K. R. Org. Lett. 2002, 4, 3043–3046; (c) Pearson, D. L.;
Tour, J. M. J. Org. Chem. 1997, 62, 1376–1387; (d) Biswas, M.; Nguyen, P.;
Marder, T. B.; Khundkar, L. R. J. Phys. Chem. A 1997, 101, 1689–1695; (e)
Stiegman, A. E.; Graham, E.; Perry, K. J.; Khundbar, L. R.; Cheng, L.-T.; Perry, J. W.
J. Am. Chem. Soc. 1991, 113, 7658–7666; (f) Wu, M.; Wei, L.; Lin, C.; Leou, S.;
Wei, L. Tetrahedron 2001, 57, 7839–7844.
(125 MHz, DMSO-d6)
d 88.4, 126.7, 142.1, 142.6, 155.2; Anal. Calcd for
C12H10B2N2O4: C, 53.81; H, 3.76; N, 10.46. Found: C, 53.53; H, 3.80; N, 9.91.
14. Preparation of 5,50-diphenyl-2,20-dipyridylacetylene (6). Compound 5 (100 mg,
0.37 mmol) and iodobenzene (160 mg, 0.78 mmol) were added to a mixture of
sodium carbonate (198 mg, 1.86 mmol) and tetrakis(triphenylphosphine)-
palladium(0) (43 mg, 0.037 mmol) in 1,4-dioxane (10 mL) and distilled water
(4 mL). The mixture was refluxed for 24 h and concentrated under the reduced
pressure. The residue was diluted with water (10 mL), extracted with
dichloromethane (15 mL ꢁ 3), washed with brine (20 mL), dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure. This
2. (a) Blaser, H.-U.; Indolese, A.; Schnyder, A. Curr. Sci. 2000, 78, 1336–1344; (b)
Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101–109.
3. (a) Zaman, M. B.; Tomura, M.; Yamashita, Y. Org. Lett. 2000, 2, 273–275; (b)
Teitei, T.; Collin, P. J.; Sasse, W. H. F. Aust. J. Chem. 1972, 25, 171–182; (c) Zaman,
M. B.; Tomura, M.; Yamashita, Y. J. Org. Chem. 2001, 66, 5987–5995; (d) Zaman,
M. B.; Smith, M. D.; Ciurtin, D. M.; Loye, H. Z. Inorg. Chem. 2002, 41, 4895–4903.
4. (a) Abele, E.; Abele, R.; Arsenyan, P.; Lukevics, E. Tetrahedron Lett. 2003, 44,
3911–3913; (b) Negishi, E.; Xu, C.; Tan, Z.; Kotora, M. Heterocycles 1997, 46,
209–214; (c) Fleckenstein, C. A.; Plenio, H. Green Chem. 2008, 10, 563–570.
material was passed through
a silica gel column, eluted with 9:1
dichloromethane–ether, and crystallized from a mixture of chloroform and
hexane to give a sheeny white solid of 6 (43 mg, 35%); 1H NMR (500 MHz,
CDCl3) d 7.41 (m, 2H), 7.48 (m, 4H), 7.60 (m, 4H), 7.70 (d, 2H, J = 8 Hz), 7.89 (dd,
2H, J = 8 Hz, J = 2 Hz), 8.88 (d, 2H, J = 2 Hz); 13C NMR (125 MHz, CDCl3) d 88.8,
127.3, 127.9, 128.7, 129.4, 134.6, 136.4, 137.4, 141.6, 148.9.