In situ formation and reaction of 2-pyridylboronic esters

Article abstract of DOI:10.1016/S0040-4039(03)00419-2

2-Pyridylboronic esters were generated by cross-coupling 2-bromopyridines with bis(pinacolato)diboron in the presence of a base and palladium catalyst. The boronic esters reacted in situ with unreacted 2-bromopyridines to afford high yields of 2,2′-bipyridines as homocoupled products. Depending upon the reaction conditions, varying amounts of protodeboronated products were also observed. An attempted cross-coupling between two different 2-bromopyridines produced a nearly statistical mixture of homo- and cross-coupled products.

Full text of DOI:10.1016/S0040-4039(03)00419-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2935–2938
In situ formation and reaction of 2-pyridylboronic esters
Amelia A. Fuller, Heidi R. Hester, Eric V. Salo and Erland P. Stevens*
Department of Chemistry, Davidson College, PO Box 7120, Davidson, NC 28036, USA
Received 20 December 2002; accepted 12 February 2003
Abstract—2-Pyridylboronic esters were generated by cross-coupling 2-bromopyridines with bis(pinacolato)diboron in the presence
of a base and palladium catalyst. The boronic esters reacted in situ with unreacted 2-bromopyridines to afford high yields of
2,2%-bipyridines as homocoupled products. Depending upon the reaction conditions, varying amounts of protodeboronated
products were also observed. An attempted cross-coupling between two different 2-bromopyridines produced a nearly statistical
mixture of homo- and cross-coupled products. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
theses for 3- and 4-pyridylboronic acids and esters have
been published.5 Both these classes of compounds can
be formed and isolated in high yield and efficiently
undergo Suzuki couplings.
Arylboronic acids and esters are required reagents in
the Suzuki cross-coupling reaction.1 The traditional
procedure for making an arylboronic ester (3) involves
reacting an aryllithium (2) or aryl Grignard with a
borate ester (Scheme 1).2 If desired, the newly formed
boronic ester can be hydrolyzed to the corresponding
boronic acid.3 A more recently developed procedure for
preparing boronic esters, specifically pinacol esters (5),
involves a palladium-catalyzed coupling of an aryl
halide with bis(pinacolato)diboron (4).4
In contrast, the 2-pyridylboronic acids and their deriva-
tives remain virtually unknown. Isolated reports have
noted difficulties in synthesizing these compounds.4a,6
To our knowledge, only Ogawa and co-workers have
successfully prepared and reported characterization
data for a 2-pyridylboronic acid derivative, dimethyl
2-pyridylboronate.7 This compound was not purified,
and the only characterization data listed was a 1H
NMR spectrum. The crude boronic ester coupled to an
arylhalide in modest yield in a Suzuki reaction.
While many syntheses of arylboronic acids and esters
have been reported in the literature, relatively few
heterocyclic examples have been noted. This is espe-
cially true for pyridylboronic acids. Very recently, syn-
Given the scarcity of information on 2-pyridylboronic
esters and the relative lack of efficient methods for their
synthesis, we sought to investigate the preparation of
these compounds. Boronic esters of this type may then
be more available for use in Suzuki couplings in appli-
cations ranging from pharmaceuticals to transition
metal ligand synthesis.5a,7
2. Results and discussion
Our initial work on this project followed the procedures
outlined by Ogawa. Unfortunately, in our hands these
reactions proved to be troublesome. 2-Lithiopyridine
(7) was formed by lithium–halogen exchange on 2-bro-
mopyridine (6) with n-butyllithium (Scheme 2). All
attempts to quench anion 7 with trimethyl borate failed
to afford useful amounts of the desired 2-pyridyl-
boronic ester product (8). 2-Pyridyllithium (7) could be
Scheme 1. Regents and conditions: (a) n-BuLi; (b) B(OR)3,
then H2O; (c) Pd catalyst, base.
* Corresponding author. Tel.: +1-704-894-2305; fax: +1-704-894-2709;
e-mail: erstevens@davidson.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00419-2

2936
A. A. Fuller et al. / Tetrahedron Letters 44 (2003) 2935–2938
ered bromopyridine (15) in 24 h by GC analysis with an
reacted with aldehyde electrophiles to give good yields
of alcohols after aqueous work-up. Therefore, the prob-
lem in making borate esters of type 8 appears to be
either reaction of the anion with the trialkyl borate or
isolation of the product. This is consistent with other
reports in the literature.4a,6
internal standard of biphenyl (Scheme 4).9,10
The high yield of bipyridine (16), a homocoupling
product, is in agreement with Masuda’s observations.8
Likewise, the formation of pyridine (11) by
protodeboronation is consistent with Miyaura’s
findings.4a Unfortunately, the pinacol ester of 2-pyridyl-
Since we were unable to prepare 2-pyridylboronic esters
through standard metalation–quench protocols, we
chose to investigate Miyaura’s bis(pinacolato)diboron
chemistry (Scheme 1).4 This approach is mild, direct,
and generally gives excellent yields of arylboronic esters
with a variety of functionality.
1
boronic acid (10) was not observed by GC–MS or H
NMR. Both raising the reaction temperature to 100°C
and using K3PO4 in place of KOAc increased the rate
of the reaction without significantly changing the yield
or relative ratio of the products.
The same reaction was repeated with 20 equivalents of
the diboron reagent (4) in the hope of increasing the
chances of observing boronic ester 10 and minimizing
the formation of the homocoupling product (16). While
this change did effectively prevent homocoupling, only
pyridine was observed in the reaction by GC. Pre-
sumably, boronic ester 10 is not very stable under the
reaction conditions and undergoes protodeboronation
if no other reaction pathway is available.
The literature held two reports that were directly
related to our planned work. One reference was not
encouraging. Miyaura noted that 2-chloropyridine (9)
reacts with diboron 4 in the presence of KOAc and a
palladium catalyst in DMSO to quantitatively afford
pyridine (11) (Scheme 3).4a This product presumably
arises from in situ protodeboronation of the desired
boronic ester 10. A second publication was more sup-
portive. Masuda and co-workers successfully formed an
uncharacterized poly(pyridine) (14) in 88% yield by
reacting 2,6-dibromopyridine (12) with diboron 4 in the
presence of NaOH and a palladium catalyst in DMF.8
This polymeric product forms by homocoupling of
dibromide 12 and likely procedes through a 2-pyridyl-
boronic ester intermediate (13).
A number of solvents were investigated for this reac-
tion, and DMF was found to be the best with regard to
reaction time and maximizing the yield of homocoupled
product relative to protodeboronation (16:11) (Table
1). The presence of small amounts of water did not
have a major impact on the amount of protodeborona-
tion (entries 1–3), but running the reaction in a protic
solvent such as 2-propanol (entry 7) resulted in more
protodeboronation than homocoupling. Large amounts
of pinacol were also observed when 2-propanol was
used as the solvent. Pinacol likely arises from transes-
terification of diboron ester 4. Toluene (entry 5) and
THF (entry 8) were very poor solvents for the coupling.
In both cases the pinacol ester of phenylboronic acid
and 2-phenylpyridine were observed by GC–MS. These
compounds probably form by migration of a phenyl
group off palladium-bound triphenylphosphine.11 These
side products were less prevalent in the other solvents.
Our first attempts to make 2-pyridylboronic esters used
reaction conditions similar to those outlined by
Miyaura.4 Under these conditions 2-bromopyridine (15)
and bis(pinacolato)diboron (4) reacted to give 78%
bipyridine (16) and 17% pyridine (11) with 5% recov-
Protodeboronation is a known issue for heteroaryl-
boronic acids, specifically when the boron is on a
Scheme 2. Reagents and conditions: (a) n-BuLi, THF, −78°C;
(b) B(OCH3)3, then CH3OH.
carbon
adjacent
to
a
heteroatom.4a,13
The
protodeboronation of 2-pyridylboronic acid (20) may
be related to the facile decarboxylation of pyridine-2-
Scheme 3. Reagents and conditions: (a) 4, PdCl2(dppf),
KOAc, DMSO, 80°C; (b) protodeboronation; (c) 4,
PdCl2(dppf), NaOH, DMF, 100°C.
Scheme 4. Reagents and conditions: (a) 4, PdCl2(PPh3)2,
KOAc, DMSO, 80°C.

A. A. Fuller et al. / Tetrahedron Letters 44 (2003) 2935–2938
Table 1. Homocouplingsa of 2-bromopyridine (12) (Scheme 3)12
2937
Entry
Solventa
Reaction time (h)
GC yield (%)b
Ratio 16:11
16
11
15c
1
2
3
4
5
6
7
8
DMF
6
5
6
88
78
88
75
41
84
30
54
12
18
12
25
18
13
70
24
0
4
0
0
41
3
7.3:1
4.3:1
7.3:1
3.0:1
2.3:1
6.5:1
0.4:1
2.3:1
DMFd
DMFe
DMSO
PhCH3
CH3CN
2-PrOH
THF
3
66
60
3
0
22
72
a All solvents were HPLC or ACS reagent grade and used without purification unless otherwise noted.
b GC yields are normalized to 100% total yield. The average, unnormalized GC yield for all table entries is 100.2 (|=6.6).
c Recovered starting material.
d 5% H2O.
e Distilled from CaH2.
carboxylic acid (17).14 Both processes likely proceed
through the same pyridininum ylide intermediate (19)
(Scheme 5). While it was hoped that 2-pyridylboronic
esters would be more resistant to protodeboronation
than the corresponding acids, the esters still seem prone
to decomposition. It is possible that the esters coordi-
nate to Lewis acids and bases present in solution. The
resulting zwitterion (23) could decompose to afford
pyridine through an ylide intermediate (24). The possi-
bility of decomposition occurring after transmetalation
to a 2-pyridylpalladium(II) species cannot be excluded.
Despite their apparent instability, the 2-pyridylboronic
esters do form readily and can be reacted in situ in high
yield.
ester. While 2-pyridylboronic esters do not seem suffi-
ciently stable to be isolated under our reaction condi-
tions, their solution lifetime is sufficient for them to be
trapped in situ. If 2-pyridylboronic esters are not imme-
diately reacted, they decompose through protode-
boronation. Investigations are continuing on boronic
esters of other five- and six-membered nitrogen hetero-
cycles to determine their stability and feasibility of
isolation.
The homocoupling of 2-bromo-5-methylpyridine (25) in
DMF gave essentially the same results as the homocou-
pling of 2-bromopyridine (Scheme 6). The ratio of
homocoupled product (26) to protodeboronation (27)
was 8.1:1.0. No boronic ester intermediates (28) were
1
observed by GC–MS or H NMR.
One cross-coupling was attempted between 2-bromopy-
ridine (15) and 2-bromo-5-methylpyridine (25) (Scheme
7). The experimental product distribution observed by
GC was found to be 1.2:1.9:1.0 16:29:26.15 This experi-
mental ratio is very similar to a statistical mixture of
homo- and cross-coupled products with a theoretical
value of 1:2:1 16:29:26. Although this cross-coupling
reaction to form an unsymmetrical bipyridine is not as
efficient as some Negishi6,16 and Stille5,17 approaches,
the simplicity of this one-step Suzuki procedure may
more than compensate for its lower yield. To realize the
potential of this method, a suitable protocol for sepa-
rating the products would need to be developed.
Scheme 5.
3. Conclusion
In summary, we have successfully formed and reacted
2-pyridylboronic esters to afford homo- and cross-cou-
pled 2,2%-bipyridine products in high yields. This is the
first systematic study of this elusive type of boronic
Scheme 6. Reagents and conditions: (a) 4, PdCl2(PPh3)2,
K3PO4, DMF, 100°C.

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A. A. Fuller et al. / Tetrahedron Letters 44 (2003) 2935–2938
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6. Lu¨tzen, S.; Hapke, M. Eur. J. Org. Chem. 2002, 2292–
2297.
7. Fernando, S. R. L.; Maharoof, U. S. M.; Deshayes, K.
D.; Kinstle, T. H.; Ogawa, M. Y. J. Am. Chem. Soc.
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9. Debbrecht, F. J. In Modern Practice of Chromatography,
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10. All reaction products and starting materials are commer-
cially available. The calibration curves to determine rela-
tive reponses by flame-ionization detection were
generated using commercial chemicals of at least 98%
purity. A reaction that indicated a GC yield of 79%
2,2%-bipyridine (16) afforded a purified yield of 73% after
column chromatography.
Scheme 7. Reagents and conditions: (a) 4, PdCl2(PPh3)2,
K3PO4, DMF, 100°C.
Acknowledgements
We thank the Petroleum Research Fund (35968-GB1),
Research Corporation (CC5241), and Davidson College
for financial support and Frontier Scientific Corpora-
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