Synthesis of mono-substituted 2,2′-bipyridines

Article abstract of DOI:10.1039/b203595b

The rapid synthesis of 4-aryl-2,2′-bipyridines is described leading to some previously reported compounds in good yields in addition to some new functionalized bipyridines.

Full text of DOI:10.1039/b203595b

Synthesis of mono-substituted 2,2A-bipyridines†
Joseph G. Cordaro,a James K. McCusker*b and Robert G. Bergman*a
a Department of Chemistry, University of California, Berkeley, California 94720-1460, USA.
E-mail: bergman@cchem.berkeley.edu; Fax: 1-510-642-7714; Tel: 1-510-642-2156
b Department of Chemistry, Michigan State University, East Lansing, Michigan 48824-1322, USA.
E-mail: mccusker@cem.msu.edu; Fax: 1-517-353-1793; Tel: 1-517-355-9715, ext. 106
Received (in Corvallis, OR, USA) 11th April 2002, Accepted 21st May 2002
First published as an Advance Article on the web 12th June 2002
The rapid synthesis of 4-aryl-2,2A-bipyridines is described
leading to some previously reported compounds in good
yields in addition to some new functionalized bipyridines.
yields of 40–85% [eqn. (2)].9 The reaction proceeds best
The 2,2A-bipyridine (bpy) ligand continues to play an important
role in organic and inorganic chemistry,1 photochemistry2 and,
more recently, materials science, polymer3 science and den-
drimer4 chemistry. The functionalization of bipyridines is a
crucial step for introducing these ubiquitous ligands in new
applications. Unsymmetrical derivatization of bipyridyl ligands
is of particular interest for applications in photo-induced energy
and electron transfer processes. However, only a few recent
examples of general methods for preparing such compounds are
known.5
(2)
when freshly distilled 2-acetylpyridine is used. The product
usually precipitates from the reaction mixture and can be
recrystallized from methanol to obtain analytically pure mate-
rial. Solids 1a–i can be stored for months without noticeable
decomposition but decompose readily in CDCl3.
Ciufolini and others have shown that pyridines can be
obtained from dihydropyrans.10 The conversion of 1 to the
dihydropyran 2 is catalyzed by commercially available yt-
trium(III) hexafluoroacetylacetonate, (abbreviated [Y3+]) with a
ten-fold excess of ethyl vinyl ether in THF or CH2Cl2 at room
temperature [eqn. (3)].11 The reaction can be run successfully
without inert atmosphere protection.
Early reports of the synthesis of mono-substituted bipyridines
relied on the procedure developed by Kröhnke [eqn (1)].6
(1)
Although occasionally used today as a means of preparing
4-(aryl)-2,2A-bipyridines, the yields are low (usually around
30%) and can be inconsistent. In addition, isolation of the
desired product can be difficult when isomers are formed.
Alternatively, 4-bromo-2,2A-bipyridine can be functionalized
via lithium–halogen exchange or palladium-catalyzed coupling
reactions, giving mono-substituted products. The usefulness of
this methodology is limited by the availability of the starting
material (4 steps, < 40% yield for 4-bromo-2,2A-bipyridine) and
the sensitivity of the reactions to oxygen and moisture. Mono-
deprotonation of 4,4A-dimethyl-2,2A-bipyridine with a strong
base followed by the addition of an electrophile has also been
used, but with limited scope. Alternative methods7 typically
require multiple steps and often arduous reaction conditions. In
view of these limitations, we sought to develop a convenient
high-yielding synthesis of mono-substituted 2,2A-bipyridines.
Åkermark et al. and then Raston et al.8 were able to
synthesize terpyridines via an aldol condensation and Michael
addition reaction utilizing acetylpyridine and substituted ben-
zaldehydes. The resulting diketone is transformed into the
pyridine product following treatment with ammonium acetate in
acetic acid. Based on this methodology, we felt that bipyridines
could similarly be synthesized using the product of the aldol
condensation reaction. Employing 2-acetylpyridine and substi-
tuted benzaldehydes hetero-diene products 1a–i were isolated in
(3)
Additionally, by adding 4 Å molecular sieves to the reaction
flask it was found that the need to use pre-dried solvents was
eliminated.12 The reaction does proceed without sieves but
reaction times are generally longer. The hygroscopic catalyst
[Y3+] can be stored in a desiccator and used as needed.
Typically, concentrations of 0.20 M 1 and 2.0 M ethyl vinyl
ether were required to observe t1/2 = 18 h; lower concentrations
of 1 drastically increased the reaction time. The reaction was
also attempted without a catalyst and with other catalysts.
Heating 1b with neat ethyl vinyl ether in a thick-walled glass
vessel at 95 °C gave little or no reaction after 24 h. Employing
bpyCu(OTf)2 (OTf = trifluoromethanesulfonate) as the catalyst
in CH2Cl2 required heating the solution to 50 °C and appeared
to give a polymer as a side product. Most products were isolated
via chromatography to give oils. Compounds 2c, e, h and i can
be crystallized directly from the crude reaction mixture.‡
Attempts to convert 2 to 3 using refluxing AcOH with
NH4OAc provided low yields of the bipyridine and unwanted
side products. Replacing AcOH with MeOH or EtOH did not
improve the yields and required heating the solution to 135 °C
in a sealed flask. Using water as the solvent gave no detectable
reaction even after prolonged heating, presumably due to the
poor solubility of 2. In our reaction, an oxidation is necessary to
achieve the required oxidation state in the new pyridine ring,
which may explain the unidentifiable reaction products. Turn-
ing again to the work of Ciufolini,10 we utilized H2NOH·HCl as
the source of nitrogen for making pyridine derivates from
† Electronic supplementary information (ESI) available: experimental
details and full characterization of new compounds. See http://www.rsc.org/
suppdata/cc/b2/b203595b/
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CHEM. COMMUN., 2002, 1496–1497
This journal is © The Royal Society of Chemistry 2002

dihydropyrans [eqn (4)]. Substitution of NH4OAc with
yields ( < 30%). The product was usually purified via crystal-
lization from methanol or crystallization of the hydrochloride
salt from acetone–H2O.†
The range of substituents covered in this three-step reaction
sequence illustrates the functional group compatibility of this
methodology (Table 1). Yields for the isolation of the final
bipyridine products range between 10 and 40% from the starting
aldehyde, which is considerably more efficient than previously
published methods. This reaction sequence reduces the number
of steps required to access many interesting ligands. For
example, bipyridinyl ligands 3h and 3i have been synthesized in
multi-step reactions13 and have found use in the study of light
induced energy and electron transfer processes.14 Although no
photophysical studies have been done, the anthracenyl ligand 3e
could potentially enhance luminescence from chelated metals.
The bromo-substituted aryl-bipyridine 3b is poised to undergo
various coupling or lithiation reactions as previously demon-
strated.15 We hope this new method for the synthesis of
unsymmetrically substituted bipyridinyl ligands will provide
additional stimulus for the use of this robust and versatile ligand
in inorganic and materials chemistry.
(4)
H2NOH·HCl resulted in successful transformation of 2 to 3.
Refluxing acetonitrile gave good yields of bipyridine for all
substrates in reaction times near 6 h. To our surprise, the
reaction is very sensitive to solvent. Methanol, ethanol and
acetic acid all give the desired bipyridine product but in low
Table 1 Yields for reactions in eqn. (2)–(4)
This work was supported by grants from the NSF (Grant no.
CHE-0094349), the Chemical Sciences, Geosciences and
Biosciences Division, Office of Basic Energy Sciences, Office
of Science, U.S. Department of Energy (Grant nos. DE-FG03-
96ER14665 and DE-FG02-01ER15282) and the Alfred P.
Sloan Foundation (JKM). Additionally, we would like to thank
Professors Jeffrey S. Johnson and Dirk Trauner for their helpful
suggestions and advice.
% yield
% yield (1) % yield (2) (3)
Series
a
R
51
66
78
98
92
56
35, 21a
Notes and references
‡ The crude product 2 was successfully used in the last step of the reaction,
although yields were diminished. See entry 2a in Table 1.
b
c
41
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f
79
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90
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57
18
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g
h
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65
77
66
36
25b
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i
46
65, 78c
51
a Yield of product without isolation of intermediate 2a. b Crude yield, see
supporting data. c Isolated yield via chromatography
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