Synthesis of Differently Disubstituted 2,2′-Bipyridines by a Modified Negishi Cross-Coupling Reaction

Article abstract of DOI:10.1002/ejoc.200300192

A general practical approach to a number of differently disubstituted 2,2′-bipyridines from substituted 2-bromo- and 2-chloropyridines by application of modified Negishi cross-coupling conditions has been developed. These 2,2′-bipyridines carry versatile functional groups that can be elaborated further, as demonstrated for some examples. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300192

FULL PAPER
Synthesis of Differently Disubstituted 2,2Ј-Bipyridines by a Modified Negishi
Cross-Coupling Reaction[‡]
Arne Lützen,*[a] Marko Hapke,[a] Holger Staats,[a] and Jens Bunzen[a]
Dedicated to Prof. Dr. Manfred Weidenbruch on the occasion of his 65th birthday
Keywords: Biaryls / Cross-coupling / Negishi reaction / 2,2Ј-Bipyridines
A general practical approach to a number of differently di-
dines carry versatile functional groups that can be elaborated
substituted 2,2Ј-bipyridines from substituted 2-bromo- and 2- further, as demonstrated for some examples.
chloropyridines by application of modified Negishi cross-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
coupling conditions has been developed. These 2,2Ј-bipyri-
Germany, 2003)
Introduction
core, often by multi-step procedures.[10] With the advent of
cross-coupling reactions over the last 30 years, more and
more efficient methods have been developed for the forma-
tion of arylϪaryl bonds.[11] Thus, also a growing number of
syntheses containing a cross-coupling reaction as the key
step for the formation of multiple substituted bipyridine
fragments have been reported in the last decade. In particu-
lar, the Stille reaction has been extensively used in this con-
text, mainly because of the stability and chemoselectivity
of the organotin reagents.[12] Although examples with the
Negishi cross-coupling reaction have also been reported,[1,3]
there has not been any systematic investigation concerning
the general applicability of organozinc reagents to the syn-
thesis of multiply substituted bipyridines. However, with the
rapid development of new and ever more efficient catalytic
systems, mainly derived from palladium and sophisticated
ligands such as phosphanes and carbenes, it has now be-
come possible to use virtually any simple and easily avail-
able aryl chloride as a substrate in these reactions.[13] One
example of these powerful catalysts is the palladium com-
plex bis(tri-tert-butylphosphane)palladium(0) [Pd(PtBu3)2],
an established source of a catalytic system for C-C coupling
reactions today thanks to the stability of the complex and
its easy accessibility from [Pd2dba3·CHCl3] and PtBu3.[13,14]
In the meantime, investigations by Hartwig et al. have also
provided more detailed information on the catalytic reac-
tion, confirming that the actual catalytically active species
derived from this palladium complex is most probably a
monophosphane palladium complex.[15]
The synthesis of multiply substituted 2,2Ј-bipyridines is
a process that has gained increasing importance with the
extensive use of bipyridine moieties as ligands in transition
metal coordination compounds, which are being found to
exhibit more and more interesting characteristics.[1] These
transition metal complexes are, for example, very valuable
building blocks for the assembly of supramolecular[1] and
macromolecular devices.[2] However, differently substituted
2,2Ј-bipyridines are also found in natural products such as
the caerulomycins,[3] the collismycins[3b] or in the very im-
portant camptothecin and its derivatives, which are used in
cancer therapy.[4] Furthermore, substituted 2,2Ј-bipyridines
are used as ligands in a number of transition metal-cata-
lysed reactions such as the recently found CϪH-activation
reactions of arenes with iridium complexes,[5] while multiply
substituted chiral 2,2Ј-bipyridines have also been used suc-
cessfully on several occasions in asymmetric synthesis, an
active area of research that has been comprehensively re-
viewed only recently.[6]
Several methods have been applied to the synthesis of di-
and polysubstituted bipyridines. One of the most wide-
spread approaches to symmetrically substituted bipyridines
is the homocoupling of halogenated pyridine precursors,
often catalysed by nickel complexes.[7] Further procedures
also allowing the elaboration of unsymmetrically substi-
tuted bipyridines include the Kröhnke reaction,[6,8] cyclis-
ation reactions[9] or modification of an existing bipyridine
We have recently been able to show that the use of this
complex in a modified Negishi coupling reaction is an excel-
lent way in which to synthesise monosubstituted 2,2Ј-bi-
pyridines from chloropyridines, with a wide variety of func-
tional groups being tolerated.[1]
[‡]
Synthesis of Substituted 2,2Ј-Bipyridines, 2. Part 1 Ref.[1]
[a]
University of Oldenburg, Department of Chemistry,
P. O. Box 2503, 26111 Oldenburg, Germany
Fax: (internat.) ϩ49-(0)441-7983329
E-mail: arne.luetzen@uni-oldenburg.de
3948
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300192
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Synthesis of Differently Disubstituted 2,2Ј-Bipyridines
FULL PAPER
While compounds 1 and 3 are commercially available or
easy to prepare in a simple protection step, for compound
2 we had to develop a new synthesis, starting from 2-amino-
pyridine (Scheme 1). The synthesis was achieved starting
with the well known electrophilic iodination of 2-aminopy-
ridine,[20] followed by Ragan’s procedure for the protection/
deprotection sequence of the amino group, and an Ullman
methoxylation, each in good to very good yields.[21] This
sequence was especially advantageous not only because of
the high yields but also because of the ease of preparation,
since none of these steps requires tedious purification pro-
cedures such as column chromatography, and the resulting
2-amino-5-methoxypyridine (6) could easily be isolated by
distillation. The subsequent Sandmeyer halogenations
could be performed through known or slightly modified
procedures.[22]
Here we would like to report on the extension of this
reaction in order to show that our one-pot procedure can
also be applied as a general approach to the preparation of
a variety of differently disubstituted 2,2Ј-bipyridines from
organozinc pyridyl reagents and several chloropyridines
containing functional groups that also allow further deri-
vatisation.
Results and Discussion
The first object of our studies was the preparation of the
substituted organozinc pyridyl reagent. We speculated on
whether the bromopyridines used in the initial lithiation
step could possibly be substituted by more easily available
chloropyridines. Since alkyllithium reagents fail as lithiating
agents in these cases, it appeared from the literature that
the use of lithium/naphthalene might be a promising re-
agent for this purpose, since there has been some reported
work in which this reagent has been successfully applied to
the lithiation of aryl chlorides and even pyridyl chlorides,
with the use either of catalytic or of stoichiometric amounts
of naphthalene.[16] All our attempts with these reagents gave
only unsatisfactory results, however, as we were not able
to bring the lithiation of the model substrate 2-chloro-5-
methylpyridine to completion, as shown by quenching
experiments with CD3OD, even if prolonged reaction times
were used.[17]
We therefore decided to return to our initial approach
and to make use of the lithiation of substituted bromopyri-
dines with t-BuLi, which has been shown to be a fast and
quantitative reaction.[18] Consequently, we were in need of
bromopyridines with functional groups that were stable
against the lithiation reagent but which could be trans-
formed into further useful functionalities. These demands
are met by the bromopyridines 1Ϫ3 (Figure 1), containing
a methyl, a methoxy (which can be regarded as a protected
hydroxy function) or an amino group, respectively, the last
of these protected in the form of the very valuable pyrrole
group, as first reported by Meakins et al.[19]
Scheme 1. Preparation of methoxy-substituted pyridyl halides from
2-aminopyridine: (a) HIO4·2 H2O, I2, CH3COOH, H2O, concd.
H2SO4, 68%; (b) 2,5-hexanedione, pTsOH, toluene, reflux, 2 h,
83%; (c) NaOMe, CuCl, MeOH, DMF, 80°C, 2 h, 96%;
(d) HONH2·HCl, Et3N, EtOH, H2O, reflux, 20 h, 81%; (e) for 2:
HBr (62%), Br2, Ϫ10 °C, then NaNO2, Ϫ5 °C to room temp., 69%;
for 7: concd. HCl, Ϫ5 °C, then NaNO2, CuCl, 0 °C to room temp.,
70 °C; 50%
As substituted chloropyridines we chose compounds
7Ϫ17 as shown in Figure 2, which carry functional groups
interesting either because of their intrinsic properties, e. g.
with regard to solubility, or because of their potential for
further derivatisation. Most of these are either commer-
cially available (9, 13, and 16, for example) or are relatively
Figure 2. 2-Chloropyridines used as coupling partners for cross-
coupling reactions
Figure 1. 2-Bromopyridines
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A. Lützen, M. Hapke, H. Staats, J. Bunzen
FULL PAPER
easy to prepare. For the aryl-substituted chloropyridines 11
With these compounds in hands, we started to set up a
and 12, regioselective Suzuki reactions between 2-chloro-5- number of cross-coupling reactions with 5-substituted 2-
iodopyridine and the appropriate aryl boronic acids were bromopyridines, using 3 mol-% [Pd(PtBu3)2] (Table 1).[23]
developed, giving the desired coupling products in good Although the method has its obvious limitations in the case
yields.
of the boronic ester-functionalized pyridine 15, with which
we were able to prove the formation of the corresponding
bipyridine 22 by NMR and MS investigations of the crude
product mixture but failed to isolate either the desired prod-
uct or the corresponding deprotected boronic acid, the pro-
cess usually gave the desired 2,2Ј-bipyridines in good to
very good yields, up to 85% in the case of the 6-methoxy-
5-methyl-2,2Ј-bipyridine (23) after column chromatography
on silica gel (Table 1). Only in the case of the pyrrole- and
trifluoromethyl-substituted bipyridine 29 did we face the
problem of obtaining the desired compound only as an in-
separable 2:1 mixture together with the bis(trifluorome-
thyl)-substituted homocoupling product, whereas the for-
mation of homocoupling products was not observed in sig-
nificant amounts in the other cases.
Table 1. Synthesis of disubstituted 2,2Ј-bipyridines
Product
Bromopyridine
Chloropyridine
Yield (%)
As already shown for the monosubstituted bipyridine,[1]
the pyrrole protecting group can readily be removed by
treatment with hydroxylamine, as we were able to demon-
strate with the pyrrole-protected, methoxy-substituted bi-
pyridine 26, and the corresponding free amine 30.
18
19
20
21
22
23
24
25
26
27
28
29
1b
1b
1b
1b
1b
1b
2
7
56
77
71
8
10
12
15
16
11
13
14
9
46
0[a]
85
The above deprotection strategy, however, also enabled
us to circumvent the problems associated with the purifi-
cation of bipyridines containing pyrrole substituents
through the removal of the protective group from the crude
cross-coupling product mixture obtained after filtration
through a short column of silica. This caused a substantial
change in the chromatographic behaviour and allowed the
isolation of amino-substituted bipyridines, thought to rep-
resent desirable starting materials for further transform-
ations anyway. This could be demonstrated for compound
29, with which the removal of the pyrrole group furnished
free amine 31, which could be separated from the homo-
coupling product, yielding 16% of the deprotected coupling
product 31 over two steps.
72
2
55
2
60[b]
77
3
3
11
13
42
[c]
3
In order to extend the scope of the reaction further, we
used bromopyridines 1, each with a methyl group in the 4-,
5- or 6-position, respectively, for the preparation of the
transmetallation reagent and chloropyridine 17, possessing
a pyrrole group in the 4-position, as partners for the coup-
ling reaction (Table 2). In each case the expected coupling
products could be isolated and identified by NMR and MS
techniques, but we were again facing the problem that the
isolated products still contained some level of impurities,
which could not even be removed by repeated column chro-
matography with different eluents. We thus again changed
our strategy to that used above for the isolation of free am-
ine 31. By doing so, we were able to isolate the desired bi-
pyridines 32Ϫ34 as pure products in acceptable yields.
All of these bipyridines provide valuable functional
groups that can be addressed selectively and offer numerous
possibilities for further derivatisation. In some representa-
tive reactions we were able, for instance, to perform a lith-
ium-mediated alkylation to give 35[25] and a lithium-me-
diated silylation to yield 36, followed by a subsequent
[a]
NMR and MS experiments indicated the formation of the de-
sired product 22, but all attempts to isolate it by column chroma-
tography failed.
bromopyridine 3 and chloropyridine 7, the yield was lower (ca.
50%) and the obtained coupling product still contained impurities
[b]
If the reaction was performed starting from
[c]
even after repeated chromatographic purification.
The product
was isolated as an inseparable 2:1 mixture together with the homo-
coupling product 5,5Ј-bis(trifluoromethyl)-2,2Ј-bipyridine.[24]
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Synthesis of Differently Disubstituted 2,2Ј-Bipyridines
FULL PAPER
thesis of valuable difunctionalised bipyridines that can be
further derivatised in manifold ways.
Table 2. Synthesis of disubstituted 2,2Ј-bipyridines containing a 4-
amino group
Experimental Section
General Remarks: 2-Bromo-4-methylpyridine (1a), 2-bromo-5-
methylpyridine (1b), 2-bromo-6-methylpyridine (1c), 4-amino-2-
chloropyridine, 2-chloro-5-methylpyridine (9), 2-chloro-5-(trifluoro-
methyl)pyridine (13), 2-chloro-6-methoxypyridine (16), (3,5-di-
methylphenyl)boronic acid, and (4-methoxyphenyl)boronic acid
were purchased from SigmaϪAldrich Chemie GmbH or Alfa
Aesar GmbH and were used as received. The syntheses of 2-chloro-
5-phenylpyridine (10), 1-(2-chloropyridin-5-yl)-2,5-dimethyl-1H-
pyrrole (14) and 2-chloro-5-[(trimethylsilyl)ethynyl]pyridine[12c] (8)
have already been mentioned in our preceding paper.[1] The syn-
thesis of the required 5-amino-2-bromopyridine for the preparation
of compound 3 started with the bromination of the commercially
available 2-hydroxy-5-nitropyridine with PBr5 or PBr3/Br2, followed
by reduction of the nitro group with iron in acetic acid.[27] The
synthesis of 2-bromo-5-methoxypyridine (2) from 2-amino-5-meth-
oxypyridine (6) was performed by the procedure described by Lee-
son and Emmett.[28] 2-(2-Chloropyridine-5-yl)-4,4Ј,5,5Ј-tetra-
methyl-1,3-dioxaborolane (15) was prepared by a method recently
published by Rault et al.[29] Zinc() chloride was dried thoroughly
before use. THF was dried with and distilled from sodium benzo-
phenone ketyl. The complex [Pd(PtBu3)2] was prepared from
[Pd2dba3·CHCl3] and PtBu3 by a method published by Fu et al.[14]
tBuLi solutions were purchased from Merck or SigmaϪAldrich
Chemie GmbH and were titrated prior to use against N-pivaloyl-
o-toluidine.[30] Reactions with air- and moisture-sensitive transition
metal compounds were performed under an argon atmosphere in
oven-dried glassware by use of standard Schlenk techniques.
Product
Bromopyridine
Chloropyridine
Yield (%)[a]
32
33
34
1a
1b
1c
17
17
17
47
28
45
[a]
Isolated overall yields after both steps.
chlorination to 37, each starting from methyl groups. The
last two transformations were performed by use of a pro-
cedure published by Fraser et al.[26] We were also able to
achieve an iodination through a Sandmeyer reaction of 33,
resulting in the further elaborated bipyridine 38 (Scheme 2).
Thin layer chromatography was performed on Merck aluminum
TLC plates (60 F254 silica gel). Detection was done with UV light
(254 nm). Products were purified by column chromatography on
Merck silica gel 60 (70Ϫ230 mesh). 1H and 13C NMR spectra were
recorded in deuterated chloroform or dimethyl sulfoxide solutions
on a Bruker Avance 500 spectrometer at 300 K at 500.1 and
125.8 MHz, respectively. 19F NMR spectra were recorded on a
Bruker Avance 300 spectrometer in deuterated chloroform at 300 K
at 282.4 MHz. 1H NMR chemical shifts are reported on the δ scale
in ppm relative to residual nondeuterated solvent as internal stand-
ards. 13C NMR chemical shifts are reported on the δ scale in ppm
relative to deuterated solvent as internal standard. 19F NMR
chemical shifts are reported on the δ scale in ppm relative to CCl3F
as external standard. Mass spectra were measured on a Finnigan-
MAT 212 instrument with MMS data system and ISIS processing
system or on a Finnigan MAT 95 with DEC-Station 5000 data
system in EI or CI mode with isobutane as reactant gas. Melting
points were measured with a Leitz SM-Lux hot-stage microscope
and are not corrected.
Scheme 2. Further functionalisation of cross-coupled 2,2Ј-bipyri-
dines: (a) THF, LDA, Ϫ78 °C to 0 °C; (b) hexyl iodide, room temp.;
(c) THF, LDA, Ϫ78 °C to 0 °C; d) TMSCl, 0 °C; (e) CsF, C2Cl6,
CH3CN, 60 °C; (f) NaNO2, 4  H2SO4, H2O, Ϫ10 °C, then KI,
Ϫ10 °C to 80 °C
Synthesis of Substituted Bromo- and Chloropyridines
General Procedure for the Protection of Amines as Pyrroles, Demon-
strated for 1-(2-Bromopyridin-5-yl)-2,5-dimethyl-1H-pyrrole (3): 5-
Amino-2-bromopyridine[27] (2 g, 11.6 mmol), 2,5-hexanedione
(1.65 mL, 14.0 mmol), and pTsOH (23 mg, 0.08 mmol) were dis-
solved in toluene (10 mL) and heated in a DeanϪStark appa-
ratus for 2 h. After cooling, the dark brown reaction mixture was
washed with sat. aqueous NaHCO3 solution, five times with water,
Conclusion
In conclusion, we have presented a versatile approach to
a number of differently disubstituted 2,2Ј-bipyridines star-
ting from easily available pyridyl bromides and chlorides by
application of modified Negishi cross-coupling conditions.
This methodology is almost generally applicable to the syn- and with brine. After the mixture had been dried with MgSO4, the
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A. Lützen, M. Hapke, H. Staats, J. Bunzen
FULL PAPER
solvent was removed in vacuo. The dark residue was dried under
high vacuum and was used for the coupling reaction without
further purification (2.68 g, 92%). An analytically pure sample was
obtained after column chromatography on silica gel with hexane/
ethyl acetate/triethylamine (3:1:0.02 v/v) as eluent. M.p. 72Ϫ74 °C.
1H NMR (CDCl3. 500.1 MHz): δ ϭ 2.03 (s, 6 H), 5.93 (s, 2 H),
7.42 (dd, J ϭ 8.2, 2.7 Hz, 1 H), 7.60 (d, J ϭ 8.2 Hz, 1 H), 8.28 (d,
2.7 Hz, 1 H) ppm. 13C NMR (CDCl3. 125.8 MHz): δ ϭ 12.9, 107.1,
128.4, 128.7, 135.0, 137.9, 140.7, 149.4 ppm. MS (CI): m/z (%) ϭ
250.9 (100) [MHϩ, 79Br], 252.9 (75) [MHϩ, 81Br]. C11H11N2Br
(251.12): calcd. C 52.61, H 4.42, N 11.16; found C 52.92, H 4.51,
N 11.13.
[MHϩ]. C12H14N2O (202.25): calcd. C 71.26, H 6.98, N 13.85;
found C 71.63, H 6.92, N 13.90.
2-Amino-5-methoxypyridine (6):[22] A mixture of 1-(5-methoxypyri-
din-2-yl)-2,5-dimethyl-1H-pyrrole (8, 3.5 g, 17.3 mmol), hy-
droxylamine hydrochloride (12.02 g, 173 mmol), triethylamine
(4.8 mL, 34.6 mmol), ethanol (30 mL), and water (15 mL) was
heated at reflux for 20 h. The cooled solution was quenched with
cold HCl (50 mL), washed with diisopropyl ether, and the pH was
adjusted to 9Ϫ10 with 6  NaOH. The resulting mixture was ex-
tracted several times with dichloromethane. The combined organic
phases were dried with K2CO3 and the solvent was removed in
vacuo. The oily residue was distilled in high vacuum to yield the
product as a slightly yellow oil (1.75 g, 81%). 1H NMR (CDCl3,
500.1 MHz): δ ϭ 3.74 (s, 3 H), 4.45 (br. s, 2 H), 6.45 (d, J ϭ 8.8 Hz,
1 H), 7.07 (dd, J ϭ 8.8, 3.3 Hz, 1 H), 7.72 (d, J ϭ 3.3 Hz, 1 H)
ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 56.3, 109.5, 125.9, 132.8,
149.4, 152.9 ppm. MS (CI): m/z (%) ϭ 125.2 (100) [MHϩ].
1-(2-Chloropyridin-4-yl)-2,5-dimethyl-1H-pyrrole (17): The N-pro-
tected chloropyridine 17 was prepared by the General Procedure as
used for 3, from 4-amino-2-chloropyridine (2 g, 15.6 mmol) and
2,5-hexanedione (2.2 mL, 18.8 mmol), and was obtained as a red-
brown solid (3.01 g, 93%) after column chromatography on silica
gel with hexane/ethyl acetate/triethylamine (3:1:0.02 v/v) as eluent.
M.p. 107 °C. 1H NMR (CDCl3, 500.1 MHz): δ ϭ 2.03 (s, 6 H),
5.93 (s, 2 H), 7.42 (dd, J ϭ 8.2, 2.7 Hz, 1 H), 7.60 (d, J ϭ 8.2 Hz,
1 H), 8.28 (d, 2.7 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz):
δ ϭ 13.1, 108.0, 121.5, 123.1, 128.3, 148.7, 150.4, 152.3 ppm. MS
(CI): m/z (%) ϭ 129.1 (100) [MHϩ Ϫ C6H8, 35Cl], 131.1 (23) [MHϩ
2-Chloro-5-methoxypyridine (7):[22] 2-Amino-5-methoxypyridine (6,
895 mg, 7.2 mmol) was dissolved in concd. HCl (20 mL) and the
system was cooled to ca. Ϫ5 °C. A solution of sodium nitrite
(600 mg, 8.7 mmol) in water (4 mL) was slowly added, the tempera-
ture being kept under 0 °C. After completion the reaction mixture
was briefly stirred, and a precooled solution of copper() chloride
(1 g, 10.1 mmol) in concd. HCl (8 mL) was then added. The stirring
was continued for 30 min at 0 °C, then for 2 h at room temperature
and for a short period of time at 70 °C. After cooling to room
temperature again, the mixture was hydrolysed with water (50 mL)
and extracted several times with dichloromethane. The organic
phases were combined, washed with water and sat. aq. NaHCO3
solution, dried with Na2SO4, and concentrated in vacuo. The resi-
due was purified by distillation and the product was obtained as a
bright yellow oil (514 mg, 50%). 1H NMR (CDCl3, 500.1 MHz):
δ ϭ 3.83 (s, 3 H), 7.16 (dd, J ϭ 8.7, 3.1 Hz, 1 H), 7.21 (d, J ϭ
8.7 Hz, 1 H), 8.03 (d, J ϭ 3.1 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.8 MHz): δ ϭ 56.0, 124.4, 124.4, 136.1, 142.5, 155.0 ppm. MS
(CI): m/z (%) ϭ 144.1 (100) [MHϩ, 35Cl], 146.1 (37) [MHϩ, 37Cl].
Ϫ C6H8, 37Cl], 221.2 (92) [Mϩ ϩ CH4, 35Cl], 223.2 (21) [Mϩ
ϩ
CH4, 35Cl]. C11H11N2Cl (206.67): calcd. C 63.93, H 5.36, N 13.55;
found C 64.09, H 5.49, N 13.33.
1-(5-Iodopyridin-2-yl)-2,5-dimethyl-1H-pyrrole (4): The N-protected
iodopyridine 4 was synthesised from 2-amino-5-iodopyridine[20]
(7 g, 31.8 mmol) and 2,5-hexanedione (4.5 mL, 38.2 mmol) by the
General Procedure as used for 3. The product was isolated as a
dark brown solid (7.91 g, 83%), which was used without further
purification. An analytically pure sample was obtained after col-
umn chromatography on silica gel with hexane/ethyl acetate (1:1 v/
v) as eluent. M.p. 118Ϫ119 °C. 1H NMR (CDCl3, 500.1 MHz):
δ ϭ 2.13 (s, 6 H), 5.89 (s, 2 H), 7.01 (d, J ϭ 8.2 Hz, 1 H), 8.09 (dd,
J ϭ 8.2, 2.2 Hz, 1 H), 8.79 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125.8 MHz): δ ϭ 13.2, 90.9, 107.4, 123.5, 128.5, 146.1,
151.2, 155.4 ppm. MS (CI): m/z (%) ϭ 299.1 (100) [MHϩ].
C11H11N2I (298.12): calcd. C 44.32, H 3.72, N 9.40; found C 44.48,
H 3.59, N 9.16.
2-Chloro-5-(3,5-dimethylphenyl)pyridine (11): For the Suzuki coup-
ling reaction, 2-chloro-5-iodopyridine (1.45 g, 6.1 mmol), (3,5-di-
methylphenyl)boronic acid (1 g, 6.7 mmol), potassium fluoride
(1.16 g, 20 mmol), and [Pd(PtBu3)2] (85 mg, 2.5 mol %) were re-
peatedly evacuated and flushed with argon in a Schlenk flask. THF
(5 mL) was then added and the black suspension was heated at
reflux until TLC monitoring showed no further consumption of
the starting material. The now brightly yellow coloured suspension
was allowed to cool to room temperature and was then diluted with
diethyl ether, filtered through celite, and the solvents were evapo-
rated in vacuo. Column chromatography on silica gel with hexane/
ethyl acetate (20:1 v/v) as eluent gave the pure pyridine as a white
1-(5-Methoxypyridin-2-yl)-2,5-dimethyl-1H-pyrrole (5): 1-(5-Iodo-
pyridin-2-yl)-2,5-dimethyl-1H-pyrrole (4, 7.5 g, 25.2 mmol), so-
dium methoxide (4.08 g, 75.6 mmol), and copper() chloride
(376 mg, 3.8 mmol) were suspended in a mixture of dry methanol
(30 mL) and dry DMF (20 mL) and heated to 80 °C for 2 h. After
the mixture had cooled, diisopropyl ether (50 mL), an aq. solution
of NH4Cl (5%, 25 mL), and water (35 mL) were added, and the
mixture was stirred overnight. Afterwards the solids were filtered
off over celite and the filtrate was extracted several times with di-
chloromethane. The combined organic phases were washed with a
10% aq. NH4OH solution and filtered through silica gel. The fil-
trate was dried with Na2SO4 and the solvents were removed in va-
cuo. After drying in high vacuum the product was isolated as a
dark solid, which was pure enough to be used directly for the next
step. Further purification could be carried out by column chroma-
tography on silica gel with hexane/ethyl acetate (1:1 v/v) as eluent
(4.91 g, 96%). M.p. 75 °C. 1H NMR (CDCl3, 500.1 MHz): δ ϭ 2.08
1
solid (866 mg, 64%). M.p. 54 °C. H NMR (CDCl3, 500.1 MHz):
δ ϭ 2.38 (s, 6 H), 7.05 (s, 1 H), 7.14 (s, 2 H), 7.36 (d, J ϭ 8.2 Hz,
1 H), 7.80 (dd, J ϭ 8.2, 2.2 Hz, 1 H), 8.57 (d, J ϭ 2.2 Hz, 1 H)
ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 21.3, 124.0, 124.9, 130.1,
135.9, 136.4, 137.1, 138.8, 148.0, 150.1 ppm. MS (CI): m/z (%) ϭ
218.2 (100) [MHϩ, 35Cl], 220.3 (40) [MHϩ, 37Cl]. C13H12ClN
(217.70): calcd. C 71.72, H 5.56, N 6.43; found C 71.21, H 5.53,
N 6.07.
2-Chloro-5-(4-methoxyphenyl)pyridine (12): 2-Chloro-5-iodopyrid-
(s, 6 H), 3.91 (s, 3 H), 5.87 (s, 2 H), 7.15 (d, J ϭ 8.7 Hz, 1 H), 7.32 ine (1.43 g, 6.0 mmol) and (4-methoxyphenyl)boronic acid (1 g,
(dd, J ϭ 8.7, 3.0 Hz, 1 H), 8.27 (d, J ϭ 3.0 Hz, 1 H) ppm. 13C
6.6 mmol) were coupled in the same way as described above for 11.
NMR (CDCl3, 125.8 MHz): δ ϭ 12.9, 55.8, 106.2, 122.3, 122.4, The product was obtained as a white solid after column chromato-
128.6, 136.2, 145.0, 154.7 ppm. MS (CI): m/z (%) ϭ 203.2 (100) graphy on silica with hexane/ethyl acetate/triethylamine (2:1:0.15 v/
3952
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3948Ϫ3957

Synthesis of Differently Disubstituted 2,2Ј-Bipyridines
FULL PAPER
v) as eluent (920 mg, 70%). M.p. 124 °C. 1H NMR (CDCl3,
δ ϭ 2.40 (s, 3 H), 7.40 (m, 1 H), 7.48 (m, 2 H) 7.64 (dd, J ϭ 7.7 Hz,
500.1 MHz): δ ϭ 3.84 (s, 3 H), 6.99 (m, 2 H), 7.34 (d, J ϭ 8.2 Hz, 2 H), 7.65 (d, J ϭ 8.2 Hz, 1 H), 8.01 (dd, J ϭ 8.2, 2.2 Hz, 1 H),
1 H), 7.46 (m, 2 H), 7.77 (dd, J ϭ 8.2, 2.2 Hz, 1 H), 8.55 (d, J ϭ
8.34 (d, J ϭ 8.2 Hz, 1 H), 8.46 (d, J ϭ 8.2 Hz, 1 H), 8.52 (s, 1 H),
2.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 55.4, 114.7, 8.90 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz):
124.1, 128.1, 128.9, 135.3, 136.7, 147.6, 149.6, 160.0 ppm. MS (CI): δ ϭ 18.4, 120.8, 120.8, 127.0, 127.0, 128.2, 129.1, 133.6, 135.3,
m/z (%) ϭ 220.0 (100) [MHϩ, 35Cl], 222.0 (33) [MHϩ, 37Cl].
136.3, 137.6, 137.8, 147.5, 149.4, 153.3, 155.0 ppm. MS (CI): m/z
C12H10ClNO (219.67): calcd. C 65.61, H 4.59, N 6.38; found C (%) ϭ 247.3 (100) [MHϩ]. HRMS (EI): C17H14N2 (M·ϩ): calcd.
66.04, H 4.63, N 6.37.
246.1157; found 246.1160. C17H14N2 (246.31): calcd. C 82.90, H
5.73, N 11.37; found C 82.94, H 5.79, N 11.39.
Synthesis of Disubstituted 2,2Ј-Bipyridines
5-(4-Methoxyphenyl)-5Ј-methyl-2,2Ј-bipyridine (21): The desired
product was obtained from 2-bromo-5-methylpyridine (1b, 500 mg,
2.9 mmol) and 2-chloro-5-(4-methoxyphenyl)pyridine (12, 580 mg,
2.6 mmol) by the General Procedure as used for 19. After column
chromatography on silica with petroleum ether 40:60/ethyl acetate/
triethylamine (2:1:0.15 v/v) as eluent, 21 was isolated as a bright
General Procedure for Negishi Coupling Reactions with Substituted
Pyridine Derivatives, Demonstrated for the Synthesis of 5-Methyl-
5Ј-[(trimethylsilyl)ethynyl]-2,2Ј-bipyridine (19): tBuLi (1.7  in pen-
tane, 1.9 mL, 2.82 mmol) was added to abs. THF (8 mL) at Ϫ78
°C. Subsequently, a solution of 2-bromo-5-methylpyridine (1b,
250 mg, 1.45 mmol) in abs. THF (2 mL) was added dropwise. After
the mixture had been stirred at Ϫ78 °C for 30Ϫ45 min, a solution
of anhydrous ZnCl2 (494 mg, 3.63 mmol) in abs. THF (5 mL) was
added slowly and the reaction mixture was stirred for 2Ϫ3 h at
room temperature. After that time a solution of [Pd(PtBu3)2]
1
yellow solid (335 mg, 46%). M.p. 134Ϫ135 °C. H NMR (CDCl3,
500.1 MHz): δ ϭ 1.84 (s, 3 H), 3.31 (s, 3 H), 6.76 (m, 2 H), 7.10
(dd, J ϭ 8.2, 2.2 Hz, 1 H), 7.25 (m, 2 H), 7.59 (dd, J ϭ 8.2, 2.2 Hz,
1 H), 8.50 (d, J ϭ 2.2 Hz, 1 H), 8.77 (d, J ϭ 8.2 Hz, 1 H), 8.85 (d,
J ϭ 8.2 Hz, 1 H), 9.01 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 125.8 MHz): δ ϭ 17.6, 54.4, 114.4, 120.4, 120.5, 128.0,
130.2, 132.8, 134.2, 135.7, 136.8, 147.2, 149.6, 154.0, 154.9,
159.8 ppm. MS (CI): m/z (%) ϭ 277.3 (100) [MHϩ]. C18H16N2O
(276.34): calcd. C 78.24, H 5.84, N 10.14; found C 78.69, H 6.03,
N 9.77.
(19 mg,
0.038 mmol,
3
mol % Pd)
and 2-chloro-5-
[(trimethylsilyl)ethynyl]pyridine (8, 264 mg, 1.29 mmol) in abs.
THF (5 mL) was added and the reaction mixture was heated at
reflux until no further consumption was observed by TLC monitor-
ing. After cooling to room temperature, a suspension of EDTA
(3 g, 10.3 mmol) in water (60 mL) was added and the resulting mix-
ture was stirred for 15 min. After neutralisation to pH 8 with satu-
rated Na2CO3, the mixture was extracted several times with di-
6-Methoxy-5Ј-methyl-2,2Ј-bipyridine (23): Treatment of 2-bromo-5-
methylpyridine (1b, 500 mg, 2.9 mmol) and 2-chloro-6-methoxy-
chloromethane, dried with Na2SO4, and the solvents were removed pyridine (16, 378 mg, 2.6 mmol) according to the General Pro-
in vacuo. The pure product was obtained after column chromatog-
raphy on silica gel with hexane/ethyl acetate/triethylamine
cedure as used for 19 gave 23 as a bright yellow, syrupy substance
(447 mg, 85%) after column chromatography on silica gel with hex-
(10:1:0.05 v/v) as eluent, as a pale yellow solid (265 mg, 77%). M.p. ane/ethyl acetate/triethylamine (2:1:0.15 v/v) as eluent. 1H NMR
106Ϫ107 °C. 1H NMR (CDCl3, 500.1 MHz): δ ϭ 0.27 (s, 9 H),
(CDCl3, 500.1 MHz): δ ϭ 2.37 (s, 3 H), 4.02 (s, 3 H), 6.73 (d, J ϭ
2.39 (s, 3 H), 7.65 (d, J ϭ 7.7 Hz, 1 H), 7.85 (dd, J ϭ 8.2, 2.2 Hz, 7.7 Hz, 1 H), 7.58 (dd, J ϭ 7.7, 1.7 Hz, 1 H), 7.67 (dd, J ϭ 7.7,
1 H), 8.31 (d, J ϭ 7.7 Hz, 1 H), 8.37 (d, J ϭ 8.2 Hz, 1 H), 8.51 (s, 7.7 Hz, 1 H), 7.96 (d, J ϭ 7.7 Hz, 1 H), 8.28 (d, J ϭ 7.7 Hz, 1 H),
1 H), 8.70 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.8 MHz): δ ϭ Ϫ0.2, 18.4, 98.9, 101.9, 119.8, 119.9, 121.0, 133.8,
137.6, 139.7, 149.6, 152.0, 152.8, 155.0 ppm. MS (CI): m/z (%) ϭ
267.2 (100) [MHϩ]. HRMS (EI): C16H18N2Si (M·ϩ): calcd.
8.47 (d, J ϭ 1.7 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz):
δ ϭ 18.3, 53.2, 110.6, 113.3, 120.5, 133.1, 137.2, 139.3, 149.5, 153.6,
153.6, 163.5 ppm. MS (CI): m/z (%) ϭ 201.3 (100) [MHϩ]. HRMS
(CI): C12H13N2O [MHϩ]: calcd. 201.1028; found 201.1027.
266.1239; found 266.1243. C16H18N2Si (266.41): calcd. C 72.13, H C12H12N2O (200.24): calcd. C 71.98, H 6.04, N 13.99; found C
6.81, N 10.52; found C 72.47, H 6.99, N 10.24.
71.52, H 6.48, N 13.58.
5-Methoxy-5Ј-methyl-2,2Ј-bipyridine (18): The disubstituted bipyri-
5-(3,5-Dimethylphenyl)-5Ј-methoxy-2,2Ј-bipyridine (24): 2-Bromo-5-
dine 18 was prepared from 2-bromo-5-methylpyridine (1b, 500 mg, methoxypyridine (2, 500 mg, 2.7 mmol) and 2-chloro-5-(3,5-di-
2.9 mmol) and 2-chloro-5-methoxypyridine (7, 378 mg, 2.6 mmol) methylphenyl)pyridine (11, 525 mg, 2.4 mmol) were treated follow-
according to the General Procedure as used for 19. The pure prod- ing the General Procedure as used for 19, and the resulting disubsti-
uct was obtained after column chromatography on silica with hex-
tuted bipyridine 24 was isolated as a yellow solid (404 mg, 57%)
ane/ethyl acetate/triethylamine (2:1:0.15 v/v) as eluent, as a slightly
yellow syrup (289 mg, 56%). H NMR (CDCl3, 500.1 MHz): δ ϭ ate/triethylamine (2:1:0.15 vv). M.p. 78Ϫ80 °C. H NMR (CDCl3,
2.35 (s, 3 H), 3.88 (s, 3 H), 7.28 (dd, J ϭ 8.8, 2.7 Hz, 1 H), 7.57 500.1 MHz): δ ϭ 2.39 (s, 6 H), 3.91 (s, 3 H), 7.04 (s, 1 H), 7.24 (s,
after column chromatography on silica gel with hexane/ethyl acet-
1
1
(dd, J ϭ 8.2, 1.7 Hz, 1 H), 8.11 (d, J ϭ 8.2 Hz, 1 H), 8.28 (d, J ϭ
8.8 Hz, 1 H), 8.33 (d, J ϭ 2.7 Hz, 1 H), 8.44 (d, J ϭ 1.7 Hz, 1 H)
ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 18.2, 55.6, 120.0, 121.0,
2 H), 7.32 (dd, J ϭ 8.2, 3.3 Hz, 1 H), 7.96 (dd, J ϭ 8.2, 2.2 Hz, 1
H), 8.35 (d, J ϭ 8.2 Hz, 1 H), 8.38 (m, 2 H), 8.84 (d, J ϭ 2.2 Hz,
1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 21.4, 55.6, 120.2,
121.4, 132.5, 136.8, 137.5, 149.0, 149.3, 153.4, 155.9 ppm. MS (CI): 120.9, 121.6, 124.9, 129.7, 135.2, 135.9, 137.0, 137.7, 138.6, 147.5,
m/z (%) ϭ 201.3 (100) [MHϩ]. HRMS (EI): C12H12N2O (M·ϩ):
calcd. 200.0950; found 200.0958.
148.8, 154.6, 156.0 ppm. MS (CI): m/z (%) ϭ 291.3 (100) [MHϩ].
HRMS (EI): C19H18N2O (M·ϩ): calcd. 290.1419; found 290.1419.
5-Methyl-5Ј-phenyl-2,2Ј-bipyridine (20): The disubstituted bipyri-
5-Methoxy-5Ј-(trifluoromethyl)-2,2Ј-bipyridine (25): The disubsti-
dine 20 was synthesised from 2-bromo-5-methylpyridine (1b, tuted bipyridine 25 was prepared from 2-bromo-5-methoxypyridine
250 mg, 1.45 mmol) and 2-chloro-5-phenylpyridine (10, 245 mg, (2, 500 mg, 2.7 mmol) and 2-chloro-5-(trifluoromethyl)pyridine
1.29 mmol) following the General Procedure as used for 19 and (13, 439 mg, 2.4 mmol) according to the General Procedure as used
obtained after column chromatography on silica gel with hexane/
for 19. The pure product was obtained as a yellow solid after col-
ethyl acetate/triethylamine (3:1:0.02 v/v), as a pale yellow solid
(226 mg, 71%). M.p. 105Ϫ106 °C. H NMR (CDCl3, 500.1 MHz): ethylamine (2:1:0.15 v/v) as eluent (320 mg, 52%). M.p. 89Ϫ91 °C.
umn chromatography on silica gel with hexane/ethyl acetate/tri-
1
Eur. J. Org. Chem. 2003, 3948Ϫ3957
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3953

A. Lützen, M. Hapke, H. Staats, J. Bunzen
FULL PAPER
1H NMR (CDCl3, 500.1 MHz): δ ϭ 3.92 (s, 3 H), 7.32 (dd, J ϭ
(0.4 mL), ethanol (6 mL), and water (1.6 mL) were heated at reflux
8.8, 2.7 Hz, 1 H), 7.98 (dd, J ϭ 8.8, 2.2 Hz, 1 H), 8.37 (d, J ϭ until TLC monitoring revealed complete consumption of the start-
2.7 Hz, 1 H), 8.40 (d, J ϭ 8.8 Hz, 1 H), 8.45 (d, J ϭ 8.8 Hz, 1 H),
ing material (usually after 20 h). After cooling to room temperature
8.86 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): the reaction mixture was quenched by pouring into 10 mL of ice-
δ ϭ 55.7, 119.9, 120.7, 122.4, 123.8 (J ϭ 272 Hz), 125.4 (J ϭ cold 1  HCl. The resulting solution was washed with isopropyl
33 Hz), 133.9 (J ϭ 4 Hz), 137.4, 146.0 (J ϭ 4 Hz), 147.4, 156.7,
ether and the pH was adjusted to 9Ϫ10 by careful addition of 6
159.1 ppm. 19F NMR (CDCl3, 282.4 MHz): δ ϭ Ϫ62.3 ppm. MS  NaOH. The resulting mixture was extracted several times with
(CI): m/z (%) ϭ 255.2 (100) [MHϩ]. HRMS (CI): C12H10F3N2O
dichloromethane and the combined organic phases were dried with
Na2SO4. After removal of the solvent in vacuo, the brown residue
was subjected to column chromatography on silica with dichloro-
methane/MeOH/triethylamine (3:1:0.04 v/v) as eluent. The pure
product was obtained as a yellow solid (122 mg, 93% yield). M.p.
139Ϫ140 °C. 1H NMR ([D6]DMSO, 500.1 MHz): δ ϭ 3.84 (s, 3
H), 5.66 (br. s, 2 H), 7.01 (dd, J ϭ 8.8, 2.7 Hz, 1 H), 7.41 (dd, J ϭ
8.8, 2.8 Hz, 1 H), 7.97 (d, J ϭ 8.8 Hz, 1 H), 7.98 (d, J ϭ 2.7 Hz,
1 H), 8.11 (d, J ϭ 8.8 Hz, 1 H), 8.25 (d, J ϭ 2.8 Hz, 1 H). 13C
NMR ([D6]DMSO, 125.8 MHz): δ ϭ 55.5, 119.4, 120.2, 120.6,
121.3, 135.1, 136.1, 143.3, 144.8, 149.0, 154.6. MS (CI): m/z (%) ϭ
202.5 (100) [MHϩ]. C11H11N3O·1/3 H2O (201.22 ϩ 1/3 ϫ 18.01 ϭ
207.22): calcd. C 63.75, H 5.67, N 20.28; found C 63.99, H 5.60,
N 20.24.
[MHϩ]: calcd. 255.0745; found 255.0739.
1-(5Ј-Methoxy-2,2Ј-bipyridin-5-yl)-2,5-dimethyl-1H-pyrrole
(26):
The disubstituted bipyridine 23 was prepared from 2-bromo-5-
methoxypyridine (2, 500 mg, 2.7 mmol) and 1-(2-chloropyridin-5-
yl)-2,5-dimethyl-1H-pyrrole (14, 500 mg, 2.4 mmol) by the General
Procedure as used for 19, and was obtained as a yellow solid
(405 mg, 60%) after column chromatography on silica gel with hex-
ane/ethyl acetate/triethylamine (5:1:0.03 v/v) as eluent. M.p.
118Ϫ119 °C. 1H NMR (CDCl3, 500.1 MHz): δ ϭ 2.07 (s, 6 H),
3.93 (s, 3 H), 5.95 (s, 2 H), 7.34 (dd, J ϭ 8.8, 2.7 Hz, 1 H), 7.64
(dd, J ϭ 8.2, 2.7 Hz, 1 H), 8.38 (m, 2 H), 8.44 (d, J ϭ 8.2 Hz, 1
H), 8.52 (d, J ϭ 2.7 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz):
δ ϭ 13.0, 55.7, 106.6, 120.5, 120.9, 121.8, 129.0, 134.8, 136.2, 137.1,
148.1, 148.2, 155.1, 156.3 ppm. MS (CI): m/z (%) ϭ 280.3 (100)
[MHϩ]. C17H17N3O (279.34): calcd. C 73.10, H 6.13, N 15.04;
found C 73.56, H 6.30, N 15.06.
5-Amino-5Ј-(trifluoromethyl)-2,2Ј-bipyridine (31): The removal of
the pyrrole group from crude 1-[5Ј-(trifluoromethyl)-2,2Ј-bipyridin-
5-yl]-2,5-dimethyl-1H-pyrrole (29, approx. 300 mg, approx.
0.9 mmol) Ϫ obtained as an inseparable 2:1 mixture together with
homocoupling product 5,5Ј-bis(trifluoromethyl)-2,2Ј-bipyridine
from the reaction of pyrrole 3 (500 mg, 2.7 mmol) with chloropyri-
dine 13 (439 mg, 2.4 mmol) according to the General Procedure as
used for 19 Ϫ was accomplished by the General Procedure as used
for 30 and gave the pure product as an orange-brown solid (89 mg,
16% over both reaction steps) after purification by column chroma-
tography on silica gel with hexane/dichloromethane/MeOH (4:4:1
1-(5Ј-Methyl-2,2Ј-bipyridin-5-yl)-2,5-dimethyl-1H-pyrrole (27):
Compound 27 was prepared from 1-(2-bromopyridin-5-yl)-2,5-di-
methyl-1H-pyrrole (3, 364 mg, 1.45 mmol) and 2-chloro-5-methyl-
pyridine (9, 165 mg, 1.29 mmol) by the General Procedure as used
for 19 and isolated after column chromatography on silica gel with
hexane/ethyl acetate/triethylamine (3:1:0.02 v/v) as a pale yellow
solid (262 mg, 77%). M.p. 100Ϫ101 °C. 1H NMR (CDCl3,
500.1 MHz): δ ϭ 2.08 (s, 6 H), 2.41 (s, 3 H), 5.95 (s, 2 H), 7.65 (m,
2 H), 8.31 (d, J ϭ 8.2 Hz, 1 H), 8.49 (d, J ϭ 8.3 Hz, 1 H), 8.52 (m,
1 H), 8.54 (d, J ϭ 2.1 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.8 MHz): δ ϭ 18.0, 18.4, 106.7, 120.7, 120.9, 129.0, 133.8, 135.2,
136.3, 137.6, 148.3, 149.8, 152.8, 155.4 ppm. MS (CI): m/z (%) ϭ
263.8 (100) [MHϩ]. HRMS (EI): C17H17N3 (M·ϩ): calcd. 263.1422;
found 263.1423. C17H17N3 (263.34): calcd. C 77.54, H 6.51, N
15.96; found C 78.11, H 6.57, N 15.65.
1
v/v) as eluent. M.p. 102Ϫ104 °C. H NMR (CDCl3, 500.1 MHz):
δ ϭ 3.90 (br. s, 2 H), 7.09 (dd, J ϭ 8.2, 2.7 Hz, 1 H), 7.95 (dd, J ϭ
8.2, 2.2 Hz, 1 H), 8.15 (d, J ϭ 2.7 Hz, 1 H), 8.26 (d, J ϭ 8.2 Hz,
1 H), 8.38 (d, J ϭ 8.2 Hz, 1 H), 8.83 (d, J ϭ 2.2 Hz, 1 H) ppm.
13C NMR (CDCl3, 125.8 MHz): δ ϭ 119.3, 121.7, 122.4, 123.9 (J ϭ
273 Hz), 128.9 (J ϭ 33 Hz), 133.7 (J ϭ 4 Hz), 136.6, 143.6, 145.3,
145.9 (J ϭ 4 Hz), 159.5 ppm. 19F NMR (CDCl3, 282.4 MHz): δ ϭ
Ϫ62.2. MS (CI): m/z (%) ϭ 240.1 (100) [MHϩ]. HRMS (EI):
C11H8F3N3 (M·ϩ): calcd. 239.0670; found 239.0660.
1-[5Ј-(3,5-Dimethylphenyl)-2,2Ј-bipyridin-5-yl]-2,5-dimethyl-1H-
pyrrole (28): Compound 28 was prepared from 1-(2-bromopyridin-
5-yl)-2,5-dimethyl-1H-pyrrole (3, 408 mg, 1.6 mmol) and 2-chloro-
5-(3,5-dimethylphenyl)-pyridine (11, 280 mg, 1.5 mmol) by the
General Procedure as used for 19 and was obtained as a yellow
solid (225 mg, 42%) after column chromatography on silica gel with
hexane/ethyl acetate (10:1 vv). M.p. 106Ϫ107 °C 1H NMR (CDCl3,
500.1 MHz): δ ϭ 2.10 (s, 6 H), 2.42 (s, 6 H), 5.97 (s, 2 H), 7.08 (s,
1 H), 7.28 (s, 2 H), 7.69 (dd, J ϭ 8.2, 2.7 Hz, 1 H), 8.03 (dd, J ϭ
8.2, 2.2 Hz, 1 H), 8.49 (d, J ϭ 8.2 Hz, 1 H), 8.58 (m, 2 H), 8.92 (d,
J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 13.0,
21.4, 106.8, 121.1, 121.2, 125.0, 129.0, 130.0, 135.4, 135.5, 136.3,
137.0, 137.3, 138.8, 147.8, 148.4, 153.8, 154.9 ppm. MS (CI): m/z
(%) ϭ 354.3 (100) [MHϩ]. HRMS (CI): C24H24N3 [MHϩ]: calcd.
354.1970; found 354.1920. C24H23N3·1/2H2O (353.46 ϩ 1/2 ϫ
18.01 ϭ 362.47): calcd. C 79.53, H 6.67, N 11.59; found C 79.35,
H 6.71, N 11.36.
4-Amino-4Ј-methyl-2,2Ј-bipyridine (32): Bromopyridine 1a (500 mg,
2.9 mmol) and pyrrole 17 (545 mg, 2.6 mmol) were reacted follow-
ing the General Procedure as used for 19. Deprotection of crude 1-
(4Ј-methyl-2,2Ј-bipyridin-4-yl)-2,5-dimethyl-1H-pyrrole (580 mg,
approx. 2.2 mmol), which was obtained after filtration of the cross-
coupling reaction product mixture through a short column of silica
with hexane/ethyl acetate/triethylamine (5:2:0.2 v/v) as eluent by
the General Procedure as used for 30, gave 32 as a light yellow
solid (232 mg, 47% yield over both the coupling and the deprotec-
tion step) after column chromatography on silica with dichloro-
methane/MeOH (2:1 v/v) as eluent. M.p. 199Ϫ201 °C. 1H NMR
([D6]DMSO, 500.1 MHz): δ ϭ 2.37 (s, 3 H), 6.20 (br. s, 2 H), 6.52
(dd, J ϭ 6.0, 2.2 Hz, 1 H), 7.20 (d, J ϭ 4.4 Hz, 1 H), 7.61 (d, J ϭ
2.2 Hz, 1 H), 8.09 (d, J ϭ 6.0 Hz, 1 H), 8.15 (s, 1 H), 8.46 (d, J ϭ
4.4 Hz, 1 H). 13C NMR ([D6]DMSO, 125.8 MHz): δ ϭ 20.7, 105.7,
108.9, 121.1, 124.4, 147.4, 148.6, 148.9, 155.1, 155.3, 155.7. MS
(CI): m/z (%) ϭ 186.4 (100) [MHϩ]. Ϫ C11H11N3·1/3 H2O (185.23
ϩ 1/3 ϫ 18.01 ϭ 191.23): calcd. C 69.09, H 6.15, N 21.97; found
C 68.88, H 6.14, N 21.35.
General Procedure for the Removal of the Pyrrole Protecting Group
from Protected Aminobipyridines, Demonstrated for 5-Amino-5Ј-
methoxy-2,2Ј-bipyridine (30): 1-(5Ј-Methoxy-2,2Ј-bipyridin-5-yl)-
2,5-dimethyl-1H-pyrrole (26, 182 mg, 0.65 mmol), hydroxylamine 4-Amino-5Ј-methyl-2,2Ј-bipyridine (33): Crude 1-(5Ј-methyl-2,2Ј-bi-
hydrochloride (910 mg, 13.0 mmol, 20 equiv.), triethylamine pyridin-4-yl)-2,5-dimethyl-1H-pyrrole (327 mg, approx. 1.2 mmol)
3954
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3948Ϫ3957

Synthesis of Differently Disubstituted 2,2Ј-Bipyridines
FULL PAPER
was obtained from the reaction of bromopyridine 1b (500 mg,
2.9 mmol) with pyrrole 17 (545 mg, 2.6 mmol) following the Gen-
eral Procedure as used for 19, after filtration of the cross-coupling
reaction product mixture through a short column of silica with
hexane/ethyl acetate/triethylamine (5:1:0.3 v/v) as eluent. Deprotec-
6-Methoxy-5Ј-[(trimethylsilyl)methyl]-2,2Ј-bipyridine (36): nBuLi
(0.86 mL, 1.44  in hexane, 1.25 mmol) was added by syringe to a
solution of diisopropylamine (0.18 mL, 1.25 mmol) in abs. THF
(5 mL) at Ϫ78 °C. The solution was stirred for 10 min, allowed to
warm to room temperature and cooled again to Ϫ78 °C. Sub-
tion of the pyrrole according to the General Procedure as used for sequently, a solution of 6-methoxy-5Ј-methyl-2,2Ј-bipyridine (24,
30 gave 33 as a white solid (136 mg, 28% over both reaction steps)
200 mg, 1 mmol) in abs. THF (5 mL) was added dropwise by sy-
after column chromatography on silica gel with dichloromethane/
ringe. After the mixture had been stirred for 1 h at Ϫ78 °C, tri-
MeOH (2:1 v/v) as eluent. M.p. 148Ϫ150 °C. 1H NMR methylsilyl chloride (0.16 mL, 1.25 mmol) was added quickly to the
([D6]DMSO, 500.1 MHz): δ ϭ 2.33 (s, 3 H), 6.17 (br. s, 2 H), 6.50
(dd, J ϭ 5.5, 2.2 Hz, 1 H), 7.58 (d, J ϭ 2.2 Hz, 1 H), 7.67 (d, J ϭ
reaction mixture and after further 5 min the reaction was quenched
by addition of ethanol (2 mL). The reaction mixture was poured
8.2 Hz, 1 H), 8.07 (d, J ϭ 5.5 Hz, 1 H), 8.19 (d, J ϭ 8.2 Hz, 1 H), into a flask containing sat. aq. NaHCO3 solution and then ex-
8.45 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 125.8 MHz): δ ϭ 17.7, tracted three times with dichloromethane. The combined organic
105.1, 108.8, 119.8, 132.9, 137.2, 148.9, 149.1, 153.3, 155.1, phases were washed with brine, dried with Na2SO4, and the sol-
155.2 ppm. MS (CI): m/z (%) ϭ 186.4 (100) [MHϩ]. HRMS (EI): vents were evaporated in vacuo. Purification by column chromatog-
C11H11N3 (M·ϩ): calcd. 185.0953; found 185.0953. C11H11N3·1/2
H2O (185.23 ϩ 1/2 ϫ 18.01 ϭ 194.24): calcd. C 68.02, H 6.23, N
21.63; found C 67.73, H 5.93, N 21.05.
raphy on silica gel with hexane/ethyl acetate (10:1 v/v) as eluent
gave the product as a colourless oil (100 mg, 37%). 1H NMR
(CDCl3, 500.1 MHz): δ ϭ 0.03 (s, 9 H), 2.11 (s, 2 H), 4.03 (s, 3 H),
6.72 (d, J ϭ 8.2 Hz, 1 H), 7.43 (dd, J ϭ 8.2, 2.2 Hz, 1 H), 7.67 (dd,
J ϭ 8.2, 7.7 Hz, 1 H), 7.96 (d, J ϭ 7.7 Hz, 1 H), 8.27 (d, J ϭ
8.2 Hz, 1 H), 8.33 (d, J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.8 MHz): δ ϭ Ϫ2.0, 24.0, 53.2, 110.4, 113.1, 120.5, 136.0, 136.5,
139.3, 148.3, 153.6, 163.5 ppm. MS (CI): m/z (%) ϭ 273.1 (100)
[MHϩ]. HRMS (EI): C15H20N2OSi (M·ϩ): calcd. 272.1345; found
272.1345.
4-Amino-6Ј-methyl-2,2Ј-bipyridine (34): Crude 1-(6Ј-methyl-2,2Ј-bi-
pyridin-4-yl)-2,5-dimethyl-1H-pyrrole (540 mg, approx. 2.1 mmol)
was obtained from treatment of bromopyridine 1c (500 mg,
2.9 mmol) and pyrrole 17 (545 mg, 2.6 mmol) by the General Pro-
cedure as used for 19, after filtration of the cross-coupling reaction
product mixture through a short column of silica with hexane/ethyl
acetate/triethylamine (5:2:0.2 v/v) as eluent. Deprotection of the
pyrrole by the General Procedure as used for 30 gave the pure pro-
duct as a white solid (220 mg, 45% over both reaction steps) after
column chromatography on silica gel with dichloromethane/MeOH
5-Chloromethyl-6Ј-methoxy-2,2Ј-bipyridine (37): 6-Methoxy-5Ј-[(tri-
methylsilyl)methyl]-2,2Ј-bipyridine (36, 80 mg, 0.29 mmol),
perchloroethane (142 mg, 0.6 mmol), and caesium fluoride (91 mg,
(2:1 v/v) as eluent. M.p. 136Ϫ138 °C. 1H NMR ([D6]DMSO, 0.6 mmol) were placed in a Schlenk flask and repeatedly evacuated
500.1 MHz): δ ϭ 2.54 (s, 3 H), 6.40 (br. s, 2 H), 6.54 (dd, J ϭ 5.5,
and flushed with argon. After addition of abs. acetonitrile (5 mL),
2.2 Hz, 1 H), 7.26 (d, J ϭ 7.7 Hz, 1 H), 7.60 (d, J ϭ 2.2 Hz, 1 H), the mixture was heated to 60 °C for 3.5 h. After cooling, the reac-
7.76 (dd, J ϭ 7.7, 7.7 Hz, 1 H), 8.07 (d, J ϭ 5.5 Hz, 1 H), 8.09 (d,
J ϭ 7.7 Hz, 1 H) ppm. 13C NMR ([D6]DMSO, 125.8 MHz): δ ϭ
24.2, 105.4, 108.9, 117.4, 122.9, 137.0, 149.0, 155.2, 155.3, 155.4,
tion solution was quenched with water and ethyl acetate. The
phases were separated and the aqueous phase was extracted several
times with ethyl acetate. The combined organic phases were dried
157.0 ppm. MS (CI): m/z (%) ϭ 186.4 (100) [MHϩ]. C11H11N3·2/3 with Na2SO4 and the solvent was removed in vacuo. The product
H2O (185.23 ϩ 2/3 ϫ 18.01 ϭ 197.24): calcd. C 66.98, H 6.30, N
21.30; found C 67.31, H 6.11, N 21.29.
(79 mg, 89%) was obtained as a bright yellow solid after column
chromatography on silica gel with hexane/ethyl acetate/triethyl-
amine (2:1:0.15 v/v) as eluent. M.p. 56Ϫ57 °C. H NMR (CDCl3,
1
5-Heptyl-5Ј-[(trimethylsilyl)ethynyl]-2,2Ј-bipyridine (35): A solution
of 5-methyl-5Ј-[(trimethylsilyl)ethynyl]-2,2Ј-bipyridine (19, 150 mg,
0.56 mmol) in abs. THF (2 mL) was added by syringe at Ϫ78 °C
to a solution of lithium diisopropylamide, previously prepared from
diisopropylamine (83 µL, 0.59 mmol) and nBuLi (1.55  in hexane,
380 µL, 0.59 mmol) in abs. THF (6 mL) at Ϫ78 °C. The reaction
mixture was allowed to warm up to 0 °C, and hexyl iodide (87 µL,
0.59 mmol) was added. The mixture was allowed to warm to room
temperature and was stirred for 48 h. The solvent was removed and
the residue was partitioned in a mixture of water and dichlorometh-
ane. The phases were separated and the aqueous phase was ex-
tracted repeatedly with dichloromethane. The combined organic
phases were dried with MgSO4, the solvent was removed in vacuo,
and the product was isolated after column chromatography on sil-
500.1 MHz): δ ϭ 4.03 (s, 3 H), 4.63 (s, 2 H), 6.78 (d, J ϭ 8.2 Hz,
1 H), 7.69 (dd, J ϭ 8.2, 7.1 Hz, 1 H), 7.83 (dd, J ϭ 8.2, 2.2 Hz, 1
H), 8.00 (d, J ϭ 7.1 Hz, 1 H), 8.40 (d, J ϭ 8.2 Hz, 1 H), 8.64 (d,
J ϭ 2.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ 43.1,
53.2, 111.4, 114.0, 120.9, 132.9, 137.1, 139.4, 148.8, 152.1, 153.6,
163.5 ppm. MS (CI): m/z (%) ϭ 235.1 (100) [MHϩ, 35Cl], 237.1 (32)
[MHϩ, 37Cl]. HRMS (CI): C12H12N2ClO [MHϩ]: calcd. 235.0638;
found 235.0637. C12H11ClN2O (234.68): calcd. C 61.41, H 4.72, N
11.94; found C 61.78, H 5.07, N 11.50.
4-Iodo-5Ј-methyl-2,2Ј-bipyridine (38): A solution of sodium nitrite
(39 mg, 0.6 mmol) in water (1.2 mL) was cooled to Ϫ10 °C and a
solution of 4-amino-5Ј-methyl-2,2Ј-bipyridine (33, 80 mg,
0.4 mmol) in 4  H2SO4 (4 mL) was added slowly, so that the tem-
ica gel with hexane/ethyl acetate/triethylamine (20:1:0.05 v/v) as perature did not exceed Ϫ5 °C. Subsequently, a solution of potas-
eluent as a waxy compound (100 mg, 51%). 1H NMR (CDCl3,
sium iodide (642 mg, 3.9 mmol) in water (0.5 mL) was also added
500.1 MHz): δ ϭ 0.27 (s, 9 H), 0.87 (s, 3 H), 1.29 (m, 8 H), 1.64 slowly. After stirring at this temperature for 30 min and for another
(m, 2 H), 2.64 (t, J ϭ 7.6 Hz, 2 H), 7.63 (dd, J ϭ 8.2, 1.8 Hz, 1 45 min at room temperature, the reaction mixture was heated to 80
H), 7.84 (dd, J ϭ 8.2, 2.1 Hz, 1 H), 8.31 (d, J ϭ 8.2 Hz, 1 H), 8.34 °C for 1 h. After cooling to room temperature the mixture was
(d, J ϭ 8.2 Hz, 1 H), 8.49 (d, J ϭ 1.8 Hz, 1 H), 8.71 (d, J ϭ 2.1 Hz,
1 H) ppm. 13C NMR (CDCl3, 125.8 MHz): δ ϭ Ϫ2.0, 14.0, 22.6, chloromethane. The combined organic phases were washed twice
29.0, 31.0, 31.7, 32.9, 99.0, 101.9, 119.9, 120.0, 121.2, 137.1, 138.8, with sat. aq. Na2S2O3 solution, then with water, dried with Na2SO4,
neutralised with sat. NaHCO3 and extracted five times with di-
139.8, 149.1, 152.0, 152.8, 154.7 ppm. MS (CI): m/z (%) ϭ 350.8 and the solvents were evaporated in vacuo. Purification by column
(100) [MHϩ]. HRMS (EI): C22H30N2Si (M·ϩ): calcd. 350.2178; chromatography on silica gel with hexane/ethyl acetate/triethyl-
found 350.2183.
amine (2:1:0.15 v/v) gave the pure product (57 mg, 45%). M.p.
Eur. J. Org. Chem. 2003, 3948Ϫ3957
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3955

A. Lützen, M. Hapke, H. Staats, J. Bunzen
FULL PAPER
76Ϫ78 °C. H NMR (CDCl3, 500.1 MHz): δ ϭ 2.38 (s, 3 H), 7.61
[10h]
1
`
N. Weibel, L. J. Charbonniere, R. F.
2002, 1101Ϫ1109.
Ziessel, J. Org. Chem. 2002, 67, 7876Ϫ7879.
(dd, J ϭ 7.7, 1.1 Hz, 1 H), 7.64 (dd, J ϭ 5.0, 1.1 Hz, 1 H), 8.25 (d,
J ϭ 7.7 Hz, 1 H), 8.28 (d, J ϭ 5.0 Hz, 1 H), 8.48 (d, J ϭ 1.1 Hz,
1 H), 8.78 (d, J ϭ 1.1 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.8 MHz): δ ϭ 18.4, 106.6, 121.1, 130.3, 132.6, 134.3, 137.9,
149.2, 149.4, 151.8, 156.4 ppm. MS (CI): m/z (%) ϭ 297.1 (100)
[MHϩ]. HRMS (EI): C11H9N2I (M·ϩ): calcd. 295.9810; found
295.9812. C11H9N2I (296.11): calcd. C 44.62, H 3.06, N 9.46; found
C 44.08, H 2.58, N 9.20.
[11] [11a]
F. Diederich, P. J. Stang (Eds.); Metal-catalysed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, 1998. [11b] J. J. Lie,
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recent special issue of the Journal of Organometallic Chemistry
outlines historically and recent developments in cross-coupling
chemistry: K. Tamao, T. Hiyama, E. Negishi (Eds.); J. Or-
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[12]
[12a]
Recent examples:
O. Henze, U. Lehmann, A. D. Schlüter,
[12b]
Synthesis 1999, 683Ϫ687.
U. S. Schubert, C. Eschbaumer,
Acknowledgments
G. Hochwimmer, Synthesis 1999, 779Ϫ782. [12c] R.-A. Fallahp-
our, M. Neiburger, M. Zehnder, New. J. Chem. 1999, 53Ϫ61.
We thank Prof. Dr. P. Köll for providing us with excellent working
conditions. Financial support from the DFG (Sachbeihilfen LU
803/1-1 and LU 803/1-3) and the Fonds der Chemischen Industrie
is gratefully acknowledged. We appreciate generous gifts of chemi-
cals from Degussa-Hüls AG, Bayer AG, BASF AG, and Wacker
Chemie GmbH. M. H. is indebted to the state of Niedersachsen
for a graduate scholarship.
[12d]
[12e]
P. N. W. Baxter, J. Org. Chem. 2000, 65, 1257Ϫ1272.
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2292Ϫ2297 and the references cited therein.
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Very recent comprehensive review: A. F. Littke, G. C. Fu, An-
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U. S. Schubert, C. Eschbaumer, Angew. Chem. 2002, 114,
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´
´
F. Trecourt, B. Gervais, M. Mallet, G. Queguiner, J. Org.
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[3b]
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F. Trecourt, B. Gervais, O.
Chem. 1996, 61, 1673Ϫ1676.
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W. Swaan, Drugs 2002, 62, 2039Ϫ2057. [4b] Synthesis: S. Bäurle,
U. Koert, in: Organic Synthesis Highlights IV, (Ed.: H.-G.
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´
[3c]
´
F. Mongin, F. Trecourt, B. Gervais,
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T. Sakamoto, Y. Kondo, N. Murata, H. Yamanaka, Tetra-
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[16c]
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N. Murata, T. Sakamoto, Heterocycles 1994, 37, 1467Ϫ1468.
[16d]
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I. Gomez, E. Alonso, D. J. Ramon, M. Yus, Tetrahedron
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[17]
The best result we were able to obtain was the formation of
5-methyl-5Ј-[(trimethylsilyl)ethynyl]-2,2Ј-bipyridine (19) in 45%
yield after lithiation of our model substrate 2-chloro-5-methyl-
pyridine (9) with 2 equiv. of lithium and 4 equiv. of naphtha-
lene, transmetallation with anhydrous zinc() chloride and sub-
sequent palladium-catalysed cross-coupling reaction with 2-
chloro-5-[(trimethylsilyl)ethynyl]-pyridine (8). However, the
very long reaction time, which was found to be essential, re-
sidual unreacted lithium, which possibly interferes in the cross-
coupling step, and also the excess of naphthalene caused prob-
lems during the isolation and purification of the product.
[6] [6a]
N. C. Fletcher, J. Chem. Soc., Perkin Trans. 1 2002,
1831Ϫ1842. [6b] G. Chelucci, R. P. Thummel, Chem. Rev. 2002,
102, 3129Ϫ3170.
[7]
´
J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359Ϫ1469.
[8] [8a]
[8b]
F. Kröhnke, Synthesis 1976, 1Ϫ24.
This approach has
been used extensively by von Zelewsky’s group for the synthesis
of chiral bipyridines: A. von Zelewsky, O. Mamula, J. Chem.
Soc., Dalton Trans. 2000, 219Ϫ231.
[9]
[9a]
Examples for cobalt-catalysed cyclisations:
J. A. Varela, L.
´
Castedo, C. Saa, J. Am. Chem. Soc. 1998, 120, 12147Ϫ12148
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[9b]
and references cited therein.
Maestro, J. Mahıa, C. Saa, Chem. Eur. J. 2001, 7, 5203Ϫ5213
J. A. Varela, L. Castedo, M.
´
´
[9c]
and references cited therein.
H. Bönnemann, W. Brijoux,
[19]
S. P. Bruekelman, S. E. Leach, G. D. Meakins, M. D. Tirel, J.
Chem. Soc., Perkin Trans. 1 1984, 2801Ϫ2807.
Y. Hama, Y. Nobuhara, Y. Aso, T. Otsubo, F. Ogura, Bull.
New J. Chem. 1987, 11, 549Ϫ559. Recent examples for the
DielsϪAlder reaction approach for substituted bipyridines: [9d]
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N. Bushby, C. J. Moody, D. A. Riddick, I. R. Waldron, Chem.
[9e]
Chem. Soc. Jpn. 1988, 61, 1683Ϫ1686.
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[9f]
J. A. Ragan, B. P. Jones, M. J. Castaldi, P. D. Hill, T. W.
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[21b]
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J. A. Ragan, T.
C. J. Moody, D. A. Riddick, I. R. Waldron, J. Chem. Soc.,
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1599Ϫ1603.
F. Effenberger, A. Krebs, P. Willrett, Chem. Ber. 1992, 125,
1131Ϫ1140 and cited references.
As well as [Pd(PtBu3)2] we also tested some other Pd/phos-
phane systems with regard to their performance in these reac-
tions, as exemplified by the synthesis of 18 from 1b and 7.
However, neither [Pd(PPh3)4] (18% yield of 18 and 43% reco-
vered 7), nor a palladacycle published by M. Beller and W. A.
Herrmann (refs. [23a, 23b]), which resulted in almost no yield
of 18 but almost complete recovery of 7, nor the use of Buch-
M. D. Watson, Tetrahedron Lett. 2003, 44, 693Ϫ694.
[22]
[23]
[10]
[10a]
Examples:
D. Wenkert, R. B. Woodward, J. Org. Chem.
1983, 48, 283Ϫ289. [10b] G. R. Newkome, J. Gross, A. K. Patri,
[10c]
J. Org. Chem. 1997, 62, 3013Ϫ3014.
Kersten, A. E. Pemp, C. D. Eisenbach, G. R. Newkome, Eur.
U. S. Schubert, J. L.
[10d]
J. Org. Chem. 1998, 2573Ϫ2581.
Balzani, Synthesis 1998, 321Ϫ324.
oury, Synthesis 2000, 2137Ϫ2140.
J. Polin, E. Schmohel, V.
R. Ziessel, A. El-ghay-
B. M. Bishop, D. G.
[10e]
[10f]
McCafferty, B. W. Erickson, Tetrahedron 2000, 56, 4629Ϫ4638.
[10g]
`
L. J. Charbonniere, N. Weibel, R. F. Ziessel, Synthesis
3956
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3948Ϫ3957

Synthesis of Differently Disubstituted 2,2Ј-Bipyridines
FULL PAPER
K. S. Chan, A. K. S. Tse, Synth. Commun. 1993, 23, 1929Ϫ34.
M. Albrecht, C. Riether, Synthesis 1997, 957Ϫ962.
A. P. Smith, J. J. S. Lamba, C. L. Fraser, Org. Synth. 2000,
78, 82Ϫ90.
[24]
[25]
[26]
wald’s Pd2dba3·CHCl3/P(2-biph)tBu2 system (27% yield of 18
besides some unidentified by-products) proved to be effective
when employed under otherwise identical conditions in a 3
mol-% Pd scale. As in our preceding study, only
Pd2dba3·CHCl3/dppf proved to be similarly effective in this
context (65% yield of 18). Interestingly, an increase in the
amount of Pd to 10 mol-% [Pd(PtBu3)2] did not result in a
significantly higher yield but actually gave 18 only in a slightly
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M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989Ϫ1992;
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Received March 21, 2003
[23b]
W. A .
Early View Article
Published Online September 8, 2003
Eur. J. Org. Chem. 2003, 3948Ϫ3957
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3957