Dehydrogenative Synthesis of 2,2′-Bipyridyls through Regioselective Pyridine Dimerization

Article abstract of DOI:10.1002/anie.201814701

2,2′-Bipyridyls have been utilized as indispensable ligands in metal-catalyzed reactions. The most streamlined approach for the synthesis of 2,2′-bipyridyls is the dehydrogenative dimerization of unfunctionalized pyridine. Herein, we report on the palladium-catalyzed dehydrogenative synthesis of 2,2′-bipyridyl derivatives. The Pd catalysis effectively works with an Ag^I salt as the oxidant in the presence of pivalic acid. A variety of pyridines regioselectively react at the C2-positions. This dimerization method is applicable for challenging substrates such as sterically hindered 3-substituted pyridines, where the pyridines regioselectively react at the C2-position. This reaction enables the concise synthesis of twisted 3,3′-disubstituted-2,2′-bipyridyls as an underdeveloped class of ligands.

Full text of DOI:10.1002/anie.201814701

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Accepted Article
Title: Dehydrogenative Synthesis of 2,2'-Bipyridyls through
Regioselective Pyridine Dimerization
Authors: Shuya Yamada, Takeshi Kaneda, Philip Steib, Kei Murakami,
and Kenichiro Itami
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814701
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10.1002/anie.201814701
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Dehydrogenative
Synthesis
of
2,2'-Bipyridyls
through
Regioselective Pyridine Dimerization
Shuya Yamada,[a] Takeshi Kaneda,[a] Philip Steib,[a] Kei Murakami,*[a] and Kenichiro Itami*[a,b]
Abstract: 2,2'-Bipyridyls have been utilized as indispensable ligands
in metal-catalyzed reactions. The most streamlined approach for the
synthesis of 2,2'-bipyridyls is the dehydrogenative dimerization of
unfunctionalized pyridine. In this communication, we report on the
palladium-catalyzed dehydrogenative synthesis of 2,2'-bipyridyl
derivatives. The Pd catalysis effectively works with Ag(I) salt as the
oxidant in the presence of pivalic acid. A variety of pyridines
regioselectively react at C2-positions. This dimerization method is
applicable for challenging substrates such as sterically hindered 3-
substituted pyridines where the pyridines regioselectively react at
C2-position. The reaction enables concise synthesis of twisted 3,3'-
disubstituted-2,2'-bipyridyls as an underdeveloped class of ligands.
substituted pyridine under ruthenium or ruthenium/cobalt
catalysis with evolution of hydrogen gas.[8] The group of Weix
reported a dimerization and trimerization reaction of pyridine in
the presence of palladium on charcoal as a catalyst.[9] While
these examples clearly demonstrated the synthetic advantage of
dehydrogenative dimerization, they focused mainly on 4-
substituted pyridines as substrates. Consequently, the
development of a general and practical method through pyridine
C–H functionalization[10] to synthesize hitherto inaccessible 2,2'-
bipyridyls has been in high demand.
2,2'-Bipyridyls[1] represent one of the most fundamental and
privileged scaffolds in metal-catalyzed reactions. For example,
4,4'-di-tert-butyl-2,2'-bipyridyl (dtbpy) has been regarded as a
highly active ligand for aromatic C–H borylation.[2] Ru(bpy)3, a
ruthenium complex with three 2,2'-bipyridyls, is known as an
efficient catalyst for emerging photoredox-catalyzed reactions.[3]
Moreover, we have found that 2,2'-bipyridyls play a key role in
C–H functionalization reactions such as C–H arylation of 5-
membered heteroaromatics[4a] and aromatic C–H imidation.[4b]
Typically, 2,2'-bipyridyls are synthesized from 2-
halopyridines through cross-coupling reactions or reductive
dimerization.[5] Although these methods are reliable and well-
established, additional steps to prepare 2-halogenated pyridines
are required and thereby it is usually an expensive and time-
consuming process. Moreover, halogenation of pyridine ring
systems generally suffers from poor regioselectivity and harsh
reaction conditions.[6] Since the catalytic activity of 2,2'-bipyridyls
is strongly affected by their structural deformation, rapid and
divergent syntheses of 2,2'-bipyridyl derivatives are valuable for
catalyst/ligand development.
Dehydrogenative dimerization reaction of unfunctionalized
pyridine is the most straightforward and attractive route from
atom- and step-economical point of view. Such dehydrogenative
bipyridyl synthesis was originally accomplished by heating a
metal catalyst such as Raney nickel or palladium on charcoal in
the pyridine solvent (neat conditions).[7] To date, several
transition-metal-catalyzed dehydrogenative dimerizations of
pyridine have been reported. For example, Suzuki and co-
workers developed the dehydrogenative dimerization of 4-
Figure 1. Representative 2,2'-bipyridyl ligands in transition metal catalysis and
synthesis of 2,2'-bipyridyls.
[a]
[b]
S. Yamada, T. Kaneda, P. Steib, Prof. Dr. K. Murakami, Prof. Dr. K.
Itami
Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate
School of Science, Nagoya University, Chikusa, Nagoya 464-8602,
Japan.
E-mail: murakami@chem.nagoya-u.ac.jp (K.M.);
itami@chem.nagoya-u.ac.jp (K.I.)
Prof. Dr. K. Itami
To achieve this goal, we initiated our study on palladium-
catalyzed pyridine dimerization. At first, we treated
stoichiometric amount of palladium with pyridine. 4-tert-
Butylpyridine (1a) was reacted with 0.50 mmol of Pd(OAc)2 in
cyclopentyl methyl ether (CPME) at 140 °C (Figure 2). The
reaction smoothly proceeded to give 4,4'-di-tert-butyl-2,2'-
bipyridyl (2a) in 98% NMR yield (0.49 mmol). Mechanistically,
the reaction would initiate from a pyridine C2–H activation by
palladium(II) acetate to form pyridylpalladium A. Successive
palladation affords bis(pyridyl)palladium intermediate B, which
JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University,
Chikusa, Nagoya 464-8602, Japan
Supporting information for this article is given via a link at the end of
the document.
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undergoes reductive elimination to furnish product 2a and Pd(0).
We envisioned that the addition of an appropriate oxidant could
perform this reaction in a catalytic manner.
when benzyl bromide was used as the oxidant.[11] Unfortunately,
the use of organic halides were not sufficiently effective for the
dimerization. After extensive screening of oxidants, silver salts
were found to be the most effective to achieve the envisioned
catalytic cycle. The choice of solvent was not essential for the
reaction efficiency where the use of other solvents such as
toluene, DMF and 1,4-dioxane resulted in similar yields as
CPME (see SI for the details). We then performed control
experiments to get insights into each reaction parameter. First,
we confirmed the role of silver salt as the sacrificial oxidant. The
reaction of 1a using 0.50 mmol of Pd(OAc)2 without AgOPiv
gave 2a in 94% yield. On the other hand, the dimerization of 1a
did not proceed without the addition of Pd(OAc)2. Consequently,
silver salt acted as the terminal oxidant to regenerate the Pd(II)
intermediate in the catalytic cycle. Next, the effect of PivO–
/PivOH was investigated. The addition of PivOH was proved to
enhance the reaction efficiency. Pyridine was reacted in the
presence of catalytic amount of Pd(OAc)2 and Ag2CO3 as the
oxidant in CPME. In the absence of PivOH, the reaction was
relatively slow and both regioisomers, 2,2'-bipyridyl (2b) and
3,3'-bipyridyl, were observed in the crude mixture. Increasing the
amount of PivOH accelerated the C2-dimerization reaction.
Finally, the yield of 2b was raised to 56% when employing 1.0
mmol of pivalic acid. The satisfactory amount of PivOH would
help to reproduce the reactive Pd(OPiv)2 intermediate.[12]
Figure 2. Pd(OAc)2-mediated formation of 2a. [a] 1H NMR yield based on Pd
using 1,1,2,2-tetrachloroethane as the internal standard.
After extensive investigation, we have established
a
palladium-catalyzed dehydrogenative dimerization of pyridines.
The optimal conditions for the dimerization are the following: 4-
tert-butylpyridine (1a) was heated in the presence of silver
pivalate, pivalic acid, and catalytic amount of Pd(OAc)2 in CPME
at 140 °C providing 2a in 71% isolated yield (Figure 3). In our
previous study, we observed 2,2'-bipyridyl as a side product
We next investigated the substrate scope of the dimerization
reaction (Table 1). Unsubstituted pyridine (1b) smoothly
dimerized to give 2b in 80% yield in the presence of 1,10-
phenanthroline. Remarkably, as observed in the control
experiments, no regioisomeric bipyridyls were observed in the
crude mixture.[13] The reactions of 4-substituted pyridine under
the optimized conditions were sluggish where the products 2c,
2d and 2e were obtained in 46%, 47% and 41% yields,
respectively. In order to improve the yields, we investigated the
effect of ligands. Fortunately, the addition of dtbpy was effective
where the product yields increased to 60% (2c), 56%(2d) and
70% (2e) yields, respectively. We postulated that the addition of
a bidentate ligand would suppress the product inhibition, which
could be caused by coordination of the resulting bipyridyl to the
palladium catalyst. It is noteworthy that 1c was a challenging
substrate in dehydrogenative dimerization reaction.[8c] For the
reaction of 4-phenylpyridine, the ligand effect on the product
yield was not significant as 2f was isolated in 56% yield without
and 54% NMR yield with dtbpy. Sterically hindered 2-picoline
participated in dimerization with dtbpy to afford 2g albeit in low
yield. 3-Picoline was converted to two regioisomers 2h and 2h'
in 56% total yield with a ratio of 34:66. 3,5-Disubstituted
pyridines were applicable for the dimerization. The reaction
provided the corresponding products in moderate yields (2i, 2j
and 2j'). It should be highlighted that regioisomers 2h/2h' and
2j/2j' are easily separable with the typical silica-gel purification.
Other 6-membered heteroaromatics such as quinoline,
pyrimidine and 2,6-dimethylpyrazine were applicable to give the
dimerized products (2k–2m) in moderate yields. Unfortunately,
our attempts to apply the dimerization protocol to unsymmetrical
Figure 3. Optimized conditions for pyridine dimerization. All 1H NMR
2,2'-bipyridyl synthesis (cross-dehydrogenative coupling[11,14]
)
yields were determined using 1,1,2,2-tetrachloroethane as the internal
standard. [a] Isolated yield based on Ag as the one electron oxidant. [b] 1
NMR yield based on Pd. [c] 1H NMR yield based on Ag.
H
was not successful for the reaction between 1a and 1i; the
dimerized products 2a, 2i and the desired cross-coupled product
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2n were provided as a mixture (see SI). Further studies on
cross-dehydrogenative coupling are ongoing in our laboratory.
conditions (20 mmol of 3,5-dichloropyridine in 1.0 mL CPME)
were employed to increase the reaction rate. The dimerization of
3-chloro-5-methylpyridne, an unsymmetrically substituted
pyridine, delivered 3b as a major product with concomitant
formation of regioisomer 3b' in 17% yield (for the structure of 3b',
see SI). 3-Chloropyridine underwent the C2-selective
dimerization to furnish 3c as the sole product.[15] When
disubstituted pyridine derivatives bearing aryl and chloro groups
were used as substrates, the corresponding dimerization
occurred only at C2 position without formation of any
regioisomers (3d and 3e).[16]
To gain some insight into the reaction mechanism,
intermolecular kinetic isotope effect was investigated (Scheme
1). In parallel, pyridine (1b) or d5-pyridine (d5-1b) were subjected
to the dimerization. A significant isotope effect (kH/kD = 4.08) was
observed between 1b and d5-1b. The results suggested that C–
H bond cleavage would be the rate-determining step.
Table 1. Substrate scope of dimerization reaction of pyridine 1.
Table 2. Substrate scope of dimerization reaction of 3-chloropyridines.
[a] Isolated yield based on Ag. [b] 20 mmol scale using 1.0 mL of CPME. [c]
The regioisomer 3b' was isolated in 17% yield (3b:3b' = 72:28).
3-Chloropyridine dimers 3 are convertible platforms to
access
various
3,3'-disubstituted-2,2'-bipyridyls,
an
underdeveloped class of bidentate ligands.[5a] Generally, such
2,2'-bipyridyls are synthesized through multistep transformation
starting from 1,10-phenanthroline or the corresponding 3-
substituted pyridine.[17] Setting 3,3'-dichloro-2,2'-bipyridyl (3c) as
a model substrate, we demonstrated further derivatization
(Figure 4). The Suzuki–Miyaura cross-coupling reaction with
phenylboronic acid provided 3,3'-diphenyl-2,2'-bipyridyl (4a) in
78% yield. The twofold Buchwald–Hartwig amination of 3c with
p-toluidine produced 4b in 78% yield. The resulting 4b could
react with electrophiles to give a new form of bipyridyls
embedding the 7-membered ring. For example, the reaction of
4b with thionyl chloride in the presence of triethylamine
successfully introduced sulfinyl group to form 4c in 64% yield.
Dimethylsilyl group was installable to give 4d in 93% yield. The
structures of 4c and 4d were unambiguously confirmed by X-ray
crystallographic analysis. Subsequently, twisted 2,2'-bipyridyls
were treated with palladium chloride. Heating the mixtures of
PdCl2 and 2,2'-bipyridyls (3c or 4d) afforded the corresponding
palladium complexes 3c-Pd or 4d-Pd. In the 1H NMR spectra of
these palladium complexes, the signals of hydrogen atoms on
pyridine core appeared as three different signals, which reflected
that both palladium complexes are axially C2 symmetric
molecules. Finally, the structures of 3c-Pd and 4d-Pd were
confirmed by X-ray crystal structure analysis (for the structural
[a] Isolated yield based on Ag. [b] 0.50 mL of 1 was used instead of CPME. [c]
0.50 mmol of 1,10-phenanthroline was added as a ligand. [d] 0.10 mmol of
dtbpy was added as a ligand. [e] 36 h.
Scheme 1. Kinetic isotope effect experiment
The efficient dimerization of sterically hindered pyridine 1i
and 1j prompted us to study the dimerization of 3-
chloropyridines (Table 2). 3,5-Dichloropyridine was found to
dimerize predominantly at C2-position to give the corresponding
2,2'-bipyridyl 3a in 61% yield. Gram scale preparation of 3a was
also feasible in 75% yield (1.1 g) where more concentrated
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[3]
[4]
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5322–5363.
details, see SI). Overall, 3-chloropyridine dimers 3 are found to
be promising platform for constructing axially twisted 2,2'-
bipyridyl ligands.
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Figure 4. Derivatization of 3c.
[5]
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Me
Me
Me
Me
X
N
N
N
N
HN NH
N
N
N
N
4a 78%[a]
4b 78%[b]
X = SO (4c) 64%[c] X-ray
[6]
[7]
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= SiMe2 (4d) 93%[d] X-ray
Pd complex syntheses
Me
Me
Me Me
Si
Cl
Cl
N
N
N
N
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V. Balzani, Synthesis 1998, 1998, 321–324.
Pd
N
N
Cl
Cl
Pd
Cl
Cl
3c-Pd 84%[e]
(starting from 3c)
X-ray
4d-Pd 70%[f]
(starting from 4d)
X-ray
[8]
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[a] 3c, PhB(OH)2, Pd(OAc)2, XPhos, K3PO4, nBuOH/H2O, 120 °C. [b] 3c, p-
toluidine, Pd(OAc)2, dppf, NaOtBu, toluene, 100 °C. [c] 4b, SOCl2, NEt3, THF,
rt. [d] 4b, SiMe2Cl2, nBuLi, THF, 0 °C to rt. [e] PdCl2 (0.20 mmol), 3c (1.0
equiv), MeOH (1.0 mL), 80 °C. [f] PdCl2 (0.10 mmol), 4d (1.0 equiv), MeCN
(1.0 mL), 80 °C.
[9]
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10624–10628.
In summary, we have developed the Pd-catalyzed C2-
selective dehydrogenative dimerization reaction of pyridines to
afford the corresponding 2,2'-bipyridyls. The present catalysis
enables rapid and scalable 2,2'-bipyridyl ligand syntheses with
only simple reagents, thereby it benefits to practical synthetic
applications. Remarkably, straightforward preparation of axially
twisted 2,2'-bipyridyl ligands is feasible with our protocol, which
stimulate the discovery of new application of twisted bidentate
ligands.
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[12]
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Acknowledgments
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This work was supported by the ERATO program from JST
(JPMJER1302 to K.I.), JSPS KAKENHI Grant Number
JP17H04868 (K.M.), the Naito Foundation (K.M.), CASIO
Science Promotion Foundation (K.M.), and the Uehara Memorial
Foundation (K.M.). We thank Dr. Yasutomo Segawa, Dr.
Tetsushi Yoshidomi, Mr. Kenta Kato for X-ray diffraction
analyses. ITbM is supported by the World Premier International
Research Center Initiative (WPI), Japan.
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heteroaromatics showed the same regioselectivity: B. Liu, Y. Huang, J.
Lan, F. Song, J. You, Chem. Sci. 2013, 4, 2163–2167.
Keywords: dehydrogenative coupling • C–H arylation • 2,2'-
bipyridyl • palladium catalyst • pyridine functionalization
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Entry for the Table of Contents
COMMUNICATION
Shuya Yamada, Takeshi Kaneda, Philip
Steib, Kei Murakami,* and Kenichiro
Itami*
Page No. – Page No.
Dehydrogenative Synthesis of 2,2'-
Bipyridyls through Regioselective
Pyridine Dimerization
Dehydrogenative dimerization: The palladium-catalyzed dehydrogenative C2-
selective dimerization reaction of pyridine is described. A variety of 2,2'-bipyridyls
can be prepared directly from unfunctionalized pyridine without additional pre-
halogenation or pre-metalation steps. The reaction is applicable to a series of
sterically hindered 3-substituted pyridine derivatives. The reaction enables concise
synthesis of twisted 3,3'-disubstituted-2,2'-bipyridyls as an underdeveloped class of
ligands.
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