Convenient synthesis of linear-extended bipyridines involving a central phenyl linking group

Article abstract of DOI:10.1246/cl.2008.1302

Linear-extended bipyridines were synthesized via the Hantzsch dihydropyridine synthesis, subsequent oxidative aro-matization with molecular oxygen in the presence of activated carbon, and decarboxylation. 4,4″-p-Terphenyldicarboxaldehyde was prepared by t

Full text of DOI:10.1246/cl.2008.1302

1302
Chemistry Letters Vol.37, No.12 (2008)
Convenient Synthesis of Linear-extended Bipyridines Involving
a Central Phenyl Linking Group
Zhibin Gan, Ayaka Okui, Yuka Kawashita, and Masahiko Hayashiꢀ
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501
(Received October 1, 2008; CL-080948; E-mail: mhayashi@kobe-u.ac.jp)
Linear-extended bipyridines were synthesized via the
OHC
CHO
EtO
OEt
OEt
step 2
Hantzsch dihydropyridine synthesis, subsequent oxidative aro-
matization with molecular oxygen in the presence of activated
carbon, and decarboxylation. 4,400-p-Terphenyldicarboxaldehyde
was prepared by the Suzuki–Miyaura cross-coupling reaction.
step 1
Hantzsch
synthesis
O2
n
Me
HN
Me
O
O
O
Me
NH
Me
activated
carbon
1: n = 1, 2: n = 2, 3: n = 3
O
O
xylene
120 °C
n
O
+ 4
OEt
+
EtO
2 NH3
4: n = 1, 5: n = 2, 6: n = 3
Supramolecular chemistry is now widely studied from the
aspect of synthesis of building blocks by molecular recognition
and self-organization, based on noncovalent interaction.1 These
investigations lead to the design of artificial supramolecules,
promising for the use in advanced technologies such as molecu-
lar machinery, molecular-based memory devices, and molecular
imprinting. In these studies, 4,40-bipyridine and its diquaternary
derivatives, such as viologens have been intensively investigated
owing to their redox, electrochemic properties, and their ability
to form intra- and intermolecular charge-transfer complexes.
So far, much attention has been paid to derivatives of 4,40-
bipyridine,2 however, ‘‘linear-extended’’ bipyridines3 represent-
ed in the general formula (Figure 1) in which phenyl, biphenyl,
or terphenyl is inserted between the two pyridine units, have not
been investigated well, because convenient methods for their
synthesis are limited. Fujita and his co-workers reported the
synthesis of 1,4-bis(2,6-dimethyl-4-pyridyl)benzene via the
Suzuki–Miyaura cross-coupling between 4-bromo-2,6-lutidine
and 1,4-phenylenebisboronic acid in their supramolecular com-
plexes using organic-pillared coordination cages.4 However,
by this method, synthesis of 4,400-bis(2,6-dimethyl-4-pyridyl)-
p-terphenyl is not facile because of the nonavailability of the
corresponding coupling precursors or difficulty of their prepara-
tion. Here, we report a practical method for the synthesis of
linear-extended bipyridines. The synthetic procedure is shown
in Scheme 1.
EtO
OEt
step 3
Me
N
O
O
O
Me
Me
Me
N
1) KOH/EtOH
78 °C, 16 h
N
N
2) CaO or SiO2
340 °C, 4 h
n
O
n
decarboxylation
Me
Me
Me
Me
EtO
OEt
10: n = 1, 11: n = 2, 12: n = 3
7: n = 1, 8: n = 2, 9: n = 3
Scheme 1. Synthesis of linear-extended bipyridines.
1 mol%
Pd catalyst
OH
OH
+
Br
Br OHC
B
OHC
CHO
K2CO3
DMF
3
3
86%
120 °C, 16 h
Cl
N Pd N
Cl
HN
Pd catalyst:
NH
Scheme 2. Preparation of 4,400-p-terphenyldicarboxaldehyde.
4,400-p-Terphenyldicarboxaldehyde (3) was prepared via the
Suzuki–Miyaura cross-coupling reaction (Scheme 2). Reaction
of 1,4-dibromobenzene with 4-formylphenylboronic acid cata-
lyzed by 2-phenylimidazoline–PdCl2 complex5 gave 3 in 86%
yield.
Hantzsch 1,4-dihydropyridines can be easily synthesized by
thermal condensation of dialdehydes with ꢀ-ketoesters in the
presence of ammonia. That is, treatment of dialdehydes 1–3 with
ethyl acetoacetate and ammonia gave the corresponding
Hantzsch 1,4-dihydropyridines that precipitated after cooling
to room temperature. The resulting suspensions were filtered
to afford Hantzsch 1,4-dihydropyridines 4–6 in 72–85% yield.
Then we focused our attention on conversion of 1,4-dihy-
dropyridines to pyridines. So far, various oxidants were studied
in the aromatization of 1,4-dihydropyridines.6 However, most of
those methods use hazardous oxidants and/or give low chemical
yield.
The oxidation of Hantzsch 1,4-dihydropyridines 4–6, which
were easily synthesized by the reaction of dicarboxaldehydes 1–
3, ꢀ-ketoesters, and ammonia provided the corresponding pyri-
dine esters 7–9. Subsequent decarboxylation gave the desired
pyridine derivatives 10–12. To realize our strategy, the corre-
sponding dicarboxaldehydes are required. 1,4-Benzenedicarbox-
aldehyde (1) and 4,40-biphenyldicarboxaldehyde (2) are com-
mercially available.
Me
N
R
R
Me
N
n
Me
R
R
Me
We recently reported oxidative aromatization with molecu-
lar oxygen in the presence of activated carbon.7 We found that
activated carbon–O2 system also exhibited high performance
in the transformation of Hantzsch 1,4-dihydropyridines to the
R = H, CO2Et, CO2H
n = 1, 2, 3
Figure 1. Linear-extended bipyridines.
Copyright Ó 2008 The Chemical Society of Japan

Chemistry Letters Vol.37, No.12 (2008)
1303
Table 1. Synthesis of linear-extended bipyridinesa
44, 1810. b) K. Ono, M. Yoshizawa, T. Kato, M. Fujita, Chem.
Commun. 2008, 2328.
K. Kawamura, S. Haneda, Z. Gan, K. Eda, M. Hayashi, Organo-
metallics 2008, 27, 3748.
Step 1
Step 2
Step 3
5
6
n
Time/h Yield/%b Time/h Yield/%b Yield/%b
HNO3: a) R. H. Boecker, F. P. Guengerich, J. Med. Chem. 1986,
29, 1596. CrO3/AcOH: b) A. Sausins, G. Duburs, Heterocycles
1988, 27, 291. PCC: c) J.-J. Vanden Eynde, A. Mayence, A.
Maquestiau, Tetrahedron 1992, 48, 463. DDQ: d) A. I. Meyers,
N. R. Natale, Heterocycles 1982, 18, 13. Cu(NO3)2: e) A.
Maquestiau, A. Mayence, J.-J. Vanden Eynde, Tetrahedron Lett.
1991, 32, 3839. (NH4)2Ce(NO3)6: f) J. R. Pfister, Synthesis
1990, 689. MnO2: g) J.-J. Vanden Eynde, F. Delfosse, A.
Mayence, Y. V. Haverbeke, Tetrahedron 1995, 51, 6511.
KMnO4: h) J.-J. Vanden Eynde, R. D’Orazio, Y. V. Haverbeke,
Tetrahedron 1994, 50, 2479. NO: i) T. Itoh, K. Nagata, M.
Okada, A. Ohsawa, Tetrahedron Lett. 1995, 36, 2269.
Bi(NO3)3: j) S. H. Mashraqui, M. A. Karnik, Synthesis 1998,
713. RuCl3/O2: k) S. H. Mashraqui, M. A. Karnik, Tetrahedron
Lett. 1998, 39, 4895. Mn(OAc)3: l) R. S. Varma, D. Kumar,
Tetrahedron Lett. 1999, 40, 21. Fe(ClO4)3–HOAc: m) M. M.
Heravi, F. K. Behbahani, H. A. Oskooie, R. H. Shoar, Tetrahe-
dron Lett. 2005, 46, 2775.
a) Y. Kawashita, N. Nakamichi, H. Kawabata, M. Hayashi, Org.
Lett. 2003, 5, 3713. b) N. Nakamichi, H. Kawabata, M. Hayashi,
J. Org. Chem. 2003, 68, 8272. c) M. Hayashi, Chem. Rec. 2008,
8, 252, and references cited therein.
The use of activated carbon available from Tokyo Chemical In-
dustry Co., Ltd., Shirasagi KL (Japan EnviroChemicals, Ltd.),
and DarcoÒ KB (Aldrich Chemical Co.) are recommended.
K. P. C. Vollhardt, N. E. Schore, Organic Chemistry: Structure
and Function, 4th ed., W. H. Freeman & Co. New York, 2003,
Chap. 25.
1
2
3
48
96
72
84
72
85
48
16
24
92
92
92
63
42
43
aAll reactions were carried out in gram scales. bIsolated yield.
corresponding pyridines. That is, Hantzsch 1,4-dihydropyridines
were treated with 50 wt % activated carbon (available from
Tokyo Chemical Industry Co., Ltd.) at 120 ꢁC in xylene for 24
to 72 h to afford the corresponding pyridines 7–9 in 92% yield.8
This simple process is not only environmentally friendly but also
economical and operationally simple. Only oxygen and commer-
cially available and inexpensive activated carbon are used. Nei-
ther metal oxides nor organic peroxides are required.
Having pyridine esters, we examined the following decar-
boxylation. Refluxing pyridine-3,5-dicarboxylates with aqueous
KOH gave the corresponding potassium salts of pyridine carbox-
ylic acid. After subsequent thermal decarboxylation, the desired
products 10–12 were obtained in 42–63%. The reaction condi-
tions and yields in each step of Scheme 1 are summarized in
the Table 1.
It should be mentioned that the decarboxylation procedure
of step 3 proceeds first by hydrolysis with KOH in EtOH, so in-
termediates for decarboxylation (actually, de-esterification) are
potassium carboxylates then the carboxylic acids. In this step,
the addition of CaO9 or SiO2 to the mixture under thermal con-
ditions improved the yield of step 3, even though the yield is still
moderate.
In summary, we have developed a convenient method for
the synthesis of some linear-extended bipyridines. That is, the
combination of Hantzsch dihydroxypyridine synthesis, then ac-
tivated carbon-promoted oxidative aromatization using molecu-
lar oxygen followed by decarboxylation of Hantzsch pyridine
esters afforded linear-extended bipyridines efficiently.10–13
7
8
9
10 Typical procedure for the synthesis of Hantzsch 1,4-dihydro-
pyridines: In a 250-mL round-bottomed flask, 1,4-benzenedi-
carboxaldehyde (1) (1.34 g, 10 mmol), ethyl acetoacetate
(5.21 g, 40 mmol), 25 wt % ammonia solution (2.00 g), and etha-
nol (20 mL) were charged and the mixture was heated to reflux
(80 ꢁC, oil bath temperature). After confirmation of the comple-
tion of the reaction by TLC, the mixture was cooled to room
temperature. The solid product 4 was obtained by filtration, then
washed with ethanol and dried in vacuum to give 4 as a pale yel-
low solid (4.88 g, 84%).
11 Typical procedure for the oxidative aromatization of
Hantzsch 1,4-dihydropyridines: A mixture of 1,4-dihydropri-
dine 4 (2.90 g, 5 mmol) and activated carbon (available from
Tokyo Chemical Industry Co., Ltd.) (1.45 g) in xylene (20 mL)
was placed in a 250-mL three-necked flask under an oxygen at-
mosphere and stirred at 120 ꢁC. After confirmation of the com-
pletion of the reaction by TLC, the mixture was filtered using
Celite. The filtrate was then concentrated, and product was iso-
lated by silica-gel column chromatography to give the corre-
sponding pyridine 7 as a pale yellow solid (2.65 g, 92%).
12 Typical procedure for decarboxylation of pyridine esters: A
suspension of pyridine ester 7 (1.15 g, 2 mmol) in KOH solution
(10 mL, 20 wt %) and ethanol (40 mL) was heated to reflux
(80 ꢁC, oil bath temperature) till a clear liquid was formed. After
solvent was removed under vacuum, the dried residue was
mixed with CaO (1.00 g) powder. After heating with stirring at
a sand bath temperature of about 340 ꢁC for 4 h, the mixture was
cooled to room temperature. After extraction using CHCl3, the
precipitates were removed by filtration. The filtrate was concen-
trated, the crude product was purified by silica-gel column chro-
matography to afford product 10 as a white solid (363 mg, 63%).
13 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas ‘‘Advanced Molecular Transfor-
mations of Carbon Resources’’ and No. B17340020 from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
This paper is dedicated to Professor Ryoji Noyori on the
occasion of his 70th birthday.
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Published on the web (Advance View) December 5, 2008; doi:10.1246/cl.2008.1302