Synthesis of new phenylpyridyl scaffolds using the Garlanding approach

Article abstract of DOI:10.1016/j.tet.2010.08.008

One-pot reaction for the synthesis of novel phenylpyridyl derivatives and mixed quater phenylpyridyl compounds is described by using the Garlanding approach. The reactions proceed with moderate to good yields in mild conditions and good reaction times. This work represents a second application of the simplicity and versatility of Garlanding concept for the construction of new phenylpyridyl scaffolds, which can be considered as non-peptidic foldamer α-helix mimetics.

Full text of DOI:10.1016/j.tet.2010.08.008

Tetrahedron 66 (2010) 8000e8005
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new phenylpyridyl scaffolds using the Garlanding approach
Anne Sophie Voisin-Chiret a, Marilena Muraglia b, Grégory Burzicki a, Serge Perato a, Filomena Corbo b,
,
Jana Sopková-de Oliveira Santos a, Carlo Franchini b, Sylvain Rault a
*
a University of Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Etudes et de Recherche sur le Médicament de Normandie, UPRES EA-4258,
FR CNRS INC3M, boulevard Becquerel, 14032 Caen Cedex, France
b University of Bari, Department of Pharmaceutical Chemistry, Via E. Orabona n.4, 70125 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Received in revised form 29 July 2010
Accepted 5 August 2010
Available online 12 August 2010
One-pot reaction for the synthesis of novel phenylpyridyl derivatives and mixed quater phenylpyridyl
compounds is described by using the Garlanding approach. The reactions proceed with moderate to good
yields in mild conditions and good reaction times. This work represents a second application of the
simplicity and versatility of Garlanding concept for the construction of new phenylpyridyl scaffolds,
which can be considered as non-peptidic foldamer a-helix mimetics.
Ó 2010 Published by Elsevier Ltd.
Keywords:
Boron
Cross-coupling
Palladium
Pyridines
Regioselectivity
1. Introduction
our experience to rapidly create several such structures with the
phenylpyridyl skeleton.
There has been a recent surge in the development of conjugated
structure synthesis because of their frequency in organic and mi-
croelectronic devices such as LEDs, FETs, and solar cells.1 Oligopyr-
idines, mainly bi-, ter-, and quater-pyridines have also attracted
strong interest and been the subject of many recent papers by reason
of their ability to complex with transition metals and for their lu-
minescence properties.2 Beyond this application, oligopyridines can
The chemical strategy we used, that we named Garlanding con-
cept (Scheme 1),6 highlights the importance both of the regiose-
lective control in the coupling reaction and of the choice of the
coupling partners. Indeed, this methodology takes advantage of the
nature as well as of the position of the halogen atom on the ring. In
addition, it uses bifunctional (hetero)arylboronic acids, which rep-
resent a highly promising platform for this typeof synthetic strategy.
To study the feasibility and the repeatability of the reaction and
to show the efficiency of the Garlanding concept a first series of
compounds (bi-, ter-, and quater-pyridines) was prepared.7
Since the Garlanding concept has demonstrated an efficient and
a good reaction time, so as a high flexibility in order to couple se-
lectively each halogen, we envisioned that it may be employed for
the synthesis of mixed phenylpyridyl compounds.
be considered as non-peptidic foldamer a-helix mimetics as well as
3,20,200-tris-substituted terphenyl derivatives described by Hamilton
and Cummings.3 To date, these terphenyl templates are the most
well-studied and diverse set of a-helix mimetics based on protein
secondary structures,4 which will furnish potent disruptors of pro-
teineprotein interactions. For example, terpyridines have been ex-
tensively studied as DNA binding agents.5
Despite of their great interest more detailed synthetic strategies
seem to be required for revealing an efficient approach to obtain
oligopyridyl isomer derivatives.
Here, as a continuation of our recent studies involving the
preparation of various bi-, ter-, and quater-pyridines using iterative
cross-coupling reactions,6,7 we would like to report the utility of
Several reasons led us to study the synthesis of such a series.
ꢀ Firstly, to show the useful extension of the Garlanding approach,
we studied the reactivity of other coupling partners as phenyl
compounds in the preparation of novel phenylpyridines.
ꢀ Secondly, we also carried out the synthesis of novel mixed
quater phenylpyridyl derivatives to explore the reactivity of the
new generated chemical intermediates phenylpyridines.
ꢀ Thirdly, we aimed to grasp the chemical arrangement (reagents
and conditions) due tothe replacementof pyridine rings by phenyl.
* Corresponding author. Tel.: þ33 231 56 6801; fax: þ33 231 56 6803; e-mail
address: sylvain.rault@unicaen.fr (S. Rault).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.08.008

A.S. Voisin-Chiret et al. / Tetrahedron 66 (2010) 8000e8005
8001
X
N
N
X''
B(OR)2
X''
N
N
N
N
B(OR)2
X
X'
N
N
N
X
base, catalyst
X
base, catalyst
X, X', X'' = Br, Cl, F
Scheme 1. The Garlanding concept.
X
X, X', X'' = Br, Cl, F
ꢀ Fourthly, in this preliminary study we planned to investigate
how the steric hindrance, due to a little moiety so as a methyl
group, can modulate the Garlanding approach.
2-Bromo-5-(4-bromophenyl)pyridine 3a, 2-bromo-5-(4-bromo-2-
methylphenyl)-3-methylpyridine 3b, 5-bromo-2-(4-bromophenyl)
pyridine 3c, and 5-bromo-2-(4-bromo-3-methylphenyl)-3-methyl-
pyridine 3d were synthesized with 60%, 30%, 46%, and 63% yields, re-
spectively (Table 1). At the beginning of our research program, three
phenylpyridines 3a,10 3b, and 3d were novel and phenylpyridine 3c
All obtained structures are summarized in Tables 1 and 2. A plau-
sible mechanism of the explored reaction is reported in Scheme 2.
X
Br
R
R
OH
Br
R
I
B
R'
Br
R'
R'
Br
OH
+
Y
Y
Y
X
X
X
X, Y=C or N
R, R'=H or CH3
X
Scheme 2. General procedure to prepare phenylpyridyl and mixed quater phenylpyridyl compounds.
2. Results
Table 1
Cross-coupling reactions between halogenated boronic acids 1aed and halides
2aed
During our ongoing investigation, we first examined the reactivity
of the coupling partners with the preparation of phenylpyridines
3aed obtained by the cross-coupling reaction between halogenated
boronic acids 1aed and halides 2aed as illustrated in Scheme 4.
Among the generated boronic acid, 4-bromo-3-methylphenyl bo-
ronic acid 1d was known because registered in a patent that suggest
the synthesis of the cited compound starting by a tetrahydroxyboron,
previously isolated.8 Anyway, no experimental data were depicted. In
order to prepare and characterize compound 1d, we used our labo-
ratory expertise in the synthesis of boronic species:9 one-pot reaction
starting with 1-bromo-4-iodo-2-methylbenzene, commercially
available, by proceeding through the reactive organolithium in-
termediate, generated by a regioselective halogenelithium exchange,
afforded the desired compound in a very good yield (77%) (Scheme 3).
Boronic acid
Halide
Phenylpyridine/Bipyridine
Yield (%)
X
N
R0
H
Y
C
R
Br
1a
1b
1c
2c
2d
2a
H
3a
3b
3c
60
30
46
Br
N
Br
H3C
H3C
Br
N
C
CH3
C
CH3
N
Br
H
N
H
N
OH
Br
I
B
H3C
Br
H3C
Br
OH
Br
Br
H3C
H3C
Br
1d
1a
C
CH3
2b
2b
N
N
CH3
CH3
3d
3e
63
86
N
N
1-bromo-4-iodo-2-methylbenzene
1d 77%
Scheme 3. Synthesis of 4-bromo-3-methylphenyl boronic acid 1d. Reagents and
conditions: (1) n-BuLi, 1.25 equiv, THFanhyd, ꢁ78 ꢂC, 1.5 h; (2) B(Oi-Pr)3, 1.25 equiv,
THFanhyd, ꢁ78 ꢂC, 1 h then rt; (3) hydrolysis.
H3C
N
H
Br
N
Br
R
OH
B
was known11 for its optical12 and luminescence properties13 and as
phosphorescent devices.14
Br
R'
Br
R
I
R'
Br
OH
Y
In order to study the versatility of our suggested synthetic ap-
proach so as to compare the reactivity of coupling partners, we
reminded of the preparation of 5,60-dibromo-3-methyl-2,30-bipyr-
idine 3e starting from 6-bromo-pyridin-3-yl boronic acid 1a and 5-
bromo-2-iodo-3-methylpyridine 2b, which was obtained with ex-
cellent yield (86%) as other analogous mono-or di-methylated
dibromobipyridines previously reported.7a
+
X
Y
X
1a-d
2a-d
X, Y=C or N
R, R'=H or CH3
3a-e
Scheme 4. Preparation of compounds 3aee. Reagents and conditions: boronic acid
1aed 1.1 equiv, halide 2aed 1 equiv, Na2CO3aq 2.5 equiv, Pd(PPh3)4 0.04 equiv, 1,4-
dioxane, reflux, 24 h.

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A.S. Voisin-Chiret et al. / Tetrahedron 66 (2010) 8000e8005
Table 2
By comparison the results reported in Table 1, it is worthy to
Cross-coupling reactions between boronic acids 4a,b and phenylpyridine/bipyridine
3e,f
note that 3aed yields are surprisingly lower than 3e yield. These
evidences led us to think that the difference of yields is probably
due to homocoupling side reactions leading to the production of
a small amount of biphenylpyridines. In fact, traces of biphe-
nylpyridyl derivatives were detected by 1H NMR and MS analysis.
In the second part of this study, we explored the reactivity of
phenylpyridines 3aed and bipyridine 3e bearing two bromine
atoms essential to the elongation of the garland. These five com-
pounds were involved in coupling reactions with pyridin-3-yl bo-
ronic acid 4a and phenyl boronic acid 4b (Scheme 5).
Phenylpyridine /
bipyridine
Mixed quater
phenylpyridyl
Compound
Yield (%)
N
N
N
N
3a
3b
3c
5a
41
N
N
X
H C
3
R
H C
3
5b
5c
63
60
B(OH)2
N
Br
R
R'
Y
X
4a-b
N
R'
Br
Y
X
X
X
N
X, Y=C or N
R, R'=H or CH3
3a-e
5a-e
N
Scheme 5. Preparation of compounds 5aee. Reagents and conditions: boronic acid
4a,b, halide 3aee, Na2CO3aq, Pd(PPh3)4, 1,4-dioxane, reflux, 24 h.
H C
3
Despite the difference in the reactivity of two bromine
atoms, one in the alpha position of the pyridine nitrogen and the
other in beta position, the presence of boronic acids in slight
excess allowed the synthesis of five novel mixed quater phenyl-
pyridyl compounds: 5-(4-pyridin-3-ylphenyl)-2,30-bipyridine 5a,
3-methyl-5-(2-methyl-4-pyridin-3-ylphenyl)-2,30-bipyridine 5b,
6-(4-pyridin-3-ylphenyl)-3,30-bipyridine 5c, 5-methyl-6-(3-methyl-
4-pyridin-3-ylphenyl)-3,30-bipyridine 5d, and 3-methyl-5,60-diph-
enyl-2,30-bipyridine 5e.
H C
3
3d
3e
5d
5e
58
80
N
N
N
H C
3
N
All desired compounds were prepared through a one-pot re-
action and products were isolated after chromatography in good
yields (5a: 41%; 5b: 63%; 5c: 60%; 5d: 58%; 5e: 80%; 5f: 73%) as
stable solids (Table 2).
N
H C
3
3e
5f
73
N
Surprisingly, the coupling reaction to obtain 3-methyl-5,60-
diphenyl-2,30-bipyridine 5e was more efficient (80% yield) if com-
pared to the yields of other compounds (5aed). At the light of these
results we may think that phenyl boronic acid 4b is a more suitable
coupling partner because of less sensitive to the protodeboronation
than pyridin-3-yl boronic acid 4a.
N
N
interactions and further investigations will be carry on to explore
their biological properties and their ability to mimic a-helix.
3. Conclusion
Then, to confirm this hypothesis we also attempted the prepara-
tion of its analogue 300-methyl-3,20:50,200:500,30-quaterpyridine 5f from
the same intermediate 3e in the presence of pyridylboronic acid 4a,
under the same condition reaction. It was synthesized in 73% yield.
Therefore, according to this result, we cannot just attribute this yield
decrease to the lower stability of pyridylboronic acid 4a. But, in con-
trast, phenylpyridyl intermediates 3aed are presumably less good
coupling partners, more sensitive to homocoupling side reactions.
The structures of new generated compounds were un-
equivocally established by the usual spectroscopic means as
reported in the Experimental section. Detail of the successfully
reactions are reported in this paper.
Finally, because terpyridines has been studied as DNA binding
agents5 and taking into account that a careful screening of the
literature describes very few cytotoxic effects of olygopyridyl de-
rivatives, all compounds described in this paper were preliminary
screened for a potential cytotoxic activity by an in vitro assay of
growth inhibition against KB cells.
In summary, we have successfullyapplied the efficient, feasibility
and versatility of the Garlanding concept through the construction
of new phenylpyridyl scaffolds. In particular, we developed a one-
pot reaction to obtain three novel phenylpyridyl derivatives and six
new mixed quater phenylpyridyl compounds. The reactions pro-
ceeded smoothly in moderate to good yields. In the light of the
majority of experimental findings we strongly suggest that phe-
nylpyridyl intermediates (3aed) are not good coupling partners by
considering their more sensitive to homocoupling side reactions.
Then, on the basis of the results presented in this work, further
applications and investigations of the Garlanding approach in the
field of mechanistic and synthetic organic chemistry as well as in
biological area are currently going on in our laboratory.
4. Experimental section
4.1. General procedure
In general, the obtained results suggest that the compounds did
not produce a relevant change in cell viability in KB cells (none of
them shows a cytotoxic activityon KB cells at 10ꢁ5 M). These datawill
furnish very valuable information in the context of the exploration of
biological properties study of perturbations of proteineprotein
Commercial reagents were used as received without additional
purification. Melting points were determined on a Kofler heating
bench.

A.S. Voisin-Chiret et al. / Tetrahedron 66 (2010) 8000e8005
8003
IR spectra were recorded on a PerkineElmer BX FT-IR spectro-
photometer. The band positions are given in reciprocal centimeters
(cmꢁ1).
Na2CO3 are used to afford pure compounds 5e and 5f by following
the same condition reaction above described.
Boronic acid 4a,b (3.2 equiv),1 equiv of compounds 3a,b,15 mol
% tetrakis(triphenylphosphine) palladium(0), and 7 equiv aqueous
Na2CO3 are used to afford pure compounds 5a and 5b. The resulting
crude products were purified by flash column chromatography
using CH2Cl2/CH3OH (95/5) solvent system.
Boronic acid 4a (4.3 equiv), 1 equiv of compounds 3c, 20 mol %
tetrakis(triphenylphosphine) palladium(0), and 9.6 equiv aqueous
Na2CO3 are used to afford pure compounds 5c. The resulting crude
products were purified by flash column chromatography using
CH2Cl2/CH3OH (98/2) solvent system.
Compounds 3aec, 3e, 5eef 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a JEOL Lambda 400 spec-
trometer. Compounds 1d, 3d, and 5aed 1H NMR (300 MHz) were
recorded on a FT Bruker Aspect 3000 spectrometer (Bruker Bio-
science, USA) and 1d, 3d, and 5aed 13C NMR (75 MHz) were
recorded on a Varian Mercury 300 NMR spectrometer. Chemical
shifts are expressed in parts per million downfield from tetrame-
thylsilane as an internal standard and coupling constants in hertz.
Chemical shift are reported in part per million (ppm) relative to the
solvent resonance.
Compounds 5e,f mass spectra were recorded on a JEOL JMS
GCMate spectrometer at ionizing potential of 70 eV (EI) and with
pfk as internal standard for high-resolution procedure, or were
performed using a spectrometer LCeMS Waters alliance 2695
(ESIþ).
Compounds 1d, 3aed, and 5aed EIMS spectra were recorded
with a HelwettePackard 6890e5973 MSD gas chromatograph/
mass spectrometer at low resolution (HelwettePackard, Palo Alto,
CA, USA).
Chromatography was carried out on a column using flash silica
gel 60 Merck (0.063e0.200 mm) as the stationary phase. The
eluting solvent indicated for each purification was determined by
thin layer chromatography (TLC) performed on 0.2 mm precoated
plates of silica gel 60F-264 (Merck) and spots were visualized using
an ultraviolet-light lamp.
4.4. 2-Bromo-5-(4-bromophenyl)pyridine 3a
Starting from 6-bromo-pyridin-3-yl boronic acid 1a (1.6 g,
7.8 mmol) and 1-bromo-4-iodobenzene 2c (2 g, 7.0 mmol) and
following the general procedure, the product 3a was obtained as
a yellow solid (1.32 g, 60%). Mp 143 ꢂC. IR (KBr): 1574, 1449, 1400,
1351, 1085, 994, 809, 682, 547 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
d
8.55 (d, J¼2.0, 1H, H6), 7.70 (dd, J¼2.0, 7.8, 1H, H4), 7.61 (d, J¼8.8,
2H, H20, H60), 7.55 (d, J¼7.8, 1H, H3), 7.41 (d, J¼8.8, 2H, H30, H50). 13C
NMR (100 MHz, CDCl3): d 148.2 (C6), 141.3 (C2), 136.7 (C5), 135.4
(C40), 134.9 (C4), 132.4 (C20, C60), 128.5 (C30,þC50), 128.1 (C3), 123.0
(C10). MS (EI): m/z (%)¼312 (Mþ,53); 314 (M þ2, 100); 316 (Mþþ4,
49). Anal. Calcd for C11H7NBr2$0.33H2O: C, 41.42; H, 2.42; N, 4.39.
Found: C, 41.15; H, 2.09; N, 4.16.
Compounds 1d, 3aed, and 5aed elemental analysis were per-
formed on a Eurovector Euro EA 3000 elemental analyzer (euro-
Vector, Milan, Italy). The data for C, H, and N were within ꢃ0.4 of
the theoretical values for all final compounds.
4.5. 2-Bromo-5-(4-bromo-2-methylphenyl)-3-methyl
pyridine 3b
Starting from 6-bromo-5-methyl-pyridin-3-yl boronic acid 1b
(1.6 g, 7.5 mmol) and 5-bromo-2-iodotoluene 2d (2 g, 6.8 mmol)
and following the general procedure, the product 3b was obtained
as a white solid (0.7 g, 30%). Mp 117 ꢂC. IR (KBr): 1585, 1540, 1451,
4.2. 4-Bromo-3-methylphenyl boronic acid 1d
1394, 1057, 993, 820, 736, 666, 559 cmꢁ1 1H NMR (400 MHz,
.
To a 2.5 M solution of n-BuLi (1.25 equiv, 11.8 mL, 29.4 mmol) in
anhydrous THF, cooled to ꢁ78 ꢂC was added dropwise a solution of
1-bromo-4-iodo-2-methylbenzene (1 equiv, 7 g, 23.4 mmol) in
anhydrous THF. The resulting mixture was allowed to react at this
CDCl3):
d
8.14 (d, J¼2.0,1H, H6), 7.45e7.44 (m, 2H, H4, H30), 7.40 (dd,
J¼1.9, 8.8, 1H, H50), 7.04 (d, J¼8.8, 1H, H60), 2.44 (s, 3H, CH3eph),
2.26 (s, 3H, CH3epy). 13C NMR (100 MHz, CDCl3):
d 147.1 (C6), 143.5
(C2), 139.1 (C3), 137.7 (C5), 135.8 (C4), 135.7 (C20), 134.7 (C60), 133.4
(C50), 131.2 (C30), 129.3 (C10), 122.3 (C40), 22.0 (CH3eph), 20.2
(CH3epy). MS (EI): m/z (%)¼339 (Mþ, 53); 341 (Mþþ2, 100); 343
(Mþþ4, 49). Anal. Calcd for C13H11NBr2: C, 45.78; H, 3.25; N, 4.11.
Found: C, 45.65; H, 3.19; N, 4.17.
temperature for over 1.5 h.
A solution of triisopropylborate
(1.25 equiv, 7 mL, 29.4 mmol) in anhydrous THF was then dropwise
added, keeping the internal temperature at ꢁ78 ꢂC. The mixture
was allowed to warm to room temperature and left to react for an
additional hour. The resulting mixture was quenched by slow ad-
dition of 3 N HCl. Extraction with ethyl acetate, evaporation of the
organic layer and crystallization from CH3CN afforded pure 4-
bromo-3-methylphenyl boronic acid 1d as a pale white solid (3.9 g,
77%). Mp >250 ꢂC (CH3CN). IR (KBr): 3434, 1591, 1385, 1344, 1095,
4.6. 5-Bromo-2-(4-bromophenyl)pyridine 3c
Starting from 4-bromo-benzene boronic acid 1c (1.56 g,
7.74 mmol) and 3-bromo-6-iodopyridine 2a (2 g, 7.04 mmol) and
following the general procedure, the product 3c was obtained as
a white solid (1.012 g, 46%). Mp 125 ꢂC. Same experimental data
described in the literature.11
1021, 735, 716 cmꢁ1. 1H NMR (400 MHz, DMSO):
d 8.13 (s, 2H, OH),
7.71 (s, 1H, H2), 7.53e7.47 (AB system, J¼7.8, 2H, H5, H6), 2.33 (s, 3H
CH3). 13C NMR (100 MHz, CDCl3): 138e1-137.5 (m, C1), 137.1 (C2),
134.0 (C3), 133.6 (C6), 132.7 (C5), 127.6 (C4), 22.9 (CH3).
4.7. 5-Bromo-2-(4-bromo-3-methylphenyl)-3-methyl
pyridine 3d
4.3. General procedure for cross-coupling reactions
A mixture of boronic acid 1aed (1.1 equiv), halides 2aed
(1 equiv), tetrakis(triphenylphosphine) palladium(0) (5 mol %) and
aqueous Na2CO3 (2.5 equiv) in 1,4-dioxane was heated at 80 ꢂC for
1 h then under reflux until the complete consumption of aryl halide
(TLC). The reaction mixture was concentrated, extracted with ethyl
acetate. Organic layer was dried over MgSO4 and concentrated. The
residue was chromatographed on silica gel (cyclohexane/ethyl ac-
etate: 95/5) to afford pure compounds 3aee.
Starting from 4-bromo-3-methylphenyl boronic acid 1d
(0.860 g, 4 mmol) and 3-bromo-5-methyl-6-iodopyridine 2b
(1.077 g, 3.62 mmol) and following the general procedure, the
product 3d was obtained as a pale white solid (0.775 g, 63%). Mp
105 ꢂC. IR (KBr): 1571, 1542, 1452, 1420, 1029, 892, 821, 697,
549 cmꢁ1. 1H NMR (300 MHz, CDCl3):
d
8.56 (d, J¼1.9, 1H, H6), 7.73
(d, J¼1.9, 1H, H4), 7.59 (d, J¼8.0,1H, H50), 7.37 (d, J¼1.9, 1H, H20), 7.16
(dd, J¼1.9, 8.0, 1H, H60), 2,45 (s, 3H, CH3eph), 2.33 (s, 3H, CH3epy).
Boronic acid 4a,b (2.5 equiv), 1 equiv of compounds 3e, 10 mol %
tetrakis(triphenylphosphine) palladium(0), and 5 equiv aqueous
13C NMR (75 MHz, CDCl3):
d 156.4 (C2), 148.2 (C6), 141.1 (C4), 138.9
(C5),138.3 (C40),132.9 (C10),132.4 (C60),131.5 (C20),127.9 (C50),125.3

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A.S. Voisin-Chiret et al. / Tetrahedron 66 (2010) 8000e8005
(C3), 119.4 (C30), 23.2 (CH3eph), 20.1 (CH3epy). MS (EI): m/z (%)¼
338 (Mþ, 52); 340 (Mþþ2, 100); 343 (Mþþ4, 53). Anal. Calcd for
C13H11NBr2$H2O: C, 43.49; H, 3.65; N, 3.90. Found: C, 43.11; H, 3.52;
N, 4.02.
(Mþ, 100). Anal. Calcd for C21H15N3 0.7H2O: C, 78.48; H, 5.12; N,
13.08. Found: C, 78.63; H, 5.46; N, 13.33.
4.12. 5-Methyl-6-(3-methyl-4-pyridin-3-ylphenyl)-3,30-
bipyridine 5d
4.8. 5,60-Dibromo-3-methyl-2,30-bipyridine 3e
Starting from pyridin-3-yl boronic acid 4a (0.580 g, 4.7 mmol)
and 2-bromo-5-(4-bromophenyl)pyridine 3d (0.500 g, 1.47 mmol)
and following the general procedure, the product 5d was obtained
as a yellow oil (0.290 g, 58%). IR (KBr): 1581, 1550, 1463, 1159, 981,
686, 551 cmꢁ1. 1H NMR (300 MHz, CDCl3): 8.68 (s, 1H, H20), 8.56 (d,
J¼4.9, 1H, H60), 8.55 (s, 1H, H2), 8.46 (s, 1H, H2000), 8.44 (d, J¼4.9, 1H,
H6000), 8.42 (d, J¼8.2, 1H, H500), 7.74 (d, J¼7.8, 1H, H40), 7.6 (d, J¼7.8,
1H, H4000), 7.41 (s, 1H, H4), 7.3 (dd, J¼7.8, 4.9, 1H, H50), 7.14 (dd, J¼7.8,
4.9, 1H, H5000), 7.12 (d, J¼8.2, 1H, H600), 6.79 (s, 1H, H200), 2.7 (s, 3H,
Starting from 6-bromo-pyridin-3-yl boronic acid 1a (1.66 g,
8.22 mmol) and 3-bromo-5-methyl-6-iodopyridine 2b (2.00 g,
6.71 mmol) and following the general procedure, the product 3e
was obtained as a yellow solid (1.90 g, 86%). Mp 150 ꢂC. Same ex-
perimental data described in the literature.7a
4.9. 5-(4-Pyridin-3-ylphenyl)-2,30-bipyridine 5a
Starting from pyridin-3-yl boronic acid 4a (0.629 g, 5.12 mmol)
and 2-bromo-5-(4-bromophenyl)pyridine 3a (0.500 g, 1.6 mmol)
and following the general procedure, the product 5a was obtained
as a pale yellow solid (0.202 g, 41%). Mp 170 ꢂC (CH3OH). IR (KBr):
1592, 1574,1463,1189, 1010, 803, 706, 558 cmꢁ1. 1H NMR (300 MHz,
CH3eph), 2.37 (s, 3H, CH3epy). 13C NMR (100 MHz, CDCl3):
d 158.65
(C6), 148.5 (C200), 147.6 (C60, C20), 146 (C600), 144 (C100), 142 (C5), 141.3
(C300), 141.1 (C2), 139 (C3000), 137.8 (C400), 133.2 (C4000), 132.9 (C200),
132.6 (C4, C40), 130.9 (C30), 130.1 (C3), 127 (C600), 122.3 (C50), 121
(C5000), 120.5 (C500), 20.75 (CH3eph), 20.12 (CH3epy). MS (EI): m/z
(%)¼337 (Mþ, 50); 336 (100). Anal. Calcd for C21H15N3: C, 81.87; H,
5.68; N, 12.45. Found: C, 81.52; H, 5.85; N, 12.11.
CDCl3):
d
9.27 (d, J¼1.9, 1H, H20), 9.02 (d, J¼1.9, 1H, H6), 8.92 (d,
J¼1.9, 1H, H2000), 8.68 (dd, J¼1.4, 4.7, 1H, H60), 8.64 (dd, J¼1.4, 4.7, 1H,
H6000), 8.41 (dt, J¼1.9, 8.0, 1H, H40), 8.06 (dd, J¼2.2, 8.2, 1H, H4), 7.95
(dt, J¼1.9, 8.0, 1H, H4000), 7.88 (d, J¼8.3, 1H, H3), 7.79e7.72 (m, 4H,
H200, H300, H500, H600), 7.48e7.40 (m, 2H, H50, H5000). 13C NMR (75 MHz,
4.13. 3-Methyl-5,60-diphenyl-2,30-bipyridine 5e
CDCl3):
d
154.0 (C2), 150.3 (C2000), 149.1 (C60), 148.6 (C20), 148.5 (C6),
Starting from phenyl boronic acid 4b (0.371 g, 3.04 mmol) and
5,60-dibromo-3-methyl-2,30-bipyridine 3e (0.400 g, 1.22 mmol) and
following the general procedure, the product 5c was obtained as
a white solid (0.315 g, 80%). Mp 141 ꢂC. IR (KBr): 3434, 1588, 1448,
1360, 902, 847, 770, 740, 694, 532 cmꢁ1. 1H NMR (400 MHz, CDCl3):
148.4 (C6000), 138.0 (C100), 137.3 (C400), 136.1 (C3000), 135.4 (2C, C40,
C4000), 135.2 (C30), 134.6 (C5), 134.4 (C50, C5000), 128.1 (C300, C500þ), 127.9
(C200, C600), 129.3 (C4), 120.7 (C3). MS (EI): m/z (%)¼309 (M , 100).
Anal. Calcd for C21H15N3.1/3H2O: C, 79.98; H, 5.01; N, 13.32. Found:
C, 80.27; H, 4.85; N, 13.01.
d
8.95 (d, J¼2.0, 1H, H20), 8.81 (d, J¼2.0, 1H, H6), 8.07 (d, J¼7.8, 2H,
H200, H600), 8.04 (dd, J¼2.0, 7.8, 1H, H40), 7.86 (d, J¼7.8, 1H, H50), 7.83
(d, J¼2.0, 1H, H4), 7.65 (d, J¼7.8, 2H, H2000, H6000), 7.51 (t, J¼7.8, 4H,
H300, H500, H3000, H5000), 7.46e7.43 (m, 2H, H400, H4000), 2.53 (s, 3H, CH3).
4.10. 3-Methyl-5-(2-methyl-4-pyridin-3-ylphenyl)-2,30-
bipyridine 5b
13C NMR (100 MHz, CDCl3):
d
156.7 (C60), 154.1 (C2), 149.8 (C20),
Starting from pyridin-3-yl boronic acid 4a (0.300 g, 3.74 mmol)
and 2-bromo-5-(4-bromo-2-methylphenyl)-3-methyl pyridine 3b
(0.400 g, 1.17 mmol) and following the general procedure, the
product 5b was obtained as a pale yellow solid (0.248 g, 63%). Mp
110 ꢂC (CH3OH/Et2O). IR (KBr): 1573,1464,1414,1380,1011, 800, 709,
607 cmꢁ1.1H NMR (300 MHz, CDCl3): 8.91 (d, J¼1.9,1H, H20), 8.89 (d,
J¼1.9, 1H, H6), 8.68 (dd, J¼1.9, 4.7, 1H, H6000), 8.63 (d, J¼3.8, 1H, H40),
8.59 (d, J¼1.9,1H, H2000), 8.00e7.92 (m, 2H, H40, H4), 7.64 (d, J¼1.9,1H,
H4000), 7.54e7.38 (m, 5H, H50, H5000, H600, H500, H300), 2,47 (s, 3H,
145.9 (C6), 139.0 (C100), 137.4 (C40), 137.2 (C4), 135.6 (C5 or C1000),
134.3 (C30), 131.1 (C3), 129.1 (C300, C500, C3000, C5000), 128.8 (C400, C4000),
128.2 (C5 or C1000),127.3 (C2000, C6000),127.1 (C200, C600), 120.0 (C50), 20.2
(CH3). MS (EI): m/z (%)¼323 (100) [Mþ1]þ. HRMS (EI) m/z calcd:
322.14625, found: 322.14699. Anal. Calcd for C23H18N2: C, 85.68; H,
5.63; N, 8.69. Found: C, 85.31; H, 5.31; N: 8,85.
4.14. 300-Methyl-3,20:50,200:500,3000-quaterpyridine 5f
CH3eph), 2.43 (s, 3H, CH3epy). 13C NMR (75 MHz, CDCl3):
d
154.2
Starting from pyridin-3-yl boronic acid 4a (0.297 g, 2.41 mmol)
(C2),150.1 (C60),149.2 (C2000),148.7 (C20),148.3 (C6),147.7 (C6000),139.5
(C200),137.9 (C5),137.5 (C30),136.9 (C40),136.8 (C4),136.4 (C3000),136.2
(C3, C50),134.7 (C5000),131.0 (C40),130.9 (C600),129.6 (C500),125.1 (C300),
123.9 (C100), 123.5 (C400), 20.6 (CH3eph), 20.0 (CH3epy). MS (EI): m/z
(%)¼337 (Mþ, 50); 336 (100). Anal. Calcd for C23H19N3: C, 81.87; H,
5.68; N, 12.45. Found: C, 81.75; H, 5.85; N, 12.33.
and
5,60-dibromo-3-methyl-2,30-bipyridine
3e
(0.305 g,
0.93 mmol) and following the general procedure, the product 5c
was obtained as a white solid (0.315 g, 80%). Mp 156 ꢂC. IR (KBr):
1591, 1577, 1465, 1414, 1378, 1367, 1190, 1013, 800, 771, 702 cmꢁ1. 1H
NMR (400 MHz, CDCl3):
d
9.28 (d, J¼2.0, 1H, H60), 8.98 (d, J¼2.0, 1H,
H600), 8.92 (d, J¼2.0, 1H, H2000), 8.82 (d, J¼2.0, 1H, H2), 8.70 (d, J¼4.9,
2H, H6, H6000), 8.42 (dt, J¼2.0, 7.8, 1H, H4), 8.09 (dd, J¼2.0, 7.8, 1H,
H40), 7.95 (dt, J¼2.0, 7.8, 1H, H4000), 7.91 (d, J¼7.8, 1H, H30), 7.86 (d,
J¼2.0, 1H, H400), 7.45 (dd, J¼4.9, 7.8, 2H, H5, H5000), 2.56 (s, 3H, CH3).
4.11. 6-(4-Pyridin-3-ylphenyl)-3,30-bipyridine 5c
Starting from pyridin-3-yl boronic acid 4a (1.014 g, 8.25 mmol)
and 5-bromo-2-(4-bromophenyl)pyridine 3b (0.600 g, 1.92 mmol)
and following the general procedure, the product 5c was obtained
as a white solid (0.356 g, 60%). Mp 201 ꢂC (CH3OH). IR (KBr): 1586,
13C NMR (100 MHz, CDCl3): 154.6 (C20), 154.2 (C200), 150.1 (C2),
d
150.0 (C6), 149.4 (C6000), 148.3 (C600), 148.1 (C2000), 145.7 (C60), 137.6
(C40), 137.2 (C400), 134.7 (C50), 134.4 (C3), 134.3 (C4, C4000), 132.9 (C500),
132.5(C3000), 131.5 (C300), 123.7 (C5), 123.6 (C5000), 120.0 (C30), 20.1
(CH3). MS (EI): m/z (%)¼112 (100), 325 (12) [Mþ1]þ. HRMS (EI) m/z
calcd: 324.13748, found: 324.13658. Anal. Calcd for C21H16N4: C,
77.76; H, 4.97; N, 17.27. Found: C, 77.49; H, 4.61; N: 17.61.
1467, 1422, 11,188, 1026, 798, 710, 615 cmꢁ1 1H NMR (300 MHz,
.
CDCl3):
d
8.96e8.93 (m, 3H, H20, H2000, H2), 8.67e8.63 (m, 2H, H60,
H6000), 8.19 (d, J¼8.3, 2H, H200, H4000), 8.02e7.90 (m, 4H, H4, H5, H300,
H500), 7.74 (d, J¼8.3, 2H, H600, H40), 7.47e7.41 (m, 2H, H50, H5000). 13C
NMR (75 MHz, CDCl3):
d
156.5 (C6), 149.5 (C60), 149.0 (C6000), 148.5
Acknowledgements
(C2000), 148.3 (C2, C20), 138.9 (C4), 138.6 (C40), 136.2 (C3), 135.4 (C4000),
134.5 (C5), 134.4 (C50), 133.5 (C30), 132.2 (C3000), 127.8 (C200, C300, C500,
C600), 124.0 (C400), 123.8 (C100), 120.7 (C5000). MS (EI): m/z (%)¼309
We thank Dr. Thierry Cresteil of the ‘Institut de Chimie des
Substances Naturelles’ for cytotoxic activity evaluations.

A.S. Voisin-Chiret et al. / Tetrahedron 66 (2010) 8000e8005
8005
20010125, 2001; (c) Marcuccio, S.M.; Rodopoulos, M.; Weigold, H. PCT Int. Appl.
WO 9912940 A1 19990318, 1999.
Supplementary data
9. (a) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron
2002, 58, 2885e2890; (b) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron 2002, 58, 3323e3328; (c) Bouillon, A.; Lancelot, J. C.;
Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 4369e4373; (d) Bouillon,
A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59,
10043e10049; (e) Voisin, A. S.; Bouillon, A.; Berenguer, I.; Lancelot, J. C.;
Lesnard, A.; Rault, S. Tetrahedron 2006, 62, 11734e11739; (f) Cailly, T.; Fabis,
F.; Bouillon, A.; Lemaître, S.; Sopková-de Olivieira Santos, J.; Rault, S. Synlett
2006, 53e56.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.08.008.
References and notes
1. Dutta, T.; Woody, K. B.; Parkin, S. R.; Watson, M. D.; Gierschner, J. J. Am. Chem.
Soc. 2009, 131, 17321e17327.
10. Commercially available (Acentex Scientific, Inc), but its synthesis is unknown in
the literature.
2. (a) Constable, E. C. Angew. Chem., Int. Ed. 2007, 46, 2748e2749; (b) Constable, E. C.
Prog. Inorg. Chem.1994, 42, 67e138; (c) Constable, E. C. Adv. Inorg. Chem.1986, 30,
69e121; (d) Fang, Y. Q.; Polson, M. I. J.; Hanan, G. S. Inorg. Chem. 2003, 42, 5e7.
3. (a) Cummings, C. G.; Hamilton, A. D. Curr. Opin. Chem. Biol. 2010, 14, 341e346;
(b) Orner, B. P.; Ernst, J. T.; Hamilton, A. D. J. Am. Chem. Soc. 2001, 123,
5382e5383.
4. Davis, J. M.; Tsou, L. K.; Hamilton, A. D. Chem. Soc. Rev. 2007, 36, 326e334.
5. Zhao, L. X.; Kim, T. S.; Ahn, S. H.; Kim, T. H.; Kim, E. K.; Cho, W. J.; Choi, H.; Lee,
C. S.; Kim, J. A.; Jeong, T. C.; Chang, C. J.; Lee, E. S. Bioorg. Med. Chem. Lett. 2001,
11, 2659e2662.
6. Voisin-Chiret, A. S.; Bouillon, A.; Burzicki, G.; Célant, M.; Legay, R.; El-Kashef, H.;
Rault, S. Tetrahedron 2009, 65, 607e612.
7. (a) Burzicki, G.; Voisin-Chiret, A. S.; Sopkovà-de Oliveira Santos, J.; Rault, S.
Tetrahedron 2009, 65, 5413e5417; (b) Burzicki, G.; Voisin-Chiret, A. S.; Sopkovà-
de Oliveira Santos, J.; Rault, S. Synthesis 2010, 16, 2804e2810.
8. (a) Ohmori, Y.; Komatsu, M. PCT Int. Appl. WO 2008023783 A1 20080228, 2008.
(b) Aono, K.; Ichihashi, T.; Kugimiya, A. PCT Int. Appl. WO 2001005768 A1
11. Thomas, S. W.; Yagi, S.; Swager, T. M. J. Mater. Chem. 2005, 15, 2829e2835.
12. (a) Langecker, J.; Rehahn, M. Macromol. Chem. Phys. 2008, 209, 258e271; (b)
Venkatesan, K.; Kouwer, P. H. J.; Yagi, S.; Mueller, P.; Swager, T. M. J. Mater.
Chem. 2008, 18, 400e407; (c) Yamamoto, T.; Zhou, Z.-h.; Kanbara, T.; Shimura,
M.; Kizu, K.; Maruyama, T.; Nakamura, Y.; Fukuda, T.; Lee, B.-L.; Ooba, N.;
Tomaru, S.; Kurihara, T.; Kaino, T.; Kubota, K.; Sasaki, S. J. Am. Chem. Soc. 1996,
118, 10389e10399; (d) Langecker, J.; Rehahn, M. Polym. Prepr. 2007, 48,
591e592.
13. (a) Grushin, V.; Petrov, V.A. PCT Int. Appl. WO 2003069961, 2003; (b)
Grushin, V.; Lecloux, D.D.; Petrov, V.A.; Wang, Y. U.S. Patent Appl.
2,002,190,250, 2002; (c) Petrov, V.A.; Wang, Y.; Grushin, V. PCT Int. Appl. WO
2002002714, 2002.
14. (a) Schulz, G. L.; Holdcroft, S. Chem. Mater. 2008, 20, 5351e5355; (b) Schulz, G.
L.; Chen, X.; Chen, S.-A.; Holdcroft, S. Macromolecules 2006, 39, 9157e9165; (c)
Zhang, Y.; Xu, Y.; Niu, Q.; Peng, J.; Yang, W.; Zhu, X.; Cao, Y. J. Mater. Chem. 2007,
17, 992e1001.