A general synthesis of halo-oligopyridines. The Garlanding concept

Article abstract of DOI:10.1016/j.tet.2008.11.024

This paper sets forth a global synthetic strategy based on the Garlanding concept to design and to produce halo-oligopyridines. This strategy allows to prepare an infinite number of these new compounds and hence to create a library of halo-oligopyridines.

Full text of DOI:10.1016/j.tet.2008.11.024

Tetrahedron 65 (2009) 607–612
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A general synthesis of halo-oligopyridines. The Garlanding concept
a
b
a
b
a
´
´
´
Anne Sophie Voisin-Chiret , Alexandre Bouillon , Gregory Burzicki , Melanie Celant , Remi Legay ,
Hussein El-Kashef c, Sylvain Rault a
,
*
a
´
´
Universite de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Etudes et de Recherche sur le Medicament de Normandie, UPRES EA-4258, FR CNRS INC3M, 5,
rue Vaube´nard, 14032 Caen Cedex, France
b BoroChem S.A.S., Immeuble Emergence, 7, rue Alfred Kastler, 14000 Caen, France
c Chemistry Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper sets forth a global synthetic strategy based on the Garlanding concept to design and to
produce halo-oligopyridines. This strategy allows to prepare an infinite number of these new compounds
and hence to create a library of halo-oligopyridines. This article is focused on the basic principle of the
Garlanding concept and on the demonstration of its feasibility.
Received 25 September 2008
Received in revised form 6 November 2008
Accepted 7 November 2008
Available online 13 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Garlanding
Suzuki cross-coupling reaction
Oligopyridine
Boronic acid
1. Introduction
2,30-bipyridine,
nemertelline.13
a fully aromatic analog of anabaseine and
Oligopyridines are widely described in the literature because of
their great importance in metallosupramolecular chemistry where
2,20-bipyridines, 2,20:60,200-terpyridines, and2,20:60,200:600,2%-quater-
pyridines were reported as bi-, tri-, and tetra-dentate chelates, re-
spectively. Indeed, these oligopyridyl complexes commonly act as
bridging ligands with many transition metals, twisting about the
centralbondtoadoptahelicalconformation, whichbindstwometals
in a bis-bidentate fashion.1 The most common oligopyridine chelates
are the oligopyridyl complexes of ruthenium(II) (Fig. 1).2 Oligopyr-
idine complexes serve as luminescent probes in biochemical, me-
dicinal diagnostics, or materials science.3 They also contribute to
formation of micelles as new drug delivery systems.4–7 Apart from
these uses as supramolecular systems, oligopyridine derivatives
were evaluated for their antitumor cytotoxicity,8 antiprion activity9
and for their ability to block hydrophilic porin channels.10
The synthesis of some terpyridine natural products, particularly
the one known as nicotelline,14 which was extracted from tobacco,
was reported.15,16 Few papers have been published on the synthesis
and structural determination of the quaterpyridine, nemertelline.17
An efficient total synthesis of this quaterpyridine has been de-
veloped in our laboratory.18
However, despite the great importance of oligopyridines, very
few general strategies of efficient access to all isomers of these
compounds have been studied.19 Generally, in oligopyridines
complexes, pyridines are only linked together by a C–C bond on
C220 using a direct homocoupling approach with catalytic loading
of long reaction time, which limits its practical applications.
First of all, we have to clarify the nomenclature we have adopted
in this paper. A dihalobipyridine was given to a bipyridine bearing
a halogen atom on each pyridine ring; a trihaloterpyridine was
given to a terpyridine bearing a halogen atom on each pyridine ring.
A dihaloterpyridine was given to a terpyridine bearing a halogen
atom on each pyridine ring at the extremities and a dihaloquater-
pyridine was given to a quaterpyridine bearing a halogen atom on
each pyridine pattern at the extremities (Fig. 2). Moreover, each
pyridine ring was identified with a prime symbol (0), double prime
symbol (00), triple prime symbol (%) etc.
Moreover, among these oligopyridines, there are pyridine-based
neurotoxic substances, called nemertines, that have been isolated
from marine worms.11,12 Extracts from the hoplonemertine contain
derivatives of pyridyl alkaloids, such as anabaseine, and the
hoplonemertine Amphiporus angulatus (Fabricius) contains a par-
ticularly diverse groups of bipyridyl and tetrapyridyl compounds:
In this paper we envisaged a new methodology to prepare halo-
oligopyridines starting from dihalopyridines, taking into account
our experience in the halopyridylboronic acids synthesis and in the
* Corresponding author. Tel.: þ33 (0) 2 31 93 64 58; fax: þ33 (0) 2 31 93 11 88.
E-mail address: sylvain.rault@unicaen.fr (S. Rault).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.024

608
A.S. Voisin-Chiret et al. / Tetrahedron 65 (2009) 607–612
N
Br
unsymmetric isomers
N
N
N
N
N
N
N
Os
N
2,3'
N
N
Ru
N
3,4'
N
N
N
N
N
N
N
2,2'
N
symmetric isomers
N
N
N
2,4'
N
N
Ru(II) oligopyridyl complexe
N
N
N
N
3,3'
N
Ru
N
N
N
4,4'
N
N
Figure 3. Unsubstituted bipyridines.
Ru(II) and Os(II) oligopyridyl
complexe
N
N
N
N
N
The regioselective control of the pyridine–pyridine linkage be-
comes more complex to manage and beyond a cross-coupling ap-
proach, it is necessary to set up a strategy for a regioselective
synthesis of the desired halo-oligopyridines. This cross-coupling
strategy should be efficient, short, convergent, and highly flexible
leading to a selective coupling with the desired halogen. Recent
reports showed that regioselective couplings are generally
achievable for a wide range of polyhaloheteroaromatics and such
regioselectivity is predictable.22–24
This paper deals with our preliminary results concerning the
utility of Suzuki–Miyaura cross-coupling reactions in the regiose-
lective synthesis and the first examples of synthesis of new oligo-
pyridines, whether halogenated or not, as new analogs of
nemertelline have been described.
Terpyridine
Quaterpyridine
Anabaseine
Nicotelline
Nemertelline
Figure 1. Oligopyridine derivatives.
knowledge of their ability as coupling partners in Suzuki–Miyaura
cross-coupling reaction.21
Thus, these dihalopyridines can serve both as starting materials
in the synthesis of the corresponding halopyridylboronic acids and
as partners to couple with the latter acids to give dihalobipyridines.
In turn, these dihalobipyridines could be used in a second Suzuki–
Miyaura cross-coupling reaction to couple with halopyridylboronic
acids leading to dihaloter- and quarter-pyridines. The obtained
dihalo-oligopyridines may be engaged further in the same reaction
as starting materials and so on.
2. Results and discussion
There are six families of unsubstituted bipyridines, classified
according to the positions at which the two pyridine rings are
linked together (Fig. 3). Some are natural products, extracted from
tobacco leaves and roots, and others were prepared using different
chemical coupling procedures to achieve a direct pyridine–pyridine
linkage where Stille and Suzuki–Miyaura cross-couplings are useful
approaches. Besides, substitutions in symmetric and unsymmetric
bipyridines by halogens have to be considered (Fig. 4). According to
all the free substitution positions and taking into account all the
halo isomers, iodo-, bromo-, chloro-, and fluoro-isomer, we
have theoretically counted 888 different dihalobipyridines, more
than 12,000 dihaloterpyridines and more than 140,000
trihaloterpyridines.
Firstly, from a synthetic point of view, Suzuki–Miyaura cross-
coupling reaction was highly useful to obtain the desired halo-
oligopyridines. Dihalopyridines were used as starting materials to
couple with halopyridinylboronic acids and esters that we pre-
viously prepared from a regioselective halogen-metal exchange
using n-BuLi or a directed ortho-metalation using LDA starting from
appropriate mono- or di-halopyridines25 (Scheme 1).
Secondly, it is necessary to verify the regioselectivity of the re-
action and to specify, which reactivities are promoted, which con-
ditions are more convenient, and which partners have to be chosen
X
N
N
X
X
Hal
Hal
2,3'
N
X
N
N
Hal
3,4'
X
N
Hal
Hal
Hal
Hal
N
N
Hal
N
N
N
X
N
2,2'
X
X
N
dihalopyridine
dihalobipyridine
trihaloterpyridine
N
N
N
N
2,4'
X
X
X
N
N
N
3,3'
N
Hal Hal
N
Hal
N
N
N
X
4,4'
dihaloterpyridine
dihaloquaterpyridine
Figure 2. Nomenclature of haloligopyridines.
Figure 4. Symmetric and unsymmetric dihalobipyridines.

A.S. Voisin-Chiret et al. / Tetrahedron 65 (2009) 607–612
609
X'
Cl
a - Halogen-metal exchange
OH
(a)
X
X
Cl
B
B(OR)2
OH
N
N
N
X
+
Br
F
N
2
F
N
1
F
N
N
3, 42%
b - Ortholithiation
OH
B
(b)
OH
X, X' = Cl, Br,F
R = H,
mixture
+
Br
Cl
Cl
N
5
N
4
Scheme 1. Synthesis of halopyridinylboronic acids and esters. Reagents and condi-
tions: (a): (1) n-BuLi, B(OiPr)3, ꢁ78 ꢂC; (2) hydrolysis or pinacol, AcOH, hydrolysis; (b):
(1) LDA, B(OiPr)3, ꢁ60 ꢂC; (2) hydrolysis or pinacol, AcOH, hydrolysis.
N
OH
B
(c)
Br
Cl
Br
Br
OH
in order to obtain only one specific halo-oligopyridine. To carry out
this study, three steps have to be mentioned:
+
N
6
N
7
Cl
Br
N
N
8, 74%
ꢀ set up the standard conditions allowing to define reaction
possibilities according to the present halogen, substituents, the
positions and the availability of the boronic species,
ꢀ optimization of general procedures to enhance the efficiency of
the cross-coupling reaction,
N
(d)
OH
B
Cl
OH
Cl
+
Br
N
9
N
4
ꢀ application of these procedures in the synthesis of halo-oli-
10, 3% and starting materials
gopyridine series.
Scheme 2. Synthesis of 5-chloro-20-fluoro-2,30-bipyridine 3, 5-bromo-60-chloro-3,30-
bipyridine 8, and 6-bromo-50-chloro-3,30-bipyridine 10. Reagents and conditions:
halopyridylboronic acid 1, 4, or 6 1.1 equiv, dihalopyridine 2, 5, 7, or 9 1 equiv, Na2CO3
aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 8 h.
Several trials of cross-coupling procedures using different re-
action conditions (base, catalyst, solvent, temperature, and reaction
time) were attempted. Accordingly, we have determined the most
convenient conditions,26 where Na2CO3 was used as base, Pd(Ph3)4
as catalyst, 1,4-dioxane as solvent. In our case, these conditions
were adapted to control the coupling reaction and not to couple
everywhere. The completion of the reaction was determined in-
dicated by the total consumption of the halide (checked by thin
layer chromatography).
5-bromo-60-chloro-3,30-bipyridine 8 (74%), respectively. On the
other hand, when the more reactive halogen (the exchanged one)
was that of the boronic acid, a mixture of products difficult to sepa-
ratewasobtained(entryb). Inentryd, asmallamountof6-bromo-50-
chloro-3,30-bipyridine 10 (3%) was obtained with starting materials
as a majority. Thus the choice of the position and the nature of the
halogen and also its position are important factors in such a reaction.
In fact, it was difficult to predict a priori the regioselectivity of
the reaction when the dihalopyridine carries two different halogen
atoms as in case of using 2-chloro-5-iodopyridine 12 as starting
material. In this case, would the coupling occur with the chlorine
More precisely, in this work, one has to focus on three key points:
ꢀ the number of halogens on the pyridine nucleus and which one
could be engaged in the cross-coupling reaction,
ꢀ the nature of halogens on the pyridine ring, taking in consid-
eration that the order of reactivity is I>Br[Cl>F for the same
position on the pyridine ring,
atom situated in the
a
-position (more reactive position but less
-position
reactive halogen)? Or with the iodine atom found in the
b
ꢀ the position of halogens; indeed, the
a- and g-position are
(less reactive position but more reactive halogen)? Briefly, what
about the reactivities of the two halogens in this case? Are they
similar or different?
generally more reactive than the -one.
b
However, when the halogen of the halopyridylboronic acids is
engaged in the cross-coupling reaction, then the prediction of re-
action product will be rather complicated. Four possibilities have to
be considered:
Practically, as shown in Scheme 3, the coupling reaction took
place with the more reactive iodine atom at the
b-position without
the formation of any trace of a product formed via
a
-coupling. This
result was the same when two differently hindered halopyridyl-
boronic acids 11 and 4 were used, where the reaction products were
identified as 2,60-dichloro-3,30-bipyridine 13 and 6-bromo-60-
chloro-3,30-bipyridine 14 in 73% and 74% yield, respectively.
ꢀ if the halogen of the dihalopyridine is in a sensitive position
and its reactivity is better than the halogen set on the boronic
acid (Scheme 2a),
ꢀ if the halogen set on the dihalopyridine is in a sensitive posi-
tion but its reactivity is lower than the halogen set on the bo-
ronic acid (Scheme 2b),
ꢀ if the halogen set on the dihalopyridine is in a lowest sensitive
position but its reactivity is better than the halogen set on the
boronic acid (Scheme 2c),
ꢀ if the halogen set on the dihalopyridine is in a lowest sensitive
position and its reactivity is lower than the halogen set on the
boronic acid (Scheme 2d).
N
Cl
OH
B
I
I
OH
+
Cl
N
Cl
Cl
N
11
N
12
13, 73%
N
Cl
OH
B
OH
+
Br
N
Br
N
N
Cl
The reactions illustrating these four possibilities were carried
out and are shown in Scheme 2, equations a to d:
4
12
14, 74%
When the exchanged halogen (the more reactive one) was that of
thedihalopyridine(entries aandc),onlyoneproductwasobtainedin
each case namely 5-chloro-20-fluoro-2,30-bipyridine 3 (42%) and
Scheme 3. Synthesis of 2,60-dichloro-3,30-bipyridine 13 and 6-bromo-60-chloro-3,30-
bipyridine 14. Reagents and conditions: halopyridylboronic acids 11 and 4 1.1 equiv,
dihalopyridine 12 1 equiv, Na2CO3 aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 8 h.

610
A.S. Voisin-Chiret et al. / Tetrahedron 65 (2009) 607–612
Thus, it is important to consider the nature of the halogen and
reactivity. In this case, using 1.1 equiv of boronic acid 4, the reaction
its position with respect to the pyridine nitrogen: in fact, the
greater reactivity of the iodo group is able to overcome the intrinsic
electronic bias of the pyridine ring system.27 This behavior is
expected to be of a general potential use in these cross-coupling
reactions: a halogen atom of higher reactivity attached to a less
gave a
mixture of 6,20-dibromo-3,40-bipyridine 21 and 4,60-
dibromo-2,30-bipyridine 22 in similar yields 17% and 20%, re-
spectively (Scheme 6).28 We did not observe the formation of
terpyridines (mass spectrometry).
reactive position for nucleophilic substitutions (
partner than a halogen atom of lower reactivity attached to more
reactive position ( or ).
In fact, we have studied such regioselective reactions through
several examples using both symmetric and unsymmetric
dihalopyridines.
b) will be a better
N
OH
B
Br
Br
21, 17%
OH
a
g
Br
+
Br
N
4
Br
N
20
Br
N
N
First, when a symmetric compound such as 2,6-dibromopyr-
idine 15 was allowed to react with 1.1 equiv of the boronic acid 4,
6,60-dibromo-2,30-bipyridine 16 was obtained with only 33% yield.
This low yield indicates a lack of selectivity between the two hal-
ogens attached to these two reactive positions. When this reaction
was carried using 2 equiv of boronic acid, a mixture of 6,60-
dibromo-2,30-bipyridine 16 (12%) and 6,600-dibromo-3,20:60,300-ter-
pyridine 17 (23%) was obtained (Scheme 4).28 So, we can foresee
that the residual bromide in 6-position of 6,60-dibromo-2,30-
22, 20%
+
Br
N
Scheme 6. Synthesis of 6,20-dibromo-3,40-bipyridine 21 and 4,60-dibromo-2,30-bipyr-
idine 22. Reagents and conditions: halopyridylboronic acid 4 1.1 equiv, dihalopyridine
20 1 equiv, Na2CO3 aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 8 h.
In order to explore the utility of our methodology in the syn-
thesis of new terpyridines and quaterpyridines, analogs of nic-
otelline and nemertelline, the synthesis of one example of each
family was described in this first part.29
bipyridine 16 is more reactive than one of the bromide in a-position
of 2,6-dibromopyridine 15, then the dihaloterpyridine 17 was
generated to the detriment of the dihalobipyridine 16.
Thus, as shown in Scheme 7, 6,600-dichloro-3,20;40,300-terpyridine
23 could be easily prepared in a good yield (77%) via Suzuki–
Miyaura cross-coupling reaction of 6-chloropyridin-3-yl boronic
acid 6 (2.5 equiv) and with 2,4-dibromopyridine 20. We obtained
one product only confirming the regioselectivity of the cross-cou-
pling reaction toward the more reactive bromine atom at the re-
OH
B
OH
N
Br
+
active
intermediate.
a
-position of the 6-chloro-20-bromo-3,40-bipyridine
Br
Br
N
4
Br
N
15
Br
Br
N
N
16, 12%
+
N
OH
B
Br
N
17, 23%
N
Br
OH
Scheme 4. Synthesis of 6,60-dibromo-2,30-bipyridine 16 and 6,60-dibromo-3,20:60,300-
terpyridine 17. Reagents and conditions: halopyridylboronic acid 4 2 equiv, dihalo-
pyridine 15 1 equiv, Na2CO3 aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 8 h.
+
N
Cl
Cl
N
6
Br
N
20
Cl
N
23, 77%
Scheme 7. Synthesis of 6,600-dichloro-3,20;40,300-terpyridine 23. Reagents and condi-
tions: boronic acid 6 2.5 equiv, dihalopyridine 20 1 equiv, Na2CO3 aq 5 equiv, Pd(PPh3)4
10%, 1,4-dioxane, reflux, 8 h.
Unlike compound 15, the two bromine atoms of 3,5-dibromo-
pyridine 7 are located in b-position. The reaction of 7 with 1.1 equiv
of the boronic acid 4 led to a mixture of 5,60-dibromo-3,30-bipyr-
idine 18 (20%) and 500,6-dibromo-3,20:50,300-terpyridine 19 (13%) as
shown in Scheme 5. Thus, the formation of 19 showed that the
boronic acid has reacted selectively with the bromine atom at the
On the other hand, the synthesis of 3,20:50,200:500,3%-quaterpyr-
idine 27 is shown in Scheme 8. Thus, the Suzuki–Miyaura
cross-coupling reaction between the boronic acid 4 and 2,5-
dibromopyridine 24 gave the corresponding 5,60-dibromo-2,30-
bipyridine 26, but in a rather poor yield (15%), along with
by-products. The yield of 26 could be ameliorated when the
a
-position of 18 rather than with that at the b-position of 7. How-
ever, when 2 equiv of boronic acid was used, the yield was inverted
in favor of the terpyridine giving a mixture of 18 (11%) and 19 (27%).
Here again, the reactivity of the a
-bromine atom at 60-position of
5,60-dibromo-3,30-bipyridine 18 is better than the
5-position of 3,5-dibromopyridine 7.28
b
-one at the 3- or
Br
OH
B
Br
OH
N
i
N
+
OH
Br
N
4
X
N
24, X=Br
Br
N
B
Br
Br
26, 15% (X=Br) and 77% (X=I)
OH
Br
25, X=I
+
OH
Br
N
4
N
7
Br
Br
N
B
ii
N
18, 20%
N
OH
28
+
N
Br
N
N
19, 13%
N
N
Scheme 5. Synthesis of 5,60-dibromo-3,30-bipyridine 18 and 500,6-dibromo-3,20:50,300-
terpyridine 19. Reagents and conditions: halopyridylboronic acid 4 1.1 equiv, dihalo-
pyridine 7 1 equiv, Na2CO3 aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux, 8 h.
N
27, 41%
Scheme 8. Synthesis of 5,60-dibromo-2,30-bipyridine 26 and 3,20:50,200:500,3%-qua-
terpyridine 27. Reagents and conditions: (i) halopyridylboronic acid 1.1 equiv,
4
Secondly, using asymmetric compounds, such as 2,4-dibromo-
pyridine 20, allowed us to find out that both halo substituents,
dihalopyridine 24 or 25 1 equiv, Na2CO3 aq 2.5 equiv, Pd(PPh3)4 5%, 1,4-dioxane, reflux,
24 h; (ii) pyridylboronic 28 2.5 equiv, 26 1 equiv, Na2CO3 aq 5 equiv, Pd(PPh3)4 10%, 1,4-
dioxane, reflux, 24 h.
attached to the reactive positions
a and g have the equivalent

A.S. Voisin-Chiret et al. / Tetrahedron 65 (2009) 607–612
611
reaction was repeated using 5-bromo-2-iodopyridine 25 to give 26
in 77% yield. The quaterpyridine 27 could be successfully obtained
in 41% yield through the reaction of 5,60-dibromo-2,30-bipyridine
26 with 2.5 equiv of 3-pyridyl boronic acid 28.
4.2.2. 5-Bromo-60-chloro-3,30-bipyridine 8
Beige solid (74%). Mp 115 ꢂC. IR (KBr): 3035, 1449, 830 cmꢁ1. 1H
3
4
NMR (400 MHz, CDCl3):
d
¼8.50 (dd, JHH¼4.8, JHH¼1.8, 2H), 7.68
(dd, 3JHH¼7.5, 4JHH¼1.8, 2H), 7.38 (dd, 3JHH¼7.5, 3JHH¼4.8, 2H). Anal.
Calcd for C10H6BrClN2: C, 44.56; H, 2.24; N, 10.39. Found: C, 44.54;
H, 2.29; N, 10.34.
3. Conclusion
These examples were selected as model reactions to explore
under what conditions regiochemically exhaustive functionaliza-
tion reactions can be carried out. We have developed conditions for
efficient, short, convergent, and highly flexible cross-coupling re-
actions. These reactions proceed with a high degree of regiose-
lectivity and reasonable-to-good overall yield. The implementation
of this strategy will allow to create a library of diverse of novel halo-
oligopyridines. Exploration of this methodology is currently under
investigation, i.e., several building possibilities, and the results will
be reported in due course elsewhere.
4.2.3. 6-Bromo-50-chloro-3,30-bipyridine 10
Beigesolid(3%). Mp100 ꢂC.IR(KBr):2916,1701,1461, 721 cmꢁ1.1H
NMR (400 MHz, CDCl3):
d
¼8.94 (d, 4JHH¼2.9, 1H), 8.73 (d, 4JHH¼4.8,
4
3
1H), 8.21 (dd, JHH¼2.9, JHH¼8.8, 1H), 7.84–7.80 (m, 1H), 7.74 (d,
3JHH¼8.8, 1H), 7.61 (d, 3JHH¼8.8, 1H). Anal. Calcd for C10H6BrClN2: C,
44.56; H, 2.24; N, 10.39. Found: C, 44.53; H, 2.22; N, 10.33.
4.2.4. 2,60-Dichloro-3,30-bipyridine 13
Beige solid (73%). Mp 124 ꢂC. IR (KBr): 3391, 3042, 2360, 1548,
1405, 1347, 1112, 994, 803, 738, 642 cmꢁ1 1H NMR (400 MHz,
.
CDCl3):
d
¼8.48–8.47 (m, 2H), 7.81 (dd, 3JHH¼7.8, 4JHH¼1.9, 1H), 7.69
3
4
3
4. Experimental section
4.1. General procedure
(dd, JHH¼6.8, JHH¼1.9, 1H), 7.45 (d, JHH¼8.8, 1H), 7.38 (dd,
3JHH¼4.4, 3JHH¼7.8, 1H); 13C NMR (100 MHz, CDCl3):
¼154.3, 151.5,
d
149.6, 149.5, 139.5, 132.3, 132.1, 130.2, 123.9, 122.8; HRMS (EI): m/z
ꢀ
calcd for C10H6Cl2N2 (Mþ ) 223.9908, found 223.9910.
Commercial reagents were used as received without additional
purification. Melting points were determined on a Kofler heating
bench. IR spectra were recorded on a Perkin Elmer BX FTIR spec-
trophotometer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded on a JEOL Lambda 400 spectrometer. Chemical shifts
are expressed in parts per million downfield from tetramethylsi-
lane as an internal standard and coupling constants in hertz. The
NMR spectrum of quaterpyridine 27 was recorded on a Bru¨cker
Avance DRX 400 spectrometer. 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 LC-MS Waters alliance 2695
(ESIþ). Chromatography was carried out on a column using flash
silica gel 60 Merck (0.063–0.200 mm) as the stationary phase. Thin
layer chromatography (TLC) was performed on 0.2 mm precoated
plates of silica gel 60F264 (Merck) and spots were visualized using
an ultraviolet-light lamp. Elemental analyses for new compounds
were performed at the ‘Institut de Recherche en Chimie Organique
Fine’ (Rouen).
4.2.5. 6-Bromo-60-chloro-3,30-bipyridine 14
Beige solid (74%). Mp >250 ꢂC. IR (KBr): 3035, 1576, 1449, 1338,
1111, 1094, 995 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼8.59 (d,
4
3
4
4JHH¼1.9, 1H), 8.57 (d, JHH¼2.9, 1H), 7.83 (dd, JHH¼8.8, JHH¼2.9,
1H), 7.73 (dd, 3JHH¼7.8, 4JHH¼1.9, 1H), 7.62 (d, 3JHH¼7.8, 1H), 7.46 (d,
3JHH¼8.8, 1H); 13C NMR (100 MHz, CDCl3):
¼151.8, 148.2, 147.7,
d
142.3, 136.9, 136.7, 131.6, 131.3, 128.5, 124.7; HRMS (EI) calcd for
ꢀ
C10H6BrClN2 (Mþ ) 267.9402, found 267.9401.
4.2.6. 6,60-Dibromo-2,30-bipyridine 16
White solid (20%). Mp 177 ꢂC. IR (KBr): 3029, 1463, 1430, 1261,
1090, 1003, 804, 703 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼8.90 (d,
3
4
3
4JHH¼2.9, 1H), 8.23 (dd, JHH¼8.8, JHH¼2.9, 1H), 7.69 (d, JHH¼8.6,
1H), 7.64–7.57 (m, 2H), 7.60 (d, 3JHH¼7.8, 1H), 7.50 (d, 3JHH¼7.8, 1H);
13C NMR (100 MHz, CDCl3):
d¼153.3, 154.8, 149.0, 148.4, 143.4,
139.3, 137.0, 128.4, 127.7, 119.0; m/z: 314; HRMS (EI) calcd for
ꢀ
C10H6Br2N2 (Mþ ) 311.8897, found 311.8905.
Starting materials were purchased from Aldrich, Acros Organics,
and Alfa Aesar and used without purification.
4.2.7. 6,60-Dibromo-3,20:60,300-terpyridine 17
Beige solid (23%). Mp 200 ꢂC. IR (KBr): 2961, 1568, 1452, 1281,
1091, 1017, 818, 791 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d¼10.24
4.2. General procedure for the coupling reactions30
(s, 2H), 7.90 (d, JHH¼4.6, 2H), 7.80 (d, JHH¼4,6, 1H), 7.40 (d,
3
3
3
3JHH¼8.7, 2H), 7.14 (d, JHH¼8.7, 2H); MS (EI) m/z: 389–391–393
A mixture of halopyridylboronic acid (1.1 equiv), halopyridine
(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 extracted with ethyl
acetate. The organic layer was separated, dried over MgSO4, and
concentrated till dryness. The residue was chromatographied on
silica gel (cyclohexane/ethylacetate, 80:20) to afford halo-
oligopyridines.
[Mþ]ꢀ, 310–312 [MþꢁBr]ꢀ, 230 [Mþꢁ2Br]ꢀ.
4.2.8. 5,60-Dibromo-3,30-bipyridine 18
White solid (20%). Mp 177 ꢂC. IR (KBr): 3029, 1463, 1430, 1261,
1090, 1003, 804, 703 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼8.67 (s,
1H), 8.51 (s, 1H), 7.69 (d, 3JHH¼8.6, 1H), 7.58 (s, 1H), 7.26 (s, 1H), 7.09
ꢀ
3
(d, JHH¼8.6, 1H); MS (EI) m/z: 312–314–316 [Mþ] , 233–235
[MþꢁBr]ꢀ, 154 [Mþꢁ2Br]ꢀ.
4.2.9. 500,6-Dibromo-3,20:50,300-terpyridine 19
4.2.1. 5-Chloro-20-fluoro-2,30-bipyridine 3
White solid (13%). Mp 182 ꢂC. IR (KBr): 3028, 2359, 1463, 1430,
Beige solid (42%). Mp 102 ꢂC. IR (KBr): 2962, 1576, 1108,
1089, 805, 703, 640 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
¼8.74 (d,
761 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
¼8.69 (d, 4JHH¼2.5, 1H), 8.55
4JHH¼1.7, 1H), 8.73 (d, 4JHH¼1.7, 1H), 8.57 (s, 1H), 8.58 (s, 1H), 8.04 (s,
1H), 7.75 (d, 3JHH¼8.2, 1H), 7.64 (d, 3JHH¼8.2, 1H), 7.35 (d, 3JHH¼8.6,
3
4
4
3
(ddd, JHH¼7.4, JHH¼2.0, JHF¼9.7, 1H), 8.27 (ddd, JHH¼4.9,
ꢀ
4
3
3
3
4JHH¼2.0, JHF¼3.5, 1H), 7.88 (d, JHH¼8.5, 1H), 7.78 (dd, JHH¼8.5,
1H), 7.12 (d, JHH¼8.6, 1H); MS (EI) m/z: 389–391–393 [Mþ] , 310–
4JHH¼2.5, 1H), 7.35 (dd, 3JHH¼7.4, 3JHH¼4.9, 1H); 13C NMR (100 MHz,
312 [MþꢁBr]ꢀ, 230 [Mþꢁ2Br]ꢀ.
3
CDCl3):
d
¼160.0 (d, 1JCF¼239.4), 149.0 (d, JCF¼6.5), 148.8, 147.9 (d,
3JCF¼14.8), 141.0 (d, JCF¼3.3), 131.7, 124.7 (d, JCF¼11.5), 122.1 (d,
4.2.10. 6,20-Dibromo-3,40-bipyridine 21
5
4
4JCF¼4.2), 121.2 (d, JCF¼26.4); m/z: 208; HRMS (EI) calcd for
Beige solid (17%). Mp <50 ꢂC. IR (KBr): 2926, 1554, 1448, 1355,
2
ꢀ
C10H6ClFN2 (Mþ ) 208.0203, found 208.0200.
1130, 1079, 825, 772, 744 cmꢁ1 1H NMR (400 MHz, DMSO-d6):
.

612
A.S. Voisin-Chiret et al. / Tetrahedron 65 (2009) 607–612
d
¼8.29 (d, 3JHH¼5.2, 1H), 8.27 (d, 3JHH¼5.4, 1H), 7.89 (s, 1H), 7.77 (s,
References and notes
3
3
1H), 7.67 (d, JHH¼5.2, 1H), 7.64 (d, JHH¼5.4, 1H); m/z: 314; HRMS
ꢀ
(EI) calcd for C10H6Br2N2 (Mþ ) 311.8897, found 311.8903.
1. (a) Constable, E. C. Angew. Chem., Int. Ed. 2007, 46, 2748–2749; (b) Constable,
E. C. Prog. Inorg. Chem. 1994, 42, 67–138; (c) Constable, E. C. Adv. Inorg. Chem.
1986, 30, 69–121.
2. Fang, Y.-Q.; Polson, M. I. J.; Hanan, G. S. Inorg. Chem. 2003, 42, 5–7.
3. Kozhevnikov, V. N.; Kozhevnikov, D. N.; Rusinov, V. L.; Chupakhin, O. N.; Koenig,
B. Synthesis 2003, 15, 2400–2404.
4. Hofmeier, H.; Gohy, J.-F.; Schubert, U. S. Abstracts of Papers, 225th National
Meeting of the American Chemical Society, New Orleans, LA, March 23–27,
2003; American Chemical Society: Washington, DC, 2003; 69DSA4.
5. Mirzadeh, S.; Packard, A. B. Abstracts of Papers, 210th National Meeting of the
American Chemical Society, Chicago, IL, Aug 20–24, 1995; American Chemical
Society: Washington, DC, 1995; 61XGAC.
4.2.11. 4,60-Dibromo-2,30-bipyridine 22
Beige solid (20%). Mp 142 ꢂC. IR (KBr): 3044, 1562, 1444, 1383,
1089, 1011, 823, 797 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
¼9.09 (s,
1H), 8.58 (d, 3JHH¼5.1, 1H), 8.43 (d, 1H, 3JHH¼8.4), 8.40 (s, 1H), 7.79
3
3
(d, JHH¼8.4, 1H), 7.73 (d, JHH¼5.1, 1H); m/z: 314; HRMS (EI) calcd
ꢀ
for C10H6Br2N2 (Mþ ) 311.8897, found 311.8891.
4.2.12. 600,6-Dichloro-3,20:40,300-terpyridine 23
6. Lowe, G.; Droz, A. S.; Vilaivan, T.; Weaver, G. W.; Tweedale, L.; Pratt, J. M.; Rock,
P.; Yardley, V.; Croft, S. L. J. Med. Chem. 1999, 42, 999–1006.
Halopyridylboronic acid (2.5 equiv), 1 equiv of halopyridine, 10
% tetrakis(triphenylphosphine) palladium(0), and 5 equiv
7. Ross, S. A.; Carr, C. A.; Briet, J. W.; Lowe, G. Anti Cancer Drug Des. 2000,15, 431–439.
8. (a) 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, 2659–2662; (b) Basnet, A.; Thapa, P.; Karki, R.; Na, Y.; Jahng, Y.; Jeong,
B. S.; Jeong, T. C.; Lee, C. S.; Lee, E. S. Bioorg. Med. Chem. 2007, 15, 4351–4359.
9. Fukuuchi, T.; Doh-ura, K.; Yoshihara, S.; Ohta, S. Bioorg. Med. Chem. Lett. 2006,
16, 5982–5987.
10. Shi, A.; Pokhrel, M. R.; Niederweis, M.; Bossmann, S. H. Abstracts of Papers, 40th
Midwest Regional Meeting of the American Chemical Society, Joplin, MO, Oct
26–29, 2005; American Chemical Society: Washington, DC, 2005; 69HOLN.
11. Kem, W. R.; Scott, K. N.; Duncan, J. H. Experientia 1976, 32, 684–686.
12. Kem, W. R. Hydrobiologia 1988, 156, 145–151.
mol
aqueous Na2CO3 are used. White solid (77%). Mp 226 ꢂC. IR (KBr):
3057, 1601, 1569, 1452, 1345, 1110, 1020, 1010, 831 cmꢁ1 1H NMR
.
4
3
(400 MHz, CDCl3):
d
¼8.96 (d, JHH¼2.5, 1H), 8.75 (d, JHH¼5.1, 1H),
4
3 4
8.65 (d, JHH¼2.6, 1H), 8.30 (dd, JHH¼8.4, JHH¼2.5, 1H), 7.88 (dd,
3JHH¼8.2, JHH¼2.6, 1H), 58 (s, 1H), 7.80 (s, 1H), 7.45–7.34 (m, 3H);
4
13C NMR (100 MHz, CDCl3):
d
¼154.7, 150.9, 150.5, 148.1, 147.9, 145.3,
ꢀ
137.2, 137.1; HRMS (EI): m/z: 301 calcd for C15H9Cl2N3 (Mþ
)
301.0173, found 301.0162.
13. Kem, W. R.; Soti, F. Hydrobiologia 2001, 456, 221–231.
14. (a) Pictet, A.; Rotschy, A. Chem. Ber. 1901, 34, 696–708; (b) Pictet, A. Arch. Pharm.
(Weinheim, Ger.) 1906, 244, 375–389.
4.2.13. 5,60-Dibromo-2,30-bipyridine 26
Yellow solid (77%). Mp 194 ꢂC. IR (KBr): 3010, 1575, 1461, 1376,
15. Yamamoto, Y.; Azuma, Y.; Mitoh, H. Synthesis 1986, 7, 564–565.
16. Yamamoto, Y.; Tanaka, T.; Yagi, M.; Inamoto, M. Heterocycles 1996, 42, 189–194.
17. (a) Cruskie, M. P., Jr.; Zoltewicz, J. A.; Abboud, K. A. J. Org. Chem. 1995, 60, 7491–
7495; (b) Zoltewicz, J. A.; Cruskie, M. P., Jr. Tetrahedron 1995, 51, 11401–11410.
18. Bouillon, A.; Voisin, A. S.; Robic, A.; Lancelot, J. C.; Collot, V.; Rault, S. J. Org.
Chem. 2003, 68, 10178–10180.
1090, 1005, 823 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
¼8.92 (d,
4
3
4
4JHH¼2.0, 1H), 8.76 (d, JHH¼2.0, 1H), 8.18 (dd, JHH¼8.8, JHH¼2.0,
1H), 7.93 (dd, 3JHH¼8.8, 4JHH¼2.0, 1H), 7.64 (d, 3JHH¼8.8, 1H), 7.60 (d,
3JHH¼8.8, 1H); 13C NMR (100 MHz, CDCl3):
¼152.1, 151.3, 148.3,
d
19. Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. J. Org. Chem. 2002,
67, 7541–7543.
143.0, 139.7, 136.6, 133.1, 128.2, 121.3, 120.6; HRMS (EI): m/z calcd
ꢀ
for C10H6Br2N2 (Mþ ) 311.8897, found 311.8892.
20. Lehmann, U.; Henze, O.; Schlu¨ ter, A. D. Chem.dEur. J. 1999, 5, 854–859.
21. For leading references, see: (a) Miyaura, N. In Metal-Catalysed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: New York, NY, 2004;
Chapter 2; (b) Suzuki, A. In Hand-book of Organopalladium Chemistry for Organic
Synthesis; Negishi, E. I., Ed.; Wiley Intersciences: New York, NY, 2002; Chapter
III.2.2.
22. Schroeter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245–2267.
23. (a) Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299–301; (b) Handy, S. T.;
Sabatini, J. J. Org. Lett. 2006, 8, 1537–1539.
4.2.14. 3,20:50,200:500,3%-Quaterpyridine 27
Pyridylboronic acid (2.5 equiv), 1 equiv of halopyridine, 10 mol
% tetrakis(triphenylphosphine) palladium(0), and 5 equiv aqueous
Na2CO3 are used. Beige solid (41%). Mp 198 ꢂC. IR (KBr): 3420,
3036, 1584, 1465, 1360, 1013, 804, 710 cmꢁ1
.
1H NMR
24. Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036–1045.
4
5
(400 MHz, CDCl3):
d
¼9.40 (dd, JHH¼2.3, JHH¼0.8, 1H), 9.31 (dd,
25. (a) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2002,
58, 2885–2890; (b) Bouillon, A.; Lancelot, J. C.; Collot, V.; Bovy, P. R.; Rault, S.
Tetrahedron 2002, 58, 3323–3328; (c) Bouillon, A.; Lancelot, J. C.; Collot, V.;
Bovy, P. R.; Rault, S. Tetrahedron 2002, 58, 4369–4373; (d) Bouillon, A.; Lancelot,
J. C.; Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59, 10043–10049.
26. Unpublished results.
27. Handy, S. T.; Wilson, T.; Muth, A. J. Org. Chem. 2007, 72, 8496–8500.
28. These yields are particularly low. We did not observe debromination of the
boronic acid but we noticed a protodeboronation reaction in such a way that
we recovered small amounts of starting materials. Moreover, in cross-coupling
reactions, we often observed a polymerization reaction leading to by-products,
which are not isolated.
4JHH¼2.3, 5JHH¼0.8, 1H), 9.01 (dd, 4JHH¼2.3, 5JHH¼0.8, 1H), 8.95 (dd,
4JHH¼2.3, JHH¼0.8, 1H), 8.72 (dd, JHH¼1.8, JHH¼4.8, 1H), 8.71
5
4
3
(dd, 4JHH¼1.8, 3JHH¼4.8, 1H), 8.54 (dd, 3JHH¼8.3, 4JHH¼2.3, 1H), 8.44
3
4
4
3
(ddd, JHH¼7.9, JHH¼2.3, JHH¼1.8, 1H), 8.06 (dd, JHH¼8.3,
4JHH¼2.3, 1H), 7.98 (ddd, JHH¼7.9, JHH¼2.3, JHH¼1.6, 1H), 7.97
3
4
4
(dd, 3JHH¼8.2, 5JHH¼0.8, 1H), 7.94 (dd, 3JHH¼8.3, 5JHH¼0.8, 1H), 7.48
3
3
5
3
(ddd, JHH¼7.9, JHH¼4.8, JHH¼0.8, 1H), 7.47 (ddd, JHH¼7.9,
3JHH¼4.8, JHH¼0.8, 1H); 13C NMR (100 MHz, CDCl3):
d¼155.5,
5
154.3, 150.6, 149.9, 148.9, 148.8, 148.7, 148.6, 135.8, 135.7, 134.8,
134.7, 134.6, 133.7, 133.4, 133.1, 124.3, 124.1, 120.9 (2C); HRMS (EI):
29. Preparation of other ter- and quater-pyridines will be described in a following
paper.
30. Unless otherwise specified.
ꢀ
m/z calcd for C20H14N4 (Mþ ) 310.1218, found 310.1208.