Synthesis of novel halo-oxybispyridines, new building blocks in cholinergic medicinal chemistry

Article abstract of DOI:10.1016/j.tet.2006.04.002

This paper describes a method for the preparation of oxybispyridines bearing several halogens, which could be further transformed into other functional groups thus giving access to libraries with the bis-pyridyl ether moiety as the common structural feature of interest in cholinergic medicinal chemistry. Scope and limitation of the method are outlined.

Full text of DOI:10.1016/j.tet.2006.04.002

Tetrahedron 62 (2006) 6000–6005
Synthesis of novel halo-oxybispyridines, new building blocks
in cholinergic medicinal chemistry
a
Anne Sophie Voisin, Alexandre Bouillon, Jean-Charles Lancelot, Aurelien Lesnard
b
a
a
´
and Sylvain Raulta,
*
a
´
Centre d’Etudes et de Recherche sur le Medicament de Normandie, UPRES EA-3915, U.F.R. des Sciences Pharmaceutiques 5,
´
rue Vaubenard, 14032 Caen Cedex, France
bBoroChem S.A.S., Immeuble Emergence 7, rue Alfred Kastler, 14000 Caen, France
Received 15 March 2006; revised 28 March 2006; accepted 3 April 2006
Available online 2 May 2006
Abstract—This paper describes a method for the preparation of oxybispyridines bearing several halogens, which could be further transformed
into other functional groups thus giving access to libraries with the bis-pyridyl ether moiety as the common structural feature of interest in
cholinergic medicinal chemistry. Scope and limitation of the method are outlined.
Ó 2006 Elsevier Ltd. All rights reserved.
CN
1. Introduction
O
N
O
n
R
A considerable amount of literature has been published con-
cerning the pyridylethers as nicotinic cholinergic receptor
ligands. For example, A-85380 and its derivatives,1 ABT-
5942 and ABT-0893 have been described to be highly selec-
tive agents of a4b2 receptors (Fig. 1).
HN
N
Cl
N
Cl
n = 1,2,3
Pyridylethers
RWJ-314313
Figure 2.
In this study, we chose to develop the synthesis of novel
pyridylethers such as halo-oxybispyridines. A few examples
of symmetrical and dissymmetrical oxybispyridines have
been described5–8 and some of these were obtained through
nucleophilic substitution.9–12
R
O
O
O
N
H
N
H
N
H
H3C
N
N
H
N
Cl
A-85380 R =
A
BT-594
ABT-089
Indeed, from a synthetic point of view, halo-oxybispyridines
afford more potentialities because of particular reactivity in
metal-catalyzed cross-coupling reactions like Suzuki cou-
pling, either as electrophilic agents or in preparing their
own boronic acids. In this study, we pay particular attention
to synthesize various halo-oxybispyridines as valuable
building blocks.
Figure 1. Pyridylethers as nicotinic cholinergic agonists (a4b2).
Besides, synthesis and structure–activity relationship of
novel pyridylethers have been published by Lee et al.4 The
authors described that the only criteria left on the molecule
was to place the second nitrogen in an optimal distance
from the 3-position of the pyridine.
The two methodologies allowing the preparation of oxybis-
pyridines (Scheme 1) are as follows: either the Chan–Lam
coupling reaction13–15 or the nucleophilic substitution. For
these two reactions, halohydroxypyridines have to be
prepared. Recently, we described a general method for the
synthesis of halohydroxypyridines from novel halopyridyl-
boronic acids and esters using an efficient hydroxydeborona-
tion reaction.17
From these observations, numerous derivatives have been
synthesized and among them, RWJ-3143134 as a potent
ligand bound to the a4b2 nAChR subtype (Fig. 2).
* Corresponding author. E-mail: sylvain.rault@unicaen.fr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.002

A. S. Voisin et al. / Tetrahedron 62 (2006) 6000–6005
6001
O
2-benzyloxy-5-(6-bromopyridin-3-yloxy)pyridine gave the
expected product 2 (Scheme 2).
X
X
N
N
Chan–Lam
coupling
Nucleophilic
substitution
O
B
OH
O
O
OR
B
16%
+
HO
Br
HO
BnO
Br
BnO
Br
N
N
N
N
OR
X
2
X
X
X
+
+
N
N
N
N
Scheme 2. Synthesis of oxybispyridine 2. Reagents and conditions: Cu(Ac)2
(1 equiv), pyridine (5 equiv), CH2Cl2, 4 A molecular sieves, 25 ꢀC,
˚
R
= H,
X = H, Br, Cl, F
4 days.
But, this route to obtain novel halo-oxybispyridines led to
poor results even if two examples 1 and 2 have been pro-
duced with 11 and 16% yields, respectively.
Scheme 1. Two synthetic approaches to halo-oxybispyridines.
2. Results and discussion
To explain this lack of reactivity, we suggested that when the
hydroxyl compound used in coupling reactions contained an
electron-withdrawing group, the reaction was unsuccessful.
More precisely, the coordination step seemed to depend on
the stability of the anion in accordance with the pKa of the
hydroxyl compound. Indeed, we considered the coupling re-
action of p-chlorophenol and halopyridylboronic esters in
the previous conditions. We obtained arylheteroarylethers
3–5 with 63, 67, and 57% yields, respectively (Scheme 3).
The Chan–Lam coupling reaction has been considered first
because of our knowledge in the halopyridylboronic acid
synthesis18–21 and in the study of their reactivity in cross-
coupling reactions illustrated, for example, by the synthesis
of the quaterpyridine nemertelline22 and in the Petasis
reaction.23
Firstly, halopyridylboronicacidshave beenusedunderclassi-
cal conditions,13–14 but the reaction was unsuccessful.
Secondly, halopyridylboronic esters have been involved,
considering our precedent and fruitful works concerning
N-arylations.24 Several conditions were then tested at room
temperature (if no reaction occurred, the mixture was then
heated to reflux). All these tests are summarized in Table 1.
O
B
OH
O
3
O
Hal
Hal
+
2
6
Cl
N
Cl
N
Hal
Yields
2-Br
3-Br
6-Cl
63%
67%
57%
3
4
5
Table 1. Several conditions for Chan–Lam coupling reaction (NR: no
reaction)
Scheme 3. Synthesis of arylheteroarylethers 3–5. Reagents and conditions:
ꢀ
˚
Cu(Ac)2 (1 equiv), pyridine (5 equiv), CH2Cl2, 4 A molecular sieves, 25 C,
4 days.
O
B
O
OH
O
We observed the same trend with several hydroxyl com-
pounds, shown in Table 2: the higher the pKa value is, the
more unstable the anion is and the more efficient the coordi-
nation step is.
+
Br
Br
Br
Br
N
N
N
N
1
Entry
Cu(OAc)2
Base
Solvent
Yields
113,14
213,14
313,14
413,14
1 equiv
1 equiv
1 equiv
1 equiv
Pyridine
Pyridine
N(Et)3
CH2Cl2
DMF
CH2Cl2
DMF
11%
NR
NR
NR
These results confirmed the lack of reactivity of halohy-
droxypyridines in Chan–Lam coupling reaction, which did
not seem to be good supports because of the electron defi-
cient feature of pyridine derivatives.
N(Et)3
5
6
1.5 equiv
1.5 equiv
Pyridine
N(Et)3
CH2Cl2
CH2Cl2
NR
NR
716
816
Cat., 5% TEMPO/air
Cat., 5% TEMPO/air
Pyridine
N(Et)3
CH2Cl2
CH2Cl2
NR
NR
A second strategy has been considered to synthesize halo-
oxybispyridines. Recently, Dull et al.12 have described the
synthesis of aryl olefinic azacyclic and aryl acetylenic
azacyclic compounds, which is able to affect the nicotinic
cholinergic receptors and to be agents for the treatment of
central nervous system disorders. Among these compounds,
only one halo-oxybispyridine has been described in this
patent, 3-bromo-5-(pyridin-3-yloxy)-pyridine. This com-
pound was obtained by nucleophilic substitution from pyri-
din-3-ol and 3,5-dibromopyridine (Scheme 4).
The coupling reaction of 2-[3-(6-bromo)pyridine]-4,40,5,50-
tetramethyl-1,3-dioxaborolane and 6-bromo-pyridin-3-ol
gave the expected dibromo-oxybispyridine 1 when the reac-
tion was carried out as follows: 1 equiv of copper(II) acetate,
˚
5 equiv of pyridine in dichloromethane, and 4 A molecular
sieves at room temperature for 4 days (entry 1). Other proce-
dures (entry 2–8) gave either trace of the expected product or
degradation products.
So, we took into account this strategy and we optimized this
reaction in order to make it applicable not only to various
3,30-oxybispyridines, but also to 2,30- and 4,40-oxybispyri-
dines (Scheme 5).
According to these conditions, the reaction of 2-[3-(6-
bromo)pyridine]-4,40,5,50-tetramethyl-1,3-dioxaborolane and

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A. S. Voisin et al. / Tetrahedron 62 (2006) 6000–6005
Table 2. Influence of the pKa value in Chan–Lam coupling reactiona
Table 3. Novel halo-oxybispyridines 6–13
Entry
114b
Hydroxyl components (pKa*)
Boronic components
Yields
79%
Entry Halohydroxy- Halopyridines
pyridines
Halo-oxybispyridines Yields
(CH3)3C
HO
OH
OH Br
Br
O
Br
B
HO
CH3
1
2
3
4
5
6
66%
31%
66%
72%
63%
23%
C(CH3)3
N
N
N
N
N
6
(9.63)
Cl
OH Br
Br Cl
O
Br
OH
O
B
2
3
4
5
6
63%
16%
11%
NR
N
N
Cl
O
N
N
N
7
Br
Br
Br
Br
N
N
N
N
(9.26)
(9.17)
OH Br
O
OH
O
N
Br
N
Br
B
BnO
O
N
8
Cl
Cl
OH Br
OH Br
N
N
N
N
Cl
Br
O
OH
OH
O
Br
N
N
N
N
B
O
Br
Br
9
N
O
(8.53)
Cl
Br
Br
O
B
10
O
N
OH
Br
N
O
N
(8.32)
(7.78)
OH
Cl
N
I
N
I
O
11
B
NR
O
N
Cl
Cl
OH Br
OH
N
Br
N
Cl
O
Br
Br
Cl
N
N
7
8
27%
63%
N
N
OH
O
12
B
7
NR
O
O2N
I
Cl
O
(7.04)
N
N
N
N
Theoretical value.25
a
13
The nucleophilic substitution led to good yields whether in
2-position (entries 3, 4, and 5), in 3-position (entry 1) or in
4-position (entry 8) of the nitrogen of pyridine. But, accord-
ing to the position and the nature of the halogen, yields have
been reduced by half. Moreover, the residual halogen of halo-
oxybispyridines can be involved in a second nucleophilic
substitution. Therefore, the heterogeneity of yields can be
warranted by formation of a small amount of secondary prod-
ucts as dioxyterpyridines. In order to clearly identify the
structure of these secondary products, we have synthesized
3,5-di-(pyridin-3-yloxy)pyridine 14 by reaction of 3,5-dibro-
mopyridine with pyridin-3-ol and 2,6-di-(5-chloropyridin-3-
yloxy)pyridine 15 by reaction of 2,6-dibromopyridine with
5-chloropyridin-3-ol with 69 and 26% yields, respectively
(Scheme 6). Those synthesized dioxyterpyridines matched
to the by-products previously identified in the reaction.
OH
Br
Br
O
Br
56%
+
N
N
N
N
Scheme 4. Synthesis of halo-oxybispyridine. Reagents and conditions: NaH
80% (1 equiv), DMF, 130 ꢀC, 20 h.
X'
O
OH
X
X''
X
X''
+
N
N
N
N
X = H, Cl; X' = Br, I; X'' = Br, I
6-13
Scheme 5. Synthesis of halo-oxybispyridines 6–13. Reagents and condi-
tions: 60% NaH (1.25 equiv), DMF, reflux, 48 h.
Fortunately, we have easily achieved numerous isomers
and this methodology is now applicable to a large scale
of starting materials. It has been used with several halo-
hydroxypyridines and halopyridines to obtain novel halo-
oxybispyridines 6–13 as shown in Table 3.
It is to be noted that the nucleophilic substitution would have
been better with chlorinated compounds, but halogen–metal
exchange considered in further works is not possible with
chlorinated halo-oxybispyridines.

A. S. Voisin et al. / Tetrahedron 62 (2006) 6000–6005
6003
754, 642 cmꢁ1. 1H NMR (400 MHz, CDCl3): d¼7.86–7.85
(m, 2H), 7.44–7.43 (m, 2H), 7.27–7.26 (m, 2H). 13C NMR
(100 MHz, CDCl3): d¼155.2, 140.9, 138.8, 131.1, 122.0.
Anal. Calcd for C10H6Br2N2O: C, 36.40; H, 1.83; N, 8.49.
Found: C, 36.09; H, 1.54; N, 7.98.
OH Br
+
Br
Br
O
O
O
69%
N
N
N
N
14
N
N
N
N
N
O
Cl
Cl
OH Br
+
Cl
26%
3.2.2. 2-Benzyloxy-5-(6-bromopyridin-3-yloxy)pyridine
(2). 2-Benzyloxy-5-(6-bromopyridin-3-yloxy)pyridine was
prepared using 2-[3-(6-bromo)pyridine]-4,40,5,50-tetra-
methyl-1,3-dioxaborolane and 6-benzyloxypyridin-3-ol
according to general procedure 1 as a white solid (16%).
Mp 74 ꢀC. IR (KBr): 1678, 1575, 1420, 1345, 1360, 1276,
1186, 1091, 938, 742, 718, 653 cmꢁ1. 1H NMR (400 MHz,
CDCl3): d¼8.06 (d, J¼2.9 Hz, 1H), 7.91 (d, J¼2.8 Hz,
1H), 7.40–7.24 (m, 7H), 7.06 (dd, J¼8.7, 3.0 Hz, 1H), 6.77
(d, J¼8.9 Hz, 1H), 5.29 (s, 2H). 13C NMR (100 MHz,
CDCl3): d¼159.9, 153.5, 152.9, 141.0, 138.9, 137.6, 136.9,
131.5, 129.8 (2C), 128.3 (2C), 127.4, 126.5, 125.2, 115.5,
69.4. Anal. Calcd for C17H13BrN2O2: C, 57.16; H, 3.67; N,
7.84. Found: C, 56.68; H, 3.40; N, 7.54.
N
15
Scheme 6. Synthesis of dioxybisterpyridines 14 and 15. Reagents and
conditions: 60% NaH (1.25 equiv), DMF, reflux, 48 h.
In conclusion, we have produced novel oxybispyridines bear-
ing several halogens. Further experiments concerning the re-
activity of these compounds are currently under investigation
in order to use them as new building blocks in the production
of pyridine compounds with potential cholinergic activity.
3. Experimental
3.1. General
3.2.3. 2-Bromo-5-(4-chlorophenoxy)pyridine (3). 2-Bromo-
5-(4-chlorophenoxy)pyridine was prepared using 2-[3-(6-
bromo)pyridine]-4,40,5,50-tetramethyl-1,3-dioxa-borolane
and p-chlorophenol accordꢀing to general procedure 1 as a
white solid (63%). Mp 68 C. IR (KBr): 1486, 1449, 1375,
Commercial reagents were used as received without addi-
tional purification. Melting points were determined on a
Kofler heating bench and are uncorrected. IR spectra were
recorded on a Perkin–Elmer BX FTIR spectrophotometer.
1H NMR (400 MHz) and 13C NMR (100 MHz) were re-
corded on a JEOL Lambda 400 spectrometer. Chemical
shifts are expressed in parts per million downfield from
tetramethylsilane as an internal standard. Chromatography
was carried out on a column using flash silica gel 60 Merck
(0.063–0.200 mm) as the stationary phase. Thin-layer chro-
matography (TLC) was performed on 0.2 mm precoated
plates of silica gel 60F264 (Merck) and spots were visualized
using with an ultraviolet-light lamp. Elemental analyzes
for new compounds were performed at the ‘Institut de
Recherche en Chimie Organique Fine’ (Rouen).
1
1262, 1088, 1009, 828 cmꢁ1. H NMR (400 MHz, CDCl3):
d¼8.23 (d, J¼4.6 Hz, 1H), 7.64 (d, J¼8.3 Hz, 1H), 7.48–
7.44 (m, 3H), 7.13 (d, J¼8.9 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d¼154.5, 153.4, 141.2, 135.0, 130.2 (2C), 129.8,
128.7, 128.4, 120.3 (2C). Anal. Calcd for C11H7BrClNO: C,
46.43; H, 2.48; N, 4.92. Found: C, 46.12; H, 2.71; N, 4.71.
3.2.4. 3-Bromo-5-(4-chlorophenoxy)pyridine (4).26 3-
Bromo-5-(4-chlorophenoxy)pyridine was prepared using
2-[3-(5-bromo)pyridine]-4,40,5,50-tetramethyl-1,3-dioxa-
borolane and p-chlorophenol according to general proce-
dure 1 as an orange solid (67%). Mp 79 ꢀC. IR (KBr):
1554, 1484, 1425, 1307, 1250, 1200, 1087, 1009, 894, 871,
1
Starting materials were purchased from Aldrich, Acros
Organics, and Lancaster and used without purification.
844 cmꢁ1. H NMR (400 MHz, CDCl3): d¼8.35 (s, 1H),
8.24 (s, 1H), 7.35 (s, 1H), 7.29 (d, J¼8.8 Hz, 2H), 6.77
(d, J¼8.8 Hz, 2H).
Analytical data for known compounds were always fully
consistent with published data.
3.2.5. 2-Chloro-3-(4-chlorophenoxy)pyridine (5).27 2-
Chloro-3-(4-chlorophenoxy)pyridine was prepared using
2-[3-(2-chloro)pyridine]-4,40,5,50-tetramethyl-1,3-dioxa-
borolane and p-chlorophenol according to general proce-
dure 1 as a white solid (57%). Mp<50 ꢀC. IR (KBr): 1498,
3.2. General procedure 1 for the synthesis of arylhetero-
arylethers using Chan–Lam coupling reaction (1 and 5)
To a stirred solution of halopyridylboronic ester (2 equiv)
and halopyridinol or halophenol (1 equiv) in dichloro-
methane was added copper(II) acetate (1 equiv), pyridine
1454, 1367, 1262, 1087, 1011, 824 cmꢁ1 1H NMR
.
(400 MHz, CDCl3): d¼8.26 (d, J¼4.6 Hz, 1H), 7.59 (d,
J¼8.1 Hz, 1H), 7.48–7.44 (m, 3H), 7.06 (d, J¼8.9 Hz, 2H).
˚
(5 equiv), and 4 A molecular sieves. The reaction was then
continued at room temperature for 4 days. The mixture
was filtered, concentrated to dryness, and the residue was
purified by column chromatography (cyclohexane/ethyl-
acetate, 90/10) to afford ethers 1 and 5.
3.3. General procedure 2 for the synthesis of halo-oxy-
bispyridines using nucleophilic substitution (6 and 13)
To a stirred solution of pyridin-3-ol or chloropyridinol
(1 equiv) in dimethylformamide was slowly added 60% so-
dium hydride (1.25 equiv). The mixture was then continued
at room temperature for 1 h and mono- or di-halopyridine
(0.55 equiv) was added. The mixture was refluxed for 48 h
and then was allowed to warm to room temperature. To the
resulting suspension was added water. The mixture was
then extracted with ether and the extract was washed with
3.2.1. 2-Bromo-5-(6-bromopyridin-3-yloxy)pyridine (1).
2-Bromo-5-(6-bromopyridin-3-yloxy)pyridine was pre-
pared using 2-[3-(6-bromo)pyridine]-4,40,5,50-tetramethyl-
1,3-dioxaborolane and 6-bromopyridin-3-ol according to
general procedure 1 as a white solid (11%). Mp 82 ꢀC. IR
(KBr): 1680, 1573, 1349, 1329, 1271, 1179, 1069, 929,

6004
A. S. Voisin et al. / Tetrahedron 62 (2006) 6000–6005
brine, dried over magnesium sulfate, and concentrated on
rotary evaporator. The residue was purified by column chro-
matography (cyclohexane/ethylacetate, 80/20) to afford
halo-oxybispyridines 6 and 13.
IR (KBr): 1574, 1458, 1427, 1415, 1366, 1273, 1130, 1094,
1022, 922, 888, 826, 679 cmꢁ1 1H NMR (400 MHz,
.
CDCl3): d¼8.18 (d, J¼2.8 Hz, 1H), 8.08 (d, J¼2.8 Hz,
1H), 8.19 (dd, J¼8.7, 2.8 Hz, 1H), 7.42 (dd, J¼8.6,
2.8 Hz, 1H), 7.27 (d, J¼8.6 Hz, 1H), 6.85 (d, J¼8.7 Hz,
1H). 13C NMR (100 MHz, CDCl3): d¼161.2, 149.2, 147.9,
146.6, 143.0, 142.4, 131.8, 124.6, 114.5, 113.3. Anal. Calcd
for C10H6BrClN2O: C, 42.07; H, 2.12; N, 9.81. Found: C,
42.19; H, 2.05; N, 9.22.
3.3.1. 3-Bromo-5-(pyridin-3-yloxy)pyridine (6).12 3-
Bromo-5-(pyridin-3-yloxy)pyridine was prepared using
pyridin-3-ol and 3,5-dibromopyridine according to general
procedure 2 as an orange oil (66%). IR (KBr): 1565, 1475,
1423, 1305, 1258, 1086, 1021, 902, 798, 708, 673 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d¼8.22 (d, J¼2.4 Hz, 1H),
3.3.6. 3-Iodo-6-(pyridin-3-yloxy)pyridine (11). 3-Iodo-6-
(pyridin-3-yloxy)pyridine was prepared using pyridin-3-ol
and 2-bromo-5-iodopyridine according to general procedure
2 as a yellow oil (23%). IR (KBr): 1573, 1469, 1367, 1269,
1102, 1014, 891, 798, 715, 656 cmꢁ1. 1H NMR (400 MHz,
CDCl3): d¼8.39 (d, J¼2.4 Hz, 1H), 8.36 (dd, J¼4.6,
1.4 Hz, 1H), 8.21 (d, J¼2.2 Hz, 1H), 7.83 (dd, J¼8.6,
8.20–8.19 (m, 2H), 8.36 (d, J¼2.7 Hz, 1H), 7.48 (t,
3
J¼2.4 Hz, 1H), 7.15 (part A of system AB, JAB¼8.6 Hz,
J¼2.7, 1.7 Hz, 1H), 7.10 (part B of system AB, 3JAB¼8.6 Hz,
J¼4.6 Hz, 1H). 13C NMR (100 MHz, CDCl3): d¼153.7,
152.1, 145.6, 145.5, 141.2, 139.4, 128.3, 126.3, 124.8,
120.1.
3
2.2 Hz, 1H), 7.39 (part A of system AB, JAB¼8.3 Hz, J¼
3
3.3.2. 3-Bromo-5-(5-chloropyridin-3-yloxy)pyridine (7).
3-Bromo-5-(5-chloropyridin-3-yloxy)pyridine was prepared
using 5-chloropyridin-3-ol and 3,5-dibromopyridine accord-
ing to general procedure 2 as a white solid (31%). Mp 72 ꢀC.
IR (KBr): 1555, 1412, 1310, 1251, 1092, 1015, 925, 899,
2.4, 1.4 Hz, 1H), 7.22 (part B of system AB, JAB¼8.3 Hz,
J¼4.6 Hz, 1H), 6.71 (d, J¼8.6 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d¼162.0, 152.9, 149.9, 147.4, 145.7,
143.2, 128.4, 123.7, 113.7, 84.8. Anal. Calcd for
C10H7IN2O: C, 40.29; H, 2.37; N, 9.40. Found: C, 40.12;
H, 2.16; N, 9.18.
1
866, 692, 577 cmꢁ1. H NMR (400 MHz, CDCl3): d¼8.54
(d, J¼2.2 Hz, 1H), 8.43 (d, J¼2.2 Hz, 1H), 8.38 (d,
J¼2.2 Hz, 1H), 8.33 (d, J¼2.2 Hz, 1H), 7.52 (t, J¼2.2 Hz,
1H), 7.37 (t, J¼2.2 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d¼152.7, 152.6, 146.8, 144.7, 139.7, 139.1,
132.5, 128.7, 125.9, 120.7. Anal. Calcd for C10H6BrClN2O:
C, 42.07; H, 2.12; N, 9.81. Found: C, 41.91; H, 1.98; N, 9.69.
3.3.7. 2-Bromo-6-(5-chloropyridin-3-yloxy)pyridine (12).
2-Bromo-6-(5-chloropyridin-3-yloxy)pyridine was prepared
using 5-chloropyridin-3-ol and 2,6-dibromopyridine accord-
ing to general procedure 2 as a beige oil (27%). IR (KBr):
1609, 1579, 1558, 1509, 1418, 1304, 1242, 1186, 1160,
1090, 1015, 927, 869, 775, 723, 686 cmꢁ1 1H NMR
.
3.3.3. 3-Bromo-6-(pyridin-3-yloxy)pyridine (8). 3-
Bromo-6-(pyridin-3-yloxy)pyridine was prepared using
pyridin-3-ol and 2,5-dibromopyridine according to general
procedure 2 as a beige solid (66%). Mp<50 ꢀC. IR (KBr):
(400 MHz, CDCl3): d¼8.36 (d, J¼2.4 Hz, 1H), 8.29 (d,
J¼2.0 Hz, 1H), 7.53 (t, J¼2.0, 2.4 Hz, 1H), 7.40 (t,
J¼8.0 Hz, 1H), 6.13 (d, J¼8.0 Hz, 1H), 6.08 (d, J¼8.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): d¼160.8, 156.0, 151.0,
143.5, 141.6, 140.7, 131.2, 128.5, 100.4, 96.8. Anal. Calcd
for C10H6BrClN2O: C, 42.07; H, 2.12; N, 9.81. Found: C,
42.54; H, 2.02; N, 9.37.
1575, 1455, 1367, 1268, 1091, 1004, 881, 707, 679 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d¼8.41 (d, J¼2.4 Hz, 1H),
8.36 (dd, J¼4.6, 1.4 Hz, 1H), 8.07 (d, J¼2.4 Hz, 1H), 7.69
(dd, J¼8.6, 2.4 Hz, 1H), 7.40 (part A of system AB,
3JAB¼8.3 Hz, J¼2.4, 1.4 Hz, 1H), 7.22 (part B of system
3.3.8. 2-Chloro-4-(pyridin-4-yloxy)pyridine (13). 2-
Chloro-4-(pyridin-4-yloxy)pyridine was prepared using 2-
chloropyridin-4-ol and 4-iodopyridine according to general
procedure 2 as a beige solid (63%). Mp 75 ꢀC. IR (KBr):
1571, 1430, 1429, 1373, 1257, 1098, 1021, 1009, 929,
3
AB, JAB¼8.3 Hz, J¼4.6 Hz, 1H), 6.81 (d, J¼8.6 Hz, 1H).
13C NMR (100 MHz, CDCl3): d¼161.3, 149.9, 147.7,
145.6, 143.2, 141.9, 128.3, 123.6, 113.9, 112.9. Anal. Calcd
for C10H7BrN2O: C, 47.84; H, 2.81; N, 11.16. Found: C,
47.37; H, 2.88; N, 11.42.
1
890, 823, 653 cmꢁ1. H NMR (400 MHz, CDCl3): d¼8.73
(d, J¼5.5 Hz, 2H), 8.12 (d, J¼5.5 Hz, 1H), 6.79 (d,
J¼5.5 Hz, 2H), 6.70 (dd, J¼5.5, 2.7 Hz, 1H), 6.65 (d,
J¼2.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d¼166.4,
162.8, 153.2, 152.1 (2C), 150.8, 116.3, 114.8 (2C), 111.4.
Anal. Calcd for C10H7ClN2O: C, 58.13; H, 3.41; N, 13.56.
Found: C, 58.07; H, 3.34; N, 13.45.
3.3.4. 3-Bromo-6-(5-chloropyridin-3-yloxy)pyridine (9).
3-Bromo-6-(5-chloropyridin-3-yloxy)pyridine was prepared
using 5-chloropyridin-3-ol and 2,5-dibromopyridine accord-
ing to general procedure 2 as a white solid (72%). Mp 80 ꢀC.
IR (KBr): 1574, 1458, 1366, 1272, 1094, 1022, 921, 888,
1
826, 679 cmꢁ1. H NMR (400 MHz, CDCl3): d¼8.42 (d,
J¼1.9 Hz, 1H), 8.39 (d, J¼2.4 Hz, 1H), 8.19 (d, J¼2.7 Hz,
1H), 7.84 (dd, J¼8.7, 2.7 Hz, 1H), 7.57 (t, J¼1.9, 2.4 Hz,
1H), 6.94 (d, J¼8.7 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d¼161.1, 150.1, 147.6, 144.5, 142.9, 141.7,
130.8, 129.2, 114.3, 113.8. Anal. Calcd for C10H6BrClN2O:
C, 42.07; H, 2.12; N, 9.81. Found: C, 41.73; H, 2.02; N, 9.47.
3.4. General procedure 2 for the synthesis of dioxyter-
pyridines using nucleophilic substitution (14 and 15)
3.4.1. 3,5-Di-(pyridin-3-yloxy)pyridine (14). 3,5-Di-(pyri-
din-3-yloxy)pyridine was prepared using pyridin-3-ol
(2 equiv) and 3,5-dibromopyridine (0.55 equiv) according
to general procedure 2 as a brown oil (69%). IR (KBr):
3044, 1565, 1475, 1424, 1305, 1253, 1209, 1021, 903,
3.3.5. 3-Bromo-6-(6-chloropyridin-3-yloxy)pyridine (10).
3-Bromo-6-(6-chloropyridin-3-yloxy)pyridine was prepared
using 6-chloropyridin-3-ol and 2,5-dibromopyridine accord-
ing to general procedure 2 as a white solid (63%). Mp 80 ꢀC.
1
708 cmꢁ1. H NMR (400 MHz, CDCl3): d¼8.37–8.36 (m,
6H), 8.24 (t, J¼2.2 Hz, 1H), 7.30–7.23 (m, 4H). 13C NMR
(100 MHz, CDCl3): d¼156.6, 152.6, 149.5, 135.0, 134.8,

A. S. Voisin et al. / Tetrahedron 62 (2006) 6000–6005
6005
5. Vernin, G.; Dou, H. J. M.; Metzger, J. C. R. Acad. Sci. Ser. C
1975, 280, 385–388.
126.7, 122.3, 111.5. Anal. Calcd for C15H11N3O2: C, 67.92;
H, 4.18; N, 15.84. Found: C, 68.23; H, 4.08; N, 15.86.
6. Eggers, L.; Grahn, W.; Leuttke, W.; Knieriem, B.; Jones, P. G.;
Chrapkowski, A. Angew. Chem. 1994, 106, 903–906.
7. Kamenecka, T. M.; Vernier, J.-M.; Bonnefous, C.; Govek, S. P.;
Hutchinson, J. H. WO2005/021529 A1, 2005.
8. Schmidt, A.; Mordhorst, T. Synthesis 2005, 5, 781–786.
9. Johnson, R. M. J. Chem. Soc. B 1966, 1058–1061.
10. Eggers, L.; Grahn, W. Synthesis 1996, 6, 763–768.
11. Bromidge, S. M.; Dabbs, S.; Davies, S.; Duckworth, D. M.;
Forbes, I. T.; Jones, G. E.; Jones, J.; King, F. D.; Saunders,
D. V.; Blackburn, T. P.; Holland, V.; Kennett, G. A.; Lightowler,
S.; Middlemiss, D. N.; Riley, G. J.; Trail, B.; Wood, M. D.
Bioorg. Med. Chem. Lett. 2000, 10, 1863–1866.
12. (a) Dull, G. M.; Schmitt, J. D.; Bhatti, B. S.; Miller, C. H. U.S.
Patent 20,020,058,652 A1, 2002; (b) Dull, G. M.; Schmitt,
J. D.; Bhatti, B. S.; Miller, C. H. WO2002/088114 A2, 2002.
13. Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013–9016.
14. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941–2944; (b) Chan, D. M. T.; Monaco,
K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933–2936.
3.4.2. 2,6-Di-(5-chloropyridin-3-yloxy)pyridine (15). 2,6-
Di-(5-chloropyridin-3-yloxy)pyridine was prepared using
5-chloropyridin-3-ol (2 equiv) and 2,6-dibromopyridine
(0.55 equiv) according to general procedure 2 as a yellow
solid (26%). Mp 62 ꢀC. IR (KBr): 1572, 1469, 1427, 1418,
1287, 1243, 1189, 1021, 912, 687 cmꢁ1
.
1H NMR
(400 MHz, CDCl3): d¼8.18 (d, J¼1.9 Hz, 2H), 8.10 (d,
J¼2.0 Hz, 2H), 7.61 (t, J¼7.8 Hz, 1H), 7.24 (t, J¼2.0 Hz,
2H), 7.24 (t, J¼7.8 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d¼177.6, 154.3, 150.9, 144.8, 134.8, 132.4,
120.4, 111.3. Anal. Calcd for C15H9Cl2N3O2: C, 53.92; H,
2.71; N, 12.57. Found: C, 53.65; H, 2.11; N, 12.13.
Acknowledgements
Nicolas Saettel was gratefully acknowledged for com-
putational hand. The authors thank Laboratoires Servier,
´
Conseil Regional de Basse-Normandie and FEDER (Fonds
Europeens de Developpement Economique Regional) for
´
´
´
15. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill,
K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674–676.
16. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav,
P. K. Tetrahedron Lett. 2001, 42, 3415–3418.
their financial support.
References and notes
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