Synthesis of bisfunctionalized-oligopyridines bearing an ester group

Article abstract of DOI:10.1016/S0040-4039(01)01195-9

The synthesis of 2,2′-bipyridine, 1,10-phenantroline and 2,2′:6′,2″-terpyridine substituted by an ethylester function is described. The 5- and 6-methyl-2,2′-bipyridines bearing an ethylester group on the 6′ position as well as the ethyl 6,6″-dimethyl-2,2′:6′,2″-terpyridine-4′- carboxylate moiety were synthesized via a Stille cross-coupling reaction, starting from bromo-picoline building blocks. A radical bromination of the methyl-oligopyridine gave selectively the corresponding benzylic bromide derivatives in fair yield.

Full text of DOI:10.1016/S0040-4039(01)01195-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6113–6115
Synthesis of bisfunctionalized-oligopyridines bearing
an ester group
Gilles Ulrich,* S e´ bastien Bedel, Claude Picard and Pierre Tisn e` s
Laboratoire de Synth e` se et Physico-chimie de Mol e´ cules d’Int e´ r eˆ t Biologique, UMR 5068, Universit e´ Paul Sabatier,
118 rte de Narbonne 31062 Cedex 4, Toulouse, France
Received 4 May 2001; accepted 4 July 2001
Abstract—The synthesis of 2,2%-bipyridine, 1,10-phenantroline and 2,2%:6%,2%%-terpyridine substituted by an ethylester function is
described. The 5- and 6-methyl-2,2%-bipyridines bearing an ethylester group on the 6% position as well as the ethyl 6,6%%-dimethyl-
2,2%:6%,2%%-terpyridine-4%-carboxylate moiety were synthesized via a Stille cross-coupling reaction, starting from bromo-picoline
building blocks. A radical bromination of the methyl-oligopyridine gave selectively the corresponding benzylic bromide derivatives
in fair yield. © 2001 Elsevier Science Ltd. All rights reserved.
yield of the corresponding Eu(III) complexes, could be
obtained with bipyridine sub-units bearing a carboxylic
group on the 6 position of the 2,2%-bipyridine. In addi-
tion, the association of three of these new tritopic
sub-units on a molecular platform, led to a highly
favorable nine-coordination site cavity for lan-
The quest for highly long-lived luminescence lanthanide
complexes has generated a great deal of interest among
chemists since the middle of the 1980s. The 2,2%-
1
bipyridine chelate has been rapidly found to be one of
the most suitable chromophores for the relayed excita-
tion of the metallic center. Unfortunately, the
bipyridine unit is a poor complexant for lanthanide(III)
ions and does not lead to stable and soluble complexes
in aqueous solution. Association of a bipyridine core
with an anionic functionality forms a tridentate ligand,
which should give an efficient coordination of lan-
thanide salts. It has been recently demonstrated by
4
thanide(III) cations. These authors were able to obtain
this coordination motif by a very elegant palladium-cat-
alyzed carbonylation of the corresponding bromo-
bipyridine sub-unit, built via a classical Kr o¨ hnke
3,5
synthesis.
We now wish to present an alternative way to obtain, in
good yields, oligopyridine ligands substituted both by
an ester group and a benzylic bromide function allow-
2–4
Ziessel and co-workers, that a very efficient coordi-
nation ability, as well as high luminescence quantum
a
b
R
R
R
N
NH2
N
Br
R = 6-Me : 1a
-Me : 1b
N
SnBu3
R = 6-Me : 2a
5-Me : 2b
R
N
R = 6-Me : 4a
d
5
5
-Me : 4b
c
N
e
COOEt
R = 6-BrCH : 5a
2
5
-BrCH : 5b
2
EtOOC
N
Br
3
Scheme 1. (a) HBr, NaNO , Br , −20°C. (b) i. 1 equiv. 1, 1 equiv. n-BuLi, THF, −78°C; ii. Bu SnCl. (c) i. 1a, CrO , H SO ; ii.
2
2
3
3
2
4
EtOH, H SO cat. (d) 1 equiv. 2, 1 equiv. 3, Pd(PPh ) , toluene, reflux, 2 days (70% for 4a and 83% for 4b). (e) NBS, AIBN,
2
4
3 4
benzene, hw, reflux, 3 h (55% for 5a and 56% for 5b) or Br , benzene/H O, hw, reflux, 30 min (73% for 5b).
2
2
Keywords: Stille cross-coupling; organotin pyridines; bipyridine; terpyridine; radical bromination.
*
Corresponding author. Tel.: 33 (0) 561556288; fax: 33 (0) 561556011; e-mail: ulrich@ramses.ups-tlse.fr
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01195-9

6
114
G. Ulrich et al. / Tetrahedron Letters 42 (2001) 6113–6115
ing these molecules to readily react with a large variety
of nucleophilic compounds.
obtained by oxidation of 1a with chromium trioxide in
concentrated sulfuric acid, and the corresponding car-
boxylic acid was further esterified with ethanol under
1
1
The main difficulty for the synthesis of these ligands is
related to their unsymmetrical features. To solve this
problem, we decided to use a Stille cross-coupling
catalytic acid conditions to give 3 (Scheme 1). The
bipyridine core, via Stille cross-coupling, was obtained
by reacting one equivalent of organotin–picoline (2a or
2b) with one equivalent of ethyl 2-bromo-pyridine-6-
carboxylate 3 using a catalytic amount of [Pd(PPh ) ]
6
reaction between bromo-pyridine ester and organotin
picoline units, followed by a radical bromination.
3
4
(
10% molar) in refluxing toluene during two days
The methodology used for the preparation of organotin
derivatives and their subsequent coupling reaction via
palladium(0)-catalyzed cross-coupling was inspired
from previous studies on the synthesis of 5,5%%-bis-func-
(Scheme 1). The two ethyl bipyridine-6-carboxylate 4a
†
and 4b were obtained in respective yields of 70 and
83%.
7
tionalized-2,2%:6%,2%%-terpyridines and pyridine-based
Using the same catalytic conditions, we were able to
prepare a polyfunctional terpyridine. By reacting one
equivalent of ethyl 2,6-dibromo-pyridine-4-carboxylate
8
oligotridentate ligands.
1
2
We started these multi-step syntheses (Scheme 1) by
6
(Scheme 2) and two equivalents of 2a, we synthe-
9
‡
reacting 2-bromo-6-methyl-pyridine (1a) or 2-bromo-5-
sized the symmetrical 6,6%%-dimethyl-terpyridine 7,
which possesses an ester function at the central 4%
carbon atom.
1
0
methyl-pyridine (1b)
with n-BuLi. The resulting
organolithium compounds gave the corresponding
organotin derivatives (2a and 2b) by reaction with
8
tri-n-butyl-tin chloride with a good yield (96 and 82%,
A controlled oxidation of neocuproine with selenium
dioxide (1.5 equiv.) in pyridine, followed by an acid
catalyzed esterification, led to the rigid analog of the
respectively).
13
The halogen pyridine–ester building block 3 was
bipyridine-6-carboxylate derivatives (Scheme 3).
COOH
COOEt
a
COOEt
HO
N
OH
Br
N
Br
b
R =
CH3 : 7
6
R
N
N
R
N
c
R = BrCH : 8
2
N
SnBu3
2
a
Scheme 2. (a) i. POBr , 3 h, 180°C; ii. EtOH, H SO cat. (b) 2 equiv. 2a, 1 equiv. 6, Pd(PPh ) , toluene, reflux, 2 days (44%). (c)
3
2
4
3 4
NBS, AlBN, benzene, hw, reflux, 3 h, 27%.
R = CH : 9
a
3
b
N
N
N
N
R
COOEt
R = BrCH : 10
2
Scheme 3. (a) i. SeO , 1.5 equiv. pyridine, 55°C; ii. EtOH, H SO , reflux. (b) NBS, AlBN, hw, reflux, benzene, 3 h (17%).
2
2
4
†
1
3
[
3
Ethyl 5%-methyl-2,2%-bipyridine-6-carboxylate (4b): mp: 84–85°C; H NMR (200 MHz, CDCl ): l=1.46 (t, 3H, J=7.1 Hz), 2.39 (s, 3H),
3
H), 4.49 (q, 2H, 3J=7.1 Hz), 7.64 (ddd, 1H, J=8.1 Hz J=2.1 Hz J=0.7 Hz), 7.92 (t, 1H, J=7.8 Hz), 8.09 (dd, 1H, J=7.7 Hz 4J=1.2
Hz), 8.46 (m, 2H), 8.56 (dd, 1H, J 7.9 Hz J=1.2 Hz). C NMR (50 MHz, CDCl ): l=14.2 (CH ), 18.3 (CH ), 61.7 (CH O), 121.0 (CH), 123.7
3
4
5
3
3
3
4
13
3
3
3
2
(
(
[
CH), 124.5 (CH), 133.8 (Cq), 137.4 (CH), 137.6 (CH), 147.6 (Cq), 149.5 (CH), 152.6 (Cq), 156.4 (Cq), 165.2 (CꢀO). IR (KBr pellets): w=1738
−1 + + +
w
CꢀO), 1588, 1556 cm . MS (ES ): m/z=243.17 (M+H ), 265.15 (M+Na )].
‡
Ethyl-6,6%%-dimethyl-(2,2%:6%,2%-terpyridine)-4%-carboxylate: mp: 134–135°C; H NMR (250 MHz, CDCl ): l=1.47 (t, 3H, 3J=7.1 Hz), 2.67 (s,
1
3
3
3
3
3
13
6
H), 4.50 (q, 2H, J=7.1 Hz), 7.21 (d, 2H, J=7.6 Hz), 7.75 (t, 2H, J=7.7 Hz), 8.40 (d, 2H, J=7.8 Hz), 8.97 (s, 2H). C NMR (62.5 MHz,
CDCl ): l=14.4 (CH ), 24.6 (CH ), 61.7 (CH O), 116.3 (CH), 120.1 (CH), 123.6 (CH), 137.0 (CH), 139.7 (Cq), 154.9 (Cq), 156.8 (Cq), 158.1
3
3
3
2
−
1
+
+
(
5
Cq), 165.7 (CꢀO). IR (KBr): w=1717 (wCꢀO), 1560 cm . MS (FAB , mNBA): m/z=334 (M+H ). Anal. calcd for C20H19N O : C, 72.05; H,
.74; N, 12.60; found C, 71.86; H, 5.65; N, 12.39].
3 2

G. Ulrich et al. / Tetrahedron Letters 42 (2001) 6113–6115
6115
Functionalization of the methyl groups of our oligopy-
References
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1
4
ity of the radical bromination we used NBS, benzene
as solvent and a catalytic amount of AIBN, at reflux
and under irradiation (halogen-lamp 150 W). Benzene
appeared to a better solvent for the mono-bromination
of the benzylic methyl group than the classical CCl4
solvent. Purification of the resulting benzylic bromides
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§
is thereby facilitated. In the case of 5b, a high yield for
the radical bromination reaction was obtained by the
use of bromine and a biphasic mixture of water and
benzene, under irradiation. This method appeared to be
very selective; a small amount of a-dibromomethyl
derivative is formed (less than 5%). Improvement of the
synthesis of bromomethyl oligopyridine derivatives is
1
5
currently under investigation.
In conclusion, a convenient synthesis of NNCOO–tri-
dentate ligand precursors was developed. These com-
pounds bearing benzylic bromide function on the
opposite side of the molecule could be easily attached
to various molecular platforms, such as macrocyclic
polyamines, calixarenes or sugars, to create specific
coordination cavities for target metallic ions.
9. Adams, R.; Miyano, S. J. Am. Chem. Soc. 1954, 76,
3168–3171.
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Acknowledgements
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1
1
3. Wang, G.; Bergstrom, D. E. Synlett 1992, 422–424.
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The authors are grateful to the CNRS for its financial
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preparative HPLC facilities.
15. Bedel, S.; Ulrich, G.; Picard, C. Results to be published.
.
§
[
1
Ethyl 5%-bromomethyl-2,2%-bipyridine-6-carboxylate (5b): mp=106–
1
3
07°C. H NMR (200 MHz, CDCl ): l=1.46 (t, 3H, J=7.1 Hz),
3
.48 (q, 2H, 3J=7.1 Hz), 4.53 (s, 2H), 7.86 (dd, 1H, J=8.2 Hz
3
4
4
3
3
J=2.3 Hz), 7.94 (t, 1H, J=7.8 Hz), 8.12 (dd, 1H, J=7.7 Hz
4
4
13
J=1.2 Hz), 8.56 (m, 2H), 8.66 (d, 1H, J=2.3 Hz). C NMR (50
MHz, CDCl ): l=14.4 (CH ), 29.6 (CH Br), 61.9 (CH O), 121.7
3
3
2
2
(CH), 124.3 (CH), 125.2 (CH), 134.2 (Cq), 137.7 (CH), 137.9 (CH),
1
47.9 (Cq), 149.3 (CH), 155.2 (Cq), 155.8 (Cq), 136.3 (CꢀO).
−
1
−1
+
IR(KBr pellets, cm ): w=1738 (w ), 1589, 1557 cm . MS (FAB ,
mNBA): m/z=321/323 (M+H ), 343/345 (M+Na ). Anal. calcd for
CꢀO
+
+
C14H13BrN O : C, 52.36; H, 4.08; N, 8.72; found C, 52.18; H, 4.03;
2
2
N, 8.62].