Carboxylate derivatives of oligopyridines bearing bromomethyl groups

Article abstract of DOI:10.1055/s-2002-33347

The synthesis of various oligopyridines possessing a carboxylate and at least one bromoethyl group is reported. The bipyridine and terpyridine cores were constructed in good yields via a Stille cross-coupling, starting from bromopicolines and ethyl bromopicolinate. The bromomethyl function was obtained by free radical bromination using NBS in benzene or bromine in benzene/water biphasic mixture. The building of two model podands by nucleophilic displacement of benzylic bromine by an amine or by a phenol group is described.

Full text of DOI:10.1055/s-2002-33347

1564
PAPER
Carboxylate Derivatives of Oligopyridines Bearing Bromomethyl Groups
O
ligopyridine
é
s Bearing
B
b
r
omomethyl
a
G
roups stien Bedel, Gilles Ulrich,* Claude Picard, Pierre Tisnès
Laboratoire de Synthèse et Physico-chimie de Molécules d'Intérêt Biologique, UMR 5068, Université Paul Sabatier, 118 rte de Narbonne
31062 Cedex 4, Toulouse, France
Fax +33(5)61556011; E-mail: ulrich@chimie.ups-tlse.fr
Received 2 February 2002; revised 29 May 2002
For these reasons, we have used a multicombination syn-
Abstract: The synthesis of various oligopyridines possessing a car-
thesis based on Stille coupling of various functional pyri-
boxylate and at least one bromoethyl group is reported. The bipyri-
dine moieties, in order to obtain polytopic oligopyridines
bearing an ester group. We opted for this function which
dine and terpyridine cores were constructed in good yields via a
Stille cross-coupling, starting from bromopicolines and ethyl bro-
mopicolinate. The bromomethyl function was obtained by free rad- offers two possibilities: 1) to be the precursor of carboxy-
late to form tritopic N,N,COO– ligands when in position
ical bromination using NBS in benzene or bromine in benzene/
water biphasic mixture. The building of two model podands by nu-
to the pyridine nitrogen, and 2) to be a grafting function
cleophilic displacement of benzylic bromine by an amine or by a
for a spacer group that could be linked to a biomolecule.
phenol group is described.
For this purpose, an ester function on para position from
Key words: Stille reaction, bipyridines, terpyridines, carboxylate,
halogenation
one pyridine nitrogen, of a dibromomethylbipyridine or
terpyridine could lead to interesting macrocycles.8
Our synthetic strategy was based on the use of Pd(0)
cross-coupling of various pyridines building blocks. This
In the last two decades, significant efforts have been made
methodology, based on Stille method,9 was inspired from
in the development of efficient luminescent lanthanide
previous works on the synthesis of 5,5 -bis-functional-
complexes with the aim of labeling biomolecules for time-
ized-2,2 :6 ,2 -terpyridines,10–12 pyridine-based oligotri-
resolved fluoroimmunoassay.1 Many strategies were de-
dentate ligands13 and carboxylate derivatives of
veloped to design lanthanide systems that combine high
oligopyridines.14 We opted for the use of organotin com-
stability in coordinating solvent and high long life-time
pounds, despite their toxicity and the purification prob-
luminescence properties.2 Indeed, the organic system
lems induced by the resulting tributyltin halides,
must associate strong coordination functions suitable for
because we were confident to build the bipyridine or
Ln3+ such as carboxylates, and chromophores whose func-
terpyridine core by following the described methods.14,15
tion is to sensitize the metal emission through an energy
The coupling of organozinc derivatives, by the Negishi
transfer process. For the chromophoric part, most of the
method,16–18 seems to be a good alternative way for the
criteria can be filled by bipyridine or terpyridine subunits,
building of a bipyridine core. But in our case, the de-
which possess appropriate excited states, high absorption
scribed method for oligopyridine19,20 generated few or
and coordination ability. Many lanthanide receptors in-
corporating these heterocycles have shown very efficient
none of the desired compounds.
The starting buildings blocks were obtained using litera-
ture procedure. The stannylated compounds were made by
lithiation of 2-bromo-6-methyl-pyridine (1a)21 or 2-bro-
mo-5-methylpyridine (1b),22 and the organolithium com-
pound thus obtained reacted with tributyltin chloride13 to
generate the organotin derivatives in good yields (96 and
82%, respectively) (Scheme 1, Table). The pyridine ester
building block 2 was obtained by oxidation of 2-bromo-6-
methylpyridine (1a) with chromium trioxide in concen-
trated sulfuric acid, and the corresponding carboxylic acid
was further esterified with ethanol under acid-catalyzed
conditions.23 The trifunctional pyridine 5 was obtained in
two steps from the commercial citrazinic acid, which was
first reacted with POBr3 at 180 °C in a sealed tube24, and
the 2,6-dibromopyridine-4-carboxylic acid thus obtained
was esterified in ethanol under acid-catalyzed condi-
tions.14
absorption – ligand to metal energy transfer – metal cen-
tered emission process (A-ET-E).3–5 To obtain water sta-
ble lanthanide complexes, standard oligopyridines must
be associated with ionizable groups. One solution was
brought by Ziessel and co-workers with the building of a
bipyridine bearing a carboxylate group on the ortho posi-
tion from one nitrogen,6 forming a tridentate ligand
N,N,COO–. The association of three of these tridentate
ligands create an ideal nonadentate cavity for lanthanide
(III) ions,7 leading to highly stable and fluorescent Eu(III)
and Tb(III) complexes.
We simultaneously developed another synthetic way to
obtain bipyridine carboxylate structures. In our case, the
final structure associates a bromomethyl group to the oli-
gopyridine carboxylate, and thus can be directly attached
to a molecular platform, to create podands.
The coupling of pyridine blocks 1 and 2 with Pd(PPh3)4 as
catalyst, in refluxing degassed toluene during two days,
generated the methyl-2,2 -bipyridine-6 -esters 3 in fair
yields (Scheme 1). To produce the useful corresponding
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1564,1570,ftx,en;Z02802SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Carboxylate Derivatives of Oligopyridines Bearing Bromomethyl Groups
1565
i. nBuLi, THF, -78 °C
ii. Bu3SnCl
R
R
Br2, C6H6/H2O
N
SnBu3
N
Br
or NBS, AIBN, C6H6
Pd(PPh3)4,
1a : 6-Me
1b : 5-Me
N
H3C
hν, reflux
Tol, 110 °C, 48h
N
BrH2C
i. CrO3, H2SO4
ii. EtOH, H2SO4
N
70-83%
72-55%
N
COOEt
COOEt
3a : 6-Me
3b : 5-Me
4a : 6-BrCH2
4b : 5-BrCH2
Br
N
COOEt
2
Scheme 1
bromomethyl bipyridine derivatives, we opted for a free- 10 seems more convenient than the synthesis described,28
radical bromination of the benzylic methyl groups. The starting from 6,6 -dimethylbipyridine.
high yielding method developed by Fraser et al.18 to ob-
In order to validate our concept for the construction of
tain benzylic bromides on bipyridine could not be used
nonadentate podands, we choose two model molecular
due to the presence of the ester function, incompatible
platforms having three nucleophilic functions, where
with the generation of a methyl anion. In order to improve
three tridentate N,N,COO– arms could be grafted. These
the free radical method, which is not very high yielding
two structures can be derivatized to be linked to a biomol-
and selective in its classical conditions (NBS, CCl4), we
ecule, if the preliminary results on the fluorescent proper-
were inspired by the studies of Vögtle et al. on the solvent
ties of their Eu(III) or Tb(III) complexes are encouraging.
effect of the selectivity of the reaction.25,26 We developed
The first model is a cyclic polyamine, a mono-functional-
a short study on picoline model compounds in order to
find the best couple of solvent/bromine donors which
could raise the yield of the synthesis and the ratio of bro-
ized cyclen 11.29 The three secondary amine groups were
alkylated with 3 equivalents of 4b using Hünig’s base in
DMF at room temperature to give 12a in fair yield (51%)
involving a convenient purification step (Scheme 3, Ta-
ble). The use of alkali cation bases such as K2CO3 leads to
purification problems, probaly due to alkali metal com-
plexation.
momethyl/dibromomethyl derivatives.27 The most appro-
priate solvent for these pyridine based compounds
appeared to be benzene. Concerning the bromine donor,
we had relatively good results with the classical NBS
(with AIBN as initiator) in refluxing benzene and under
irradiation with a 150 W halogen lamp, during 3 hours.
The yields of the brominated products 3a and 3b were 55
and 56%, respectively. A better result was obtained by
using a biphasic refluxing mixture of benzene and water,
under irradiation, and with Br2 as bromine donor. This
new method is really convenient due to its rapidity (15–30
min), its selectivity, and the high yield (72%), but could
only be performed with bipyridines bearing a benzylic
methyl on the meta position from the pyridine nitrogen.
COOEt
COOEt
R
N
N
R
Pd(PPh3)4,
Tol, 110 °C, 48h
N
Br
N
Br
6 : R = CH3
44%
5
NBS, AIBN, Benzene
hν, reflux
26 %
The oligopyridines designed for the construction of mac-
rocycles were obtained by coupling of the dibromopyri-
dine 5 using the standard Pd(0) catalytic conditions
(Scheme 2, Table) with two equivalents of organotin
compounds 1a for the construction of the terpyridine 6 in
55% yield and one equivalent of 1a to obtain ethyl 6-bro-
mo-6 -methyl-2,2 -bipyridine-4-carboxylate (8) in 60%
yield. The bipyridine 8 was converted in 80% yield to eth-
yl 6,6 -dimethyl-2,2 -bipyridine-4-carboxylate (9) by a
Negishi type coupling using methylzinc chloride,19 gener-
ated in situ from methyllithium and zinc chloride, and
Pd(PPh3)4 as catalyst in refluxing THF. The two dimethyl
compounds 6 and 9 were brominated by free radical pro-
cedure using NBS in refluxing benzene under irradiation
to give the two dibromomethyl derivatives 7 and 10 in 26
and 23% yields, respectively. Our three step synthesis for
+ 2eq 1a
7 : R = CH2Br
R2
EtOOC
Pd(PPh3)4,
Tol, 110 °C, 48h
N
+ 1eq 1a
N
60 %
8 : R1 = Br; R2 = CH3
R1
MeZnCl, THF, Pd(PPh3)4,
reflux, 24h
80%
9 : R1 = R2 = CH3
NBS, AIBN, Benzene
hν, reflux
23%
10 : R1 = R2 = CH2Br
Scheme 2
Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York

1566
S. Bedel et al.
PAPER
Table Selected Spectroscopic Data for Precursors and Polypyridine Ligands
Product
Yield (%)
MS m/z
IR (cm–1)a
UV/Visb
(nm)
1H NMRc
BpyCH2X
13C NMRc
C=O
BpyCH2X
C=O
[ (M–1cm–1)]
(
*, py)
3a
70
83
55
72
56
28
60
80
23
51
51
243d
1742
1738
1713
1738
1717
1727
1724
1724
1725
1738
1737
287 (15200)
286 (17700)
287 (13100)
290 (21000)
285 (18900)
288 (18200)
293 (9700)
2.61
165.4
165.2
165.3
165.3
165.7
165.6
164.0
165.6
165.0
165.4
165.3
24.7
3b
243d
2.39
18.3
4a
321/323d
321/323e
334e
4.62
34.1
4b
4.53
36.3
6
2.67
24.6
7
490/492/494e
321/323e
257e
4.52
34.1
8
2.65
24.6
9
294 (10900)
290 (11400)
286 (50400)
288 (42800)
2.58/2.63
4.66/4.67
3.42/3.45
5.09
24.6
10
413/415/417e
983e
33.5/33.9
57.1/57.4
67.6
12a
14a
847e
a KBr pellets.
b Measured in CH2Cl2 for 7, in MeOH for the rest.
c Recorded in CDCl3.
d ES+: [M + H]+.
e FAB+, mNBA: [M + H]+.
the described method.7 Lanthanides salts complexation
studies of these triacids are under progress.
O
OR
The synthetic protocol described here provide access to
various symmetrical or unsymmetrical oligopyridines
bearing different chemical functions. We were able to ob-
tain via Stille cross-coupling two bipyridines bearing a
carboxylate, known to be an adapted chromophore for
lanthanide complexation. Moreover, the association of a
bromomethyl function on these molecules allows their
fixation on various molecular platform. The bipyridine
and the terpyridine derivatives bearing two bromomethyl
functions could be of great interest in the construction of
macrocyclic structures.
N
N
Hünig's base, DMF, RT
N
HN
HN
N
3eq 4b
N
51 %
N
NH
OR
N
N
O
N
N
12a R = Et
N
NaOH,
MeOH, H2O
80 %
O
Reactions were carried out in THF dried over sodium and ben-
zophenone, MeCN was dried over P2O5 and distilled before use.
Column chromatography was carried out on silica gel (Merck, 60–
200 m, porosity 60Å) and on alumina (Macherey-Nagel, activity
IV, 50–200 m). Melting points were determined on a Electrother-
mal IA9200 apparatus. 1H and 13C NMR spectra were recorded on
Bruker AC200 or AC250 spectrometers; chemicals shifts are given
in ppm according to the solvent peak. IR spectra were recorded on
a Perkin Elmer FT-IR 1725X spectrometer. UV spectra were re-
corded on a Hewlet Packard 8453 UV/Vis spectrometer at 23 °C.
Fast Atom Bombardment (FAB) and Electrospray (ES) mass spec-
tra were obtained on a Nermag R10-10H spectrometer and a Perkin
Elmer SCIEX API 100 spectrometer, respectively.
12b R = H
OR
Scheme 3
As a second model, we chose a triphenol, the phlorogluci-
nol, which possess a rich chemistry and can be easily de-
rivatized.30 In order to have a complete trialkylation, we
had to use cesium carbonate in DMF with 3 equivalents of
4b (Scheme 4). Under this condition, the reaction is com-
plete in overnight at room temperature, with a yield of
51%. These two triesters 12a and 14a can be easily sapon-
ified in the corresponding triacids 12b an 14b following
N,N-Diisopropylethylamine (Avocado), NBS (Lancaster), AIBN
(Janssen), Br2 (Aldrich), MeLi (1 M in THF–cumene 10:90) (Ald-
Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Carboxylate Derivatives of Oligopyridines Bearing Bromomethyl Groups
1567
Ethyl 5 -Methyl-6-(2,2 -bipyridine)carboxylate (3b)
OH
Cs2CO3, DMF, 20 °C, 12h
From 1b (4 g, 10.4 mmol), 2 (2 g, 8.7 mmol), and Pd(PPh3)4 (0.5 g,
0.44 mmol) in toluene (100 mL). Column chromatography (silica
gel, eluent: CH2Cl2–MeOH with a gradient of MeOH 0–1%) gave
1.74 g (83%) of white crystals; mp 84–85 °C; Rf 0.15 (silica gel,
CH2Cl2–MeOH, 99:1).
COOR
3eq 4b
N
N
51 %
HO
OH
IR (KBr): 1738 (s, C=O), 1588 (m), 1556 cm–1 (m).
13
O
O
1H NMR (200 MHz, CDCl3): = 1.46 (t, 3 H, 3J = 7.1 Hz,
OCH2CH3), 2.39 (s, 3 H, CH3), 4.49 (q, 2 H, 3J = 7.1 Hz,
OCH2CH3), 7.64 (ddd, 1 H, 3J = 8.1, 4J = 2.1, 5J = 0.7 Hz), 7.92 (t,
1 H, 3J = 7.8 Hz), 8.09 (dd, 1 H, 3J = 7.7 Hz 4J = 1.2 Hz), 8.46 (m,
2 H), 8.56 (dd, 1 H, 3J = 7.9, 4J = 1.2 Hz).
13C{1H} JMOD NMR (50 MHz, CDCl3): = 14.2 (CH3), 18.3
(CH3), 61.7 (CH2O), 121.0 (CH), 123.7 (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 (C=O).
N
ROOC
N
N
O
14a R = Et
N
NaOH,
MeOH, H2O
90%
COOR
14b R = H
MS (ES+, MeCN): m/z (%) = 243 (100, [M + H+]), 265 (88, [M +
Scheme 4
Na+]).
UV/Vis (MeOH):
(17700).
( , M–1cm–1) = 248 (13200), 286 nm
rich) were used as received. Cs2CO3 (Aldrich), ZnCl2 (Aldrich)
were flame dried under vacuum prior to use. 1,3,5-Trihydroxyben-
zene (13) (Avocado) was refluxed in toluene using a Dean–Stark
apparatus before use. Tetrakistriphenylphosphinepalladium,31 2-
tributylstannyl-6-methylpyridine (1a),13 2-tributylstannyl-5-meth-
ylpyridine (1b), ethyl 2,6-dibromo-4-pyridinecarboxylate24 (5) and
1-benzyl-1,4,7,10-tetraazacyclododecane (11)29 were prepared ac-
cording to literature procedures. Petroleum ether used refers to the
fraction with bp 45–60 °C.
max
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.24; H, 5.69; N, 11.41.
Ethyl 6,6 -Dimethyl-4 -(2,2 :6 ,2 -terpyridine)carboxylate (6)
From 5 (2 g, 6.4 mmol), 1a (5.4 g, 14 mmol), and Pd(PPh3)4 (0.74
g, 0.64 mmol) in toluene (150 mL). Column chromatography (alu-
mina activity IV, eluent: petroleum ether–CH2Cl2, 1:1) yielded 1.17
g (55%) of a white solid; mp 134–135 °C; Rf 0.1 (silica gel,
CH2Cl2).
Stille Cross-Coupling Reactions;14 General Procedure
A mixture of ethyl bromopyridinecarboxylate 2 or 5 (1 equiv), me-
thyltributylstannylpyridine 1 (1.2 or 2.2 equiv) and Pd(PPh3)4 (0.05
or 0.1 equiv) in degassed toluene (100 mL) was refluxed under N2
for 2 d. The resulting solution was filtered over Celite and evaporat-
ed under reduced pressure. Conc. HCl (100 mL) was added and the
solution was washed with CH2Cl2 (3 50 mL). The aqueous phase
was neutralized with solid NaHCO3 and extracted with CH2Cl2
(3 50mL). The combined organic layers were dried (MgSO4) and
evaporated. The residue was chromatographed to afford the desired
product (Table).
IR (KBr): 1717 (s, C=O), 1560 cm–1 (m).
1H NMR (250 MHz, CDCl3): = 1.47 (t, 3 H, 3J = 7.1 Hz,
OCH2CH3), 2.67 (s, 6 H, CH3), 4.50 (q, 2 H, 3J = 7.1 Hz,
3
3
OCH2CH3), 7.21 (d, 2 H, J = 7.6 Hz), 7.75 (t, 2 H, J = 7.7 Hz),
8.40 (d, 2 H, 3J = 7.8 Hz), 8.97 (s, 2 H).
13C{1H} JMOD NMR (62.5 MHz, CDCl3) : = 14.4 (CH3), 24.6
(CH3), 61.7 (CH2O), 116.3 (CH), 120.1 (CH), 123.6 (CH), 137.0
(CH), 139.7 (Cq), 154.9 (Cq), 156.8 (Cq), 158.1 (Cq), 165.7 (C=O).
MS (FAB+, mNBA): m/z (%) = 334 (100, [M + H+]).
UV/Vis (MeOH): max ( , M–1cm–1) = 285 (18900), 322 nm (9450).
Ethyl 6 -Methyl-6-(2,2 -bipyridine)carboxylate (3a)
From 1a (4 g, 10.4 mmol), 2 (2 g, 8.7 mmol), and Pd(PPh3)4 (0.5 g,
0.44 mmol) in toluene (100 mL). Column chromatography (silica
gel, eluent: CH2Cl2–MeOH with a gradient of MeOH 0–1%) yield-
ed 1.46 g (70%) of white crystals; mp 68–69 °C; Rf 0.15 (silica gel,
CH2Cl2–MeOH, 99:1).
Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60. Found: C,
71.86; H, 5.65; N, 12.39.
Ethyl 6-Bromo-6 -methyl-4-(2,2 -bipyridine)carboxylate (8)
From 5 (1 g, 3.1 mmol), 1a (1.3 g, 3.3 mmol), and Pd(PPh3)4 (0.18
g, 0.17 mmol) in toluene (50 mL). Column chromatography (silica
gel, eluent: CH2Cl2–petroleum ether 5:5→7:3) afforded 0.610 g
(61%) of a white powder; mp 115–116 °C; Rf 0.4 (silica gel,
CH2Cl2).
IR (KBr): 1742 (s, C=O), 1580 (m), 1568 cm–1 (m).
1H NMR (200 MHz, CDCl3): = 1.45 (t, 3 H, 3J = 7.3 Hz,
OCH2CH3), 2.61 (s, 3 H, CH3), 4.48 (q, 2 H, 3J = 7.3 Hz,
3
3
OCH2CH3), 7.17 (d, 1 H, J = 7.6 Hz), 7.70 (t, 1 H, J = 7.8 Hz),
7.91 (t, 1 H, 3J = 7.8 Hz), 8.10 (dd, 1 H, 3J = 7.6, 4J = 1.0 Hz), 8.34
(d, 1 H, 3J = 7.6 Hz), 8.61 (d, 1 H, 3J = 7.9 Hz).
IR (KBr): 1724 (s, C=O), 1581 (m), 1544 cm–1 (s).
1H NMR (250 MHz, CDCl3): = 1.45 (t, 3 H, 3J = 7.1 Hz,
13C{1H} JMOD NMR (50 MHz, CDCl3): = 14.4 (CH3), 24.7
(CH3), 61.9 (CH2O), 118.7 (CH), 123.8 (CH), 124.2 (CH), 124.8
(CH), 137.2 (CH), 137.8 (CH), 147.8 (Cq), 154.6 (Cq), 156.7 (Cq),
157.9 (Cq), 165.4 (C=O).
OCH2CH3), 2.65 (s, 3 H, CH3), 4.46 (q, 2 H, 3J = 7.1 Hz,
3
3
OCH2CH3), 7.22 (d, 1 H, J = 7.7 Hz), 7.71 (t, 1 H, J = 7.8 Hz),
8.01 (d, 1 H, 4J = 1.1 Hz), 8.20 (d, 1 H, 3J = 7.9 Hz), 8.91 (d, 1 H,
4J = 1.1 Hz).
MS (ES+, MeCN): m/z (%) = 243 (100, [M + H+]), 265 (65, [M +
13C{1H} JMOD NMR (62.5 MHz, CDCl3): = 14.3 (CH3), 24.6
(CH3), 62.2 (CH2O), 118.6 (CH), 119.3 (CH), 124.3 (CH), 127.1
(CH), 137.2 (CH), 141.0 (Cq), 142.9 (Cq), 153.1 (Cq), 158.3 (Cq),
158.6 (Cq), 164.0 (C=O).
Na+]).
UV/Vis (MeOH):
(15200).
( , M–1cm–1) = 243 (10250), 287 nm
max
MS (FAB+, mNBA): m/z (%) = 321/323 (100/95, [M + H+]).
UV/Vis (MeOH): max ( , M–1cm–1) = 241 (11750), 287 (9650), 293
(9700), 312 nm (11100).
Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C,
69.42; H, 5.75; N, 11.58.
Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York

1568
S. Bedel et al.
PAPER
Anal. Calcd for C14H13BrN2O2: C, 52.36; H, 4.08; N, 8.72. Found:
C, 52.51; H, 4.00; N, 8.56.
MS (ES+, MeCN): m/z (%) = 321/323 (65/67, [M + H+]), 343/345
(98/100, [M + Na+]).
UV/Vis (MeOH):
(13100).
( , M–1cm–1) = 245 (10600), 287 nm
max
Ethyl 6,6 -Dimethyl-4-(2,2 -bipyridine)carboxylate (9)
ZnCl2 (0.76 g, 5.6 mmol) in THF (10 mL) was cooled at 0 °C. MeLi
(1 M in THF/cumene, 10:90, 2.8 mL, 2.8 mmol) was added, the so-
lution was allowed to warm to r.t. and was stirred for 2 h. Com-
pound 8 (0.61 g, 1.9 mmol) and Pd(PPh3)4 (0.1 g, 0.09 mmol) were
added and the solution was refluxed for 2 d. The mixture was
poured onto an aqueous solution (40 mL) of EDTA (5 g), neutral-
ized with K2CO3, extracted with CH2Cl2 (3 20 mL) and dried
(MgSO4). Column chromatography (silica gel, eluent: CH2Cl2–
MeOH with a gradient of MeOH 0–2%) afforded 0.39 g (80%) of a
white powder; mp 73–74 °C; Rf 0.1 (silica gel, CH2Cl2–MeOH,
99:1).
Anal. Calcd for C14H13BrN2O2: C, 52.36; H, 4.08; N, 8.72. Found.
C, 52.21; H, 4.03; N, 8.61.
Ethyl 5 -Bromomethyl-6-(2,2 -bipyridine)carboxylate (4b)
Method B: From 3b (1.56 g, 6.4 mmol), and Br2 (0.33 mL, 6.4
mmol) in benzene–H2O (1:1, 200 mL). The crude solid was purified
by column chromatography (silica gel, eluent: CH2Cl2–petroleum
ether–MeOH, 80:200→99:0:1) to give 1.48 g (72%) of a white com-
pound; mp 106–107 °C; Rf 0.2 (silica gel, CH2Cl2).
IR (KBr): 1738 (s, C=O), 1589 (m), 1557 cm–1 (m).
IR (KBr): 1724 (s, C=O), 1585 (m), 1571 cm–1 (m).
1H NMR (200 MHz, CDCl3): = 1.46 (t, 3 H, 3J = 7.1 Hz,
3
1H NMR (250MHz, CDCl3): = 1.37 (t, 3 H, 3J = 7.1 Hz,
OCH2CH3), 2.58 (s, 3 H, CH3), 2.63 (s, 3 H, CH3), 4.38 (q, 2 H,
3J = 7.1 Hz, OCH2CH3), 7.09 (d, 1 H, 3J = 7.7 Hz), 7.58–7.64 (m, 2
H), 8.14 (d, 1 H, 3J = 7.7 Hz), 8.67 (s, 1 H).
OCH2CH3), 4.48 (q, 2 H, J = 7.1 Hz, OCH2CH3), 4.53 (s, 2 H,
CH2Br), 7.86 (dd, 1 H, 3J = 8.2, 4J = 2.3 Hz), 7.94 (t, 1 H, 3J = 7.8
Hz), 8.12 (dd, 1 H, 3J = 7.7, 4J = 1.2 Hz), 8.56 (m, 2 H), 8.66 (d, 1
H, 4J = 2.3 Hz).
13C{1H} JMOD NMR (50 MHz, CDCl3): = 14.4 (CH3), 29.6
(CH2Br), 61.9 (CH2O), 121.7 (CH), 124.3 (CH), 125.2 (CH), 134.2
(Cq), 137.7 (CH), 137.9 (CH), 147.9 (Cq), 149.3 (CH), 155.2 (Cq),
155.8 (Cq), 165.3 (C=O).
13C{1H} JMOD NMR (62.5 MHz, CDCl3): = 14.2 (CH3), 24.6
(CH3), 61.6 (CH2), 117.5 (CH), 118.3 (CH), 122.1 (CH), 123.4
(CH), 134.0 (CH), 138.9 (Cq), 155.0 (Cq), 157.0 (Cq), 158.0 (Cq),
158.8 (Cq), 165.6 (C=O).
MS (FAB+, mNBA): m/z (%) = 321/323 (100/95, [M + H+]), 343/
MS (FAB+, mNBA): m/z (%) = 257 (100, [M + H+]), 279 (39, [M +
345 (23/21, [M + Na+]).
Na+]).
( , M–1cm–1) = 251 (14300), 290 nm
UV/Vis (MeOH):
(10900).
( , M–1cm–1) = 237 (11700), 294 nm
UV/Vis (MeOH):
(21000).
max
max
Anal. Calcd for C14H13BrN2O2: C, 52.36; H, 4.08; N, 8.72. Found:
C, 52.18; H, 4.03; N, 8.62.
Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C,
70.75; H, 6.19; N, 10.35.
Ethyl 6,6 -Dibromomethyl-4 -(2,2 :6 ,2 -terpyridine)carboxy-
late (7)
Radical Bromination Reactions; General Procedure
Method A: A mixture of methyl-oligopyridine (1 equiv), NBS (1.1
equiv) and a catalytic amount of AIBN in benzene or benzene–H2O
(1:1) was irradiated and refluxed using a halogen lamp (150 W) for
3 h. The hot mixture was filtered and evaporated under reduced
pressure. Purification by column chromatography afforded the de-
sired compound.
Method A: From 6 (0.71 g, 2.14 mmol), and NBS (0.83 g, 4.53
mmol) in benzene (100 mL). After purification by column chroma-
tography (silica gel, eluent: CH2Cl2–petroleum ether, 3:7→5:5) 0.27
g (26%) of a white solid was obtained; mp 201–203 °C; Rf 0.4 (sil-
ica gel, CH2Cl2).
IR (KBr): 1727 (s, C=O), 1583 (m), 1566 cm–1 (m).
Method B: Methyl-oligopyridine (1 equiv) in a mixture benzene–
H2O (1:1) was irradiated and refluxed using a halogen lamp (150
W). Br2 (1 equiv) was added and the refluxing was continued for 30
min. The solution was concentrated under reduced pressure and
neutralized with an aq solution of NaHCO3. The aqueous layer was
extracted with CH2Cl2, dried (MgSO4) and evaporated in vacuo.
The crude residue was chromatographed to give the product.
1H NMR (250 MHz, CDCl3): = 1.49 (t, 3 H, 3J = 7.1 Hz,
3
OCH2CH3), 4.52 (q, 2 H, J = 7.1 Hz, OCH2CH3), 4.68 (s, 4 H,
CH2Br), 7.52 (d, 2 H, 3J = 7.7 Hz), 7.86 (t, 2 H, 3J = 7.8 Hz), 8.50
(d, 2 H, 3J = 7.8 Hz), 8.99 (s, 2 H).
13C{1H} JMOD NMR (62.5 MHz, CDCl3): = 14.4 (CH3), 34.1
(CH2Br), 62.0 (CH2O), 120.5 (CH), 120.7 (CH), 124.0 (CH), 138.0
(CH), 140.1 (Cq), 155.1 (Cq), 156.1 (Cq), 156.6 (Cq), 165.6 (C=O).
MS (FAB+, mNBA): m/z (%) = 490/492/494 (54/100/51, [M + H+]).
UV/Vis (CH2Cl2): max ( , M–1cm–1) = 288 (18200), 323 nm (9700).
Ethyl 6 -Bromomethyl-6-(2,2 -bipyridine)carboxylate (4a)
Method A: From 3a (0.68 g, 2.8 mmol), and NBS (0.55 g, 3 mmol)
in benzene (50 mL). Purification by column chromatography (silica
gel, eluent: CH2Cl2–petroleum ether–MeOH, 80:20:0→99:00:1) af-
forded 0.49 g (55%) of a white solid; mp 90–91 °C; Rf 0.2 (silica
gel, CH2Cl2).
Anal. Calcd for C20H17Br2N3O2: C, 48.91; H, 3.49; N, 8.56. Found:
C, 48.78; H, 3.57; N, 8.25.
IR (KBr): 1713 (s, C=O), 1580 cm–1 (m).
Ethyl 6,6′-Dibromomethyl-4-(2,2 -bipyridine)carboxylate (10)
Method A: From 9 (0.15 g, 0.58 mmol), and NBS (0.23 g, 1.25
mmol) in benzene–H2O (1:1, 20 mL). The residue was purified by
column chromatography (silica gel, eluent: CH2Cl2–petroleum
ether, 3:7→5:5), leading to 0.055 g (23%) of the product; mp 137–
138 °C; Rf 0.45 (silica gel, CH2Cl2).
1H NMR (200 MHz, CDCl3): = 1.47 (t, 3 H, 3J = 7.1 Hz,
3
OCH2CH3), 4.49 (q, 2 H, J = 7.1 Hz, OCH2CH3), 4.62 (s, 2 H,
CH2Br), 7.48 (dd, 1 H, 3J = 7.7, 4J = 1.0 Hz), 7.85 (t, 1 H, 3J = 7.8
Hz), 7.96 (t, 1 H, 3J = 7.8 Hz), 8.13 (dd, 1 H, 3J = 7.7, 4J = 1.2 Hz),
8.48 (dd, 1 H, 3J = 7.9, 4J = 1.0 Hz), 8.66 (dd, 1 H, 3J = 7.9, 4J = 1.2
Hz).
IR (KBr): 1725 (s, C=O), 1565 cm–1 (m).
13C{1H} JMOD NMR (50 MHz, CDCl3): = 14.4 (CH3), 34.1
(CH2Br), 61.9 (CH2O), 120.9 (CH), 123.9 (CH), 124.4 (CH), 125.1
(CH), 137.9 (CH), 138.1 (CH), 147.8 (Cq), 155.0 (Cq), 155.9 (Cq),
156.3 (Cq), 165.3 (C=O).
1H NMR (250 MHz, CDCl3): = 1.46 (t, 3 H, 3J = 7.1 Hz,
3
OCH2CH3), 4.48 (q, 2 H, J = 7.1 Hz, OCH2CH3), 4.66 (s, 2 H,
CH2Br), 4.67 (s, 2 H, CH2Br), 7.52 (d, 1 H, 3J = 7.5 Hz), 7.85 (t, 1
Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Carboxylate Derivatives of Oligopyridines Bearing Bromomethyl Groups
1569
3
3
H, J = 7.85 Hz), 8.01 (d, 1 H, 4J = 1.3 Hz), 8.39 (d, 1 H, J = 7.6
UV/Vis (MeOH):
(42800).
( , M–1cm–1) = 245 (34500), 288 nm
max
Hz), 8.88 (d, 1 H, 4J = 1.3 Hz).
13C{1H} JMOD NMR (62.5 MHz, CDCl3): = 14.3 (CH3), 33.5
(CH2), 33.9 (CH2), 62.1 (CH2), 120.0 (CH), 120.7 (CH), 122.8
(CH), 124.1 (CH), 138.1 (CH), 140.1 (Cq), 154.6 (Cq), 156.6 (Cq),
156.7 (Cq), 157.3 (Cq), 165.0 (C=O).
Anal. Calcd for C48H42N6O9: C, 68.07; H, 5.00; N, 9.92. Found: C,
67.68; H, 4.65; N, 9.66.
Saponification of the Triesters 12a and 14a; General Procedure
A mixture of the triester (0.1 mmol) in MeOH (10 mL) and a solu-
tion of NaOH (200 mg, 5 mmol) in H2O (2 mL) was refluxed for 2
h.7 After cooling, dil. HCl was added slowly until pH 4, the result-
ing precipitate was collected by centrifugation, washed with H2O
and dried under vacuum to afford the corresponding triacid as a
white powder.
MS (FAB+, mNBA): m/z (%) = 413/415/417 (58/100/49, [M + H+]).
UV/Vis (MeOH):
(11400).
( , M–1cm–1) = 241 (12800), 290 nm
max
Anal. Calcd for C15H14Br2N2O2: C, 43.51; H, 3.41; N, 6.77. Found:
C, 43.16; H, 3.28; N, 6.51.
1-Benzyl-4,7,10-tri[(6 -carboxy-2,2 -bipyridine-5-yl)methyl]-
1,4,7,10-tetraazacyclododecane (12b)
From 12a (0.08 g, 0.08 mmol) and NaOH (0.16 g, 4 mmol); yield:
0.057 mg (80%).
1-Benzyl-4,7,10-tri[(6 -ethoxycarbonyl-2,2 -bipyridine-5-yl)me-
thyl]-1,4,7,10-tetraazacyclododecane (12a)
To a solution of 11 (0.058 g, 0.22 mmol) and 4b (0.21 g, 0.66 mmol)
in anhyd DMF (20 mL), was added N,N-diisopropylethylamine
(0.21 mL, 1.2 mmol) and the resulting mixture was stirred at r.t. for
2 d. The solvent was removed under vacuum, and the residue was
chromatographed over alumina (activity IV) with CH2Cl2–MeOH
(100:0→98:2) as eluent to give 0.11 g (51%) of an yellowish oil;
Rf 0.1 (silica gel, CH2Cl2–MeOH, 98:2).
IR (KBr): 3435 (br),1632 cm–1 (m).
1H NMR (250 MHz, MeOD/NaOD/D2O): = 2.65–2.80 (m, 16 H),
3.40 (br s, 2 H), 3.47 (br s, 6 H), 7.19–7.34 (br m, 6 H), 7.56–7.62
(br m, 2 H), 7.75–8.25 (br m, 12 H), 8.48 (br s, 1 H), 8.54 (br s, 2 H).
MS (FAB+, mNBA): m/z (%) = 899 (67, [M + H+]), 921 (100, [M +
IR (KBr): 1738 (s, C=O), 1714 (s), 1585 (m), 1447 cm–1 (m).
Na+]), 943 (58, [M – H+ + 2Na+], 965 (25, [M – 2H+ + 3Na+].
1H NMR (250 MHz, CDCl3) : = 1.42 (t, 9 H, 3J = 7.1 Hz,
OCH2CH3), 2.68–2.70 (m, 16 H), 3.42–3.45 (m, 8 H), 4.45 (q, 6 H,
3J = 7.1 Hz, OCH2CH3), 7.15–7.34 (m, 5 H), 7.77–7.92 (m, 6 H),
8.03–8.07 (m, 3 H), 8.41–8.65 (m, 9 H).
1,3,5-Tri[(6 -carboxy-2,2 -bipyridine-5-yl)methyloxy]benzene
(14b)
From 14a (0.03 g, 0.037 mmol) and NaOH (0.06 g, 1.5 mmol);
13C{1H} JMOD NMR (62.5MHz, CDCl3): = 14.3 (CH3), 53.1
(CH2), 57.1 (CH2), 57.4 (CH2), 60.5 (CH2), 61.8 (CH2), 121.2 (CH),
124.1 (CH), 124.7 (CH), 128.1 (CH), 129.1 (CH), 135.8 (Cq), 135.9
(Cq), 137.6 (CH), 137.7 (CH),147.7 (Cq), 149.8 (CH), 153.9 (Cq),
156.4 (Cq), 156.5 (Cq), 165.4 (C=O).
yield: 0.027 g (90%).
IR (KBr): 3430 (br), 1613 cm–1 (m).
1H NMR (250 MHz, DMSO-d6): = 5.24 (s, 6 H, OCH2), 6.44 (s, 3
H
arom), 8.09 (m, 9 H), 8.56 (d, 6 H, 3J = 7.4 Hz), 8.7 (s, 3 H).
MS (FAB+, mNBA): m/z (%) = 763 (55, [M + H+]), 785 (91, [M +
MS (FAB+, mNBA): m/z (%) = 983 (100, [M + H+]).
Na+]), 807 (100, [M – H+ + 2Na+]), 829 (56, [M – 2H+ + 3Na+]).
UV/Vis (MeOH):
(50400).
( , M–1cm–1) = 246 (38500), 286 nm
max
References
Anal. Calcd for C57H62N10O6.H2O : C, 68.38; H, 6.44; N, 13.99.
Found: C, 68.14; H, 6.22; N, 13.56.
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1,3,5-Tri[(6 -ethoxycarbonyl-2,2 -bipyridine-5-yl)methy-
loxy]benzene (14a)
A mixture of 1,3,5-trihydroxybenzene (13; 0.024 g, 0.19 mmol) and
Cs2CO3 (0.31 g, 0.95 mmol) in anhyd DMF (20 mL) was stirred at
r.t. for 30 min. Ethyl 5 -bromomethyl-6-(2,2 -bipyridine)carboxy-
late (4b; 0.2 g, 0.62 mmol) was added and the solution was stirred
overnight. The solvent was removed under vacuum, the residue was
diluted with CH2Cl2 and the CH2Cl2 phase was washed with H2O.
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uum. Chromatographic separation (silica gel, eluent: CH2Cl2–
EtOAc, 1:0→0:1) gave 0.08 g (50%) of a white solid; mp 170–
172 °C; Rf 0.1 (silica gel, EtOAc).
IR (KBr): 1737 (s, C=O), 1717 (m), 1602 (m), 1156 cm–1 (s).
1H NMR (250 MHz, CDCl3): = 1.45 (t, 9 H, 3J = 7.1 Hz,
3
OCH2CH3), 4.47 (q, 6 H, J = 7.1 Hz, OCH2CH3), 5.09 (s, 6 H,
3
OCH2), 6.28 (s, 3 Harom), 7.90 (m, 6 H), 8.10 (dd, 3 H, J = 7.7,
4J = 0.9 Hz), 8.58 (dd, 6 H, 3J = 7.8 Hz, 4J = 0.8 Hz), 8.70 (d, 3 H,
4J = 2.0 Hz).
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(CH2), 67.6 (CH2), 95.3 (CH), 121.5 (CH), 124.2 (CH), 125.0 (CH),
132.8 (Cq), 136.3 (CH), 137.9 (CH), 147.8 (Cq), 148.3 (CH), 155.1
(Cq), 156.0 (Cq), 160.3 (Cq), 165.3 (C = O).
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Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis 2002, No. 11, 1564–1570 ISSN 0039-7881 © Thieme Stuttgart · New York