Synthesis of flexible polydendate ligands bearing 5′-substituted-6-carboxylic-2,2′-bipyridine subunits

Article abstract of DOI:10.1055/s-2002-31968

The synthetic scope of asymmetric 5′,6-disubstituted-2,2′-bipyridines in the preparation of flexible multitopic ligands has been investigated. The preparation of the pivotal 6-bromo-5′-bromomethyl-2,2′-bipyridine building block involved a Kr?hnke protocol

Full text of DOI:10.1055/s-2002-31968

PAPER
1101
Synthesis of Flexible Polydendate Ligands Bearing 5 -Substituted-6-
carboxylic-2,2 -bipyridine Subunits
Flexible
Polyde
o
ndate
L
igand
ï
s
B
ear
c
ing 5
-
Substituted
J
-6-carbox
.
Cridine Subunits harbonnière,* Nicolas Weibel, Raymond F. Ziessel*
Laboratoire de Chimie Moléculaire, Associé au CNRS UMR-7008, Ecole de Chimie, Polymères et Matériaux de Strasbourg (ECPM),
25 rue Becquerel, 67087 Strasbourg Cedex 02, France
Fax +33(3)90242689; E-mail: ziessel@chimie.u-strasbg.fr
Received 15 March 2002
luminophoric labels is less extensive than one might ex-
Abstract: The synthetic scope of asymmetric 5 ,6-disubstituted-
pect.10 This shortcoming is due largely to difficulties in
2,2 -bipyridines in the preparation of flexible multitopic ligands has
been investigated. The preparation of the pivotal 6-bromo-5 -bro-
momethyl-2,2 -bipyridine building block involved a Kröhnke pro-
preparing the prerequisite starting building blocks.11,12
A
notable advance was reported with pyridine and bpy
tocol followed by a radical bromination reaction which has been ligands bearing flexible polyacetate arms.13,14 However,
optimized. Functionalization of 6-bromo-5 -bromomethyl-2,2 -bi-
the direct connection of a carboxylate function in the 6-
pyridine has been realized by both a Delepine and a Gabriel reac-
substitution position of a bpy framework provide an ideal
tion, providing after hydrolysis the corresponding amino
anionic tridendate pocket for lanthanide complexation
compound, whereas a nucleophilic attack of acetate followed by a
and many different preorganized platforms have recently
saponification reaction provided the corresponding alcohol. Multi-
functionalized bipyridine ligands have been prepared in one step
been engineered (Figure).15
from 6-bromo-5 -bromomethyl-2,2 -bipyridine and acyclic amines
or primary alcohol via base-assisted nucleophilic substitutions. In
all cases, transformation of the bromo-function to the corresponding
ethyl esters has been made possible under mild conditions using a
palladium promoted carboethoxylation reaction, while saponifica-
tion under basic conditions provided the corresponding acids after
protonation. The utility of the herein reported protocols has been ex-
tended to the synthesis of an ethylenediamine platform bearing an
appended 4-nitrobenzyl group for potential linking to other mole-
cules.
chromophoric unit and chelating center
5'
6
N
N
anchoring unit
O
Ln
O
Key words: bromination, pyridines, bipyridines, ligands, radical
reaction, nucleophilic additions
light emitting center
anionic arm
Figure
Transition metal and lanthanide complexes involving
2,2 -bipyridine (bpy) or its derivatives have been used in
a wide variety of applications ranging from catalytic me-
diated reactions1 to amperomeric2 and luminophoric
sensors3 and more recently as thin films in electrolumines-
cent devices.4,5 The remarkable intrinsic properties of
these complexes such as intense absorption bands in the
near ultraviolet or visible region, long-lived metal-to-
ligand charge transfer or lanthanide centered excited
states and modest to high quantum yields make possible
the labelling of biological material for quantitative analyt-
ical purposes.6,7 Such highly desirable features have stim-
ulated a wealth of synthetic efforts to promote tailor-made
ligands in order to provide stable complexes with out-
standing optical properties. In this context, the coordina-
tion of lanthanide centres allow the production of very
good labels which have been used in fluoroimmunoas-
says.8,9 In comparison with other ligands with nitrogen do-
nors, in particular with the strictly related bpy platforms,
the use of anionic derivatives as auxiliaries in the field of
The objective of this study was to investigate the scope
and limitations of a methodology applied to the syn-
thesis of asymmetric 5 ,6-disubstituted-2,2 -bipyridine
bausteine, using an optimized access to the key 5 -bro-
momethyl-6-bromo-2,2 -bipyridine compounds. Three
such tridentate units were brought together on acyclic
platforms, one of them offering potentialities for further
grafting on biological compounds.
The synthetic strategy for the 5 ,6-disubstituted-2,2 -bipy-
ridine compounds is sketched in Scheme 1 and the objec-
tive of this study was to develop a concise and practical
synthesis of 5 -bromomethyl-6-bromo-2,2 -bipyridine
(5), a pivotal synthon for the targeted ligands. This has led
us to devise a flexible synthetic protocol, which employs
2-acetyl-6-bromopyridine 116 as a template. The prepara-
tion of 5 -methyl-6-bromo-bipyridine (2) was achieved in
a two steps procedure via the formation of the acetylpyri-
dinium according to the method developed by King17 fol-
lowed by condensation with a mixture of methacrolein
and (NH4)OAc according to the methodology of
Kröhnke.18 From this building block 2, further derivatiza-
tion can be achieved orthogonally either at the 5 -methyl
or at the 6-bromo positions. For example activation at the
Synthesis 2002, No. 8, 04 06 2002. Article Identifier:
1437-210X,E;2002,0,08,1101,1109,ftx,en;Z04202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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L. J. Charbonnière et al.
PAPER
(iv)
EtO
N
HO
N
N
N
(iii)
(v)
O
O
4
3
(i)
N
Br
N
Br
N
(ii)
O
2
1
N
N
+
Br
N
Br
N
Br
Br
6
5
Br
Scheme 1 Reagents and conditions: (i) I2, pyridine, 115 °C; (ii) HC(O)NH2, NH4OAc, methacrolein, 90 °C, 68% for the two steps; (iii)
Pd(PPh3)2Cl2 (3.5 mol%), EtOH, Et3N, CO (1 atm), 80 °C, 98%; (iv) EtOH, HCl, H2O, 100 °C, 89%; (v) NBS, AIBN, CCl4, 80 °C, 69% of 5,
28% of 6.
Table Various Experimental Conditions for Radical Bromination
of 2
6-bromo position is made feasible by a carboalkoxylation
reaction,19 using a stream of CO in a hot mixture of EtOH/
Et3N containing catalytic amounts of Pd(PPh3)2Cl2, af-
fording the ethyl ester 3 which upon aqueous acidic treat-
ment was converted to the tridentate ligand 4.
c
Quantities (equiv)a
Temp (°C)b
h
Products (%)d
2
NBS AIBN
5
6
Activation of the 5 -methyl position was a key step in the
development of our strategy, as it afforded the milestones
for grafting on preorganized architectures. At first, prepa-
ration of 5 was attempted using the method developed by
Fraser et al.20 in which methyl substituted bipyridines are
first transformed into trimethylsilane derivatives by
deprotonation with LDA at low temperature followed by
reaction with TMSCl. When the silane reacted with CsF
in the presence of C2F4Br2, the monobrominated com-
pounds are usually obtained with excellent yields. Despite
all synthetic efforts to extend this procedure to 2, we have
been unable to isolate the corresponding silane in reason-
able amounts. It is surmized that the presence of the bro-
mine atom in the 6 position affords competing pathways
for the metallation of the pyridine rings with LDA. As part
of our research program dealing with the synthesis of
monobromomethyl and dibromomethyl derivatives,21 it
was soon established that the radical bromination reaction
of 2 provide a non-negligible deviation from the expected
statistical distribution of the products (63% of monobro-
minated compound 5 was obtained with one equivalent
NBS, instead of the expected 50% statistical value, Table,
Scheme 1). Consequently, a set of general conditions (in-
cluding temperature, concentrations, irradiation) was es-
tablished and the main facets are gathered in the Table. As
expected, the presence of the radical initiator and light ir-
radiation during the reaction gave the best results, al-
though in the dark the reaction proceeded if the
temperature is raised to 100 °C in a Schlenk tube. Varying
the quantity of NBS leads to an optimal value of 1.25
equivalents, for which only traces of the starting material
remained, an important point for the purification by col-
umn chromatography. In this latter case, the optimal yield
reached 69% after isolation and appropriate purification
of the product. For higher quantities of NBS, the second
bromination leading to derivative 6 occured at the expense
of the monobrominated compound 5.
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.25
1.5
0
80 to 100
No
0
0
0
0
4
9
0.05
0.05
0.05
0.05
0.05
80
100
80
No
No
51
63
69
62
Yes
Yes
Yes
80
28
80
33e
a Typical conditions: 2 (50 mg) in CCl4 (10 mL).
b For T > 80 °C, the reaction was carried out in a Schlenk tube.
c Irradiation was performed with a conventional incandescence
lamp, 60 Watts.
d Percentages obtained from the integral values on the 1H NMR
spectra.
e About 5% of a compound identified as the tribrominated com-
pound were formed.
From the 5 -bromomethyl compound 5, it was then possi-
ble to prepare the corresponding hydroxymethyl deriva-
tive 7, via a nucleophilic attack of sodium acetate,
followed by a subsequent saponification of the resulting
ester (Scheme 2). This derivative could then be used in
Williamson etherification reactions (vide infra). Further-
more, the amino derivative 8, could be prepared by a
straightforward manner using a Delepine reaction with
hexamethylenetetramine, and a subsequent acidic hydrol-
ysis of the resulting ammonium salt. The direct carbo-
ethoxylation of the bromine function of amino derivative
such as 8, under standard conditions [CO, EtOH, Et3N,
catalytic amounts of Pd(PPh3)2Cl2], gave mixtures of
compounds from which the expected esters were obtained
only in low yields.22 It is surmized that during the car-
boalkoxylation process the starting primary amine and the
in situ formed secondary amide also readily reacted to
form polymeric amide species.23,24 A smarter way to ob-
tain 11 was to prepare the amine in the form of a phthal-
imide group as outlined in Scheme 2. Compound 9 was
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Flexible Polydendate Ligands Bearing 5 -Substituted-6-carboxylic-2,2 -bipyridine Subunits
1103
obtained by a nucleophilic substitution of the methyl bro- a mineral base to reach the tripode ligand 15 in excellent
mide in 5 with potassium phthalimidate under anhydrous yield. In this case, the carboalkoxylation sequence lead to
conditions according to the classical Gabriel synthesis the tris-tridentate ligand 16. The ethyl ester 16 was hy-
methodology. Then, the carboethoxylation protocol af- drolysed under basic conditions to provide the tris-acid 17
forded the ester 10. Simultaneous hydrolysis of the ester in acceptable yield. Deprotonation of the acid functions of
and the phthalimide fragments to the target compound 11 derivatives 14 and 17 provides di- and tri-anionic ligands
was feasible but the final separation of the resulting which are excellent targets for lanthanide complexation
phthalic acid from the acid 11 is tedious. A much better (Scheme 4).
way was to perform the amine deprotection as a first step
In order to induce more flexibility and solubility within
in the presence of hydrazine, allowing an easy removal of
the central polyamine frame and also to introduce an ad-
the phthalic moiety, while the ester hydrolysis was further
ditional pendant arm which could ultimately be linked to
realized under acidic conditions as depicted in Scheme 2.
a protein with an anchoring function, we have protected
Stepwise conversion of 5 to 11 was made possible in four
one nitrogen atom of ethylenediamine with a p-nitroben-
steps with a total yield of 39%.
zyl group25 affording the product 18 as outlined in
Access to the ether-bridged ditopic ligand 12 requires Scheme 5. Further alkylation of the remaining three posi-
deprotonation of 7 with NaH while the resulting alcohol- tions with 5 -bromomethyl-6-bromo-2,2 -bipyridine af-
ate induced a nucleophilic substitution at the bromide in forded ligand 19 in 74% isolated yield. This compound
compound 5 (Scheme 3). Similarly, the carboalkoxylation was allowed to react smoothly with carbon monoxide and
sequence of reactions previously applied, was repeated ethanol in a carboethoxylation reaction catalyzed by low
with compound 12 affording the bis-tridentate ligand 13. valent palladium(0). The corresponding triester com-
Hydrolysis under basic conditions and reacidification pound 20 was then saponified under basic conditions to
readily afforded the diacid compound 14.
afford the triacid derivative 21 in fair yield.
Furthermore, alkylation of the primary amine 8 with 2.2 The synthetic protocol described herein provides an expe-
equivalents of 5 can also be carried out in the presence of dient access to a novel family of polydendate bipyridyl
N
Br
N
Br
5
(ii)
(i)
N
N
Br
N
(iii)
Br
N
OH
Br
8
NH2
7
N
O
N
N
O
9
(iv)
O
N
O
N
N
O
O
10
(v)
HO
N
N
NH2
O
11
Scheme 2 Reagents and conditions: (i) NaOAc, DMF, 120 °C; MeOH, H2O, NaOH, 100 °C, 89%; (ii) hexamethylenetetramine, CH2Cl2,
40 °C; concd HCl, EtOH, 78%; (iii) potassium phthalimidate 1.1 equiv, THF, 70 °C, 16 h, 90%; (iv) Pd(PPh3)2Cl2, EtOH, Et3N, CO (1 atm),
70 °C, 67%; (v) H2NNH2 H2O, EtOH, 80 °C; HCl 3 M, 70 °C, 65%.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

1104
L. J. Charbonnière et al.
PAPER
nophoric properties, whereas the prospects seem less
favourable concerning some of their thermodynamic sta-
bility behavior in aqueous medium.
N
N
+
Br
N
Br
N
Br
N
OH
7
The 200.1 MHz (1H) and 50.3 MHz (13C) NMR spectra were record-
ed at r.t. on a Bruker AC 200 spectrometer, using perdeuterated sol-
vents as internal standard: (H) in ppm relative to residual protiated
solvent or t-BuOH ( = 1.30) for D2O solutions; (C) in ppm rela-
tive to the solvent or to t-BuOH ( = 31.6 and 68.7) for D2O solu-
tions. For compound 20, the NMR spectra were recorded before
protonation of the compound in order to avoid the broadening of the
signals. FT-IR spectra were recorded as KBr pellets on a Nicolet
210 spectrometer. High resolution mass spectral analysis (HRMS)
were performed using a Mariner ESI-Tof instrument from Applied
Bio-System/Perking Elmer. Melting points were obtained on a Bü-
chi 535 capillary melting point apparatus in open-ended capilliaries
and are uncorrected. Chromatographic purification was conducted
using 0.063–0.200 mm silica gel or aluminium oxide 90 standard-
ized obtained from Merck. Thin layer chromatography (TLC) were
performed on silica or aluminium oxide plates (Merck) coated with
fluorescent indicator. All mixtures of solvents are given in v/v ratio.
6-Bromo-2-acetylpyridine (1)16 and N-(p-nitrobenzyl)ethylenedi-
amine (18) (in its non-protonated form)25 were prepared according
to literature procedures. CH2Cl2 (Prolabo) was distilled from CaH2.
THF (Riedel-de-Haën) was dried over Na/benzophenone prior to
distillation. MeCN (Riedel-de-Haën) was filtered over aluminium
oxide (Merck, Act III) and distilled over P2O5. Pd(PPh3)2Cl2 (Ald-
rich) was recrystallized from hot DMSO. Methacrolein (Fluka,
95%), NH4OAc (Prolabo 97%), iodine (Prolabo), pyridine (Prolabo,
99.7%), Et3N (Riedel-de-Haën, >99%), EtOH (Merck, absolute),
NBS (Fluka, 97%), azobisisobutyronitrile (Janssen Chimica, 98%),
hexamethylenetetramine (Prolabo, 99%), DMF (SDS, 99.8%), for-
mamide (Acros, 99.5%) and 1,4,7-triazacyclononane (Fluka, 97%)
were used as purchased.
5
(i)
N
Br
N
N
Br
O
12
(ii)
N
N
N
N
EtOOC
HOOC
N
N
COOEt
COOH
O
13
(iii)
N
N
O
14
Scheme 3 Reagents and conditions: (i) NaH, THF, 80 °C, 84%; (ii)
Pd(PPh3)2Cl2 (10 mol% per Br atom), EtOH, Et3N, CO (1 atm), 80 °C,
39%; (iii) MeOH, H2O, NaOH, 80 °C; dilute HCl, 89%.
6-Bromo-5 -methyl-2,2 -bipyridine (2)
derivatives asymmetrically substituted at the 5 and 6 po-
sitions with various functions. The engineering of a reac-
tive bromomethyl group in the 5 position allowed
nucleophilic substitution by primary or secondary amines,
and also by alcohols. The presence of a bromine atom at
the 6 position facilitates a Pd-assisted carboethoxylation
reaction leading to esters, which after hydrolysis gave the
corresponding carboxylic acids. In addition, we reported
an optimized synthesis of 5 -bromomethyl-6-bromo-2,2 -
bipyridine, which makes this compound an attractive and
more available template for ligand synthesis and repre-
A mixture of 1 (5.0 g, 25 mmol) and I2 (6.3 g, 25 mmol) was re-
fluxed for 1 h in pyridine (30 mL). The solution was cooled to r.t.,
resulting in the precipitation of the 6-bromo-2-acetylpyridiniumio-
dide in quantitative yield. The solid was filtered, dispersed in CHCl3
(30 mL), sonicated and filtered. This washing process was repeated
and the solid filtered off and dried for 1 h under reduced pressure.
The pyridinium salt was dissolved in formamide (60 mL) contain-
ing NH4OAc (28.5 g, 370 mmol) and methacrolein (2.05 mL, 25
mmol). The solution was heated to 90 °C for 2 h. The solution rap-
idly turned orange and a precipitate appeared. The mixture was
cooled to r.t. and washed CH2Cl2 (2 250 mL). The combined or-
ganic layers were washed with H2O (50 mL), dried (MgSO4) and
sents the most efficient synthesis of these pivotal deriva- evaporated to dryness. Purification by flash column chromatogra-
phy (SiO2; CH2Cl2–hexane, 50:50; Rf 0.52, aluminium oxide;
tives to date (three steps with overall yield of 47%). The
chosen protocols allow an amalgamation of several dis-
tinct functionalities and properties. The basic architecture
CH2Cl2–hexane, 50:50) gave 2 (6.22 g, 68%) as a white solid. All
analyses correspond to those described in the literature.26
of the target molecules is the presence of a three anionic
6-Carboethoxy-5 -methyl-2,2 -bipyridine (3)
N, N, O donor fragment which is an ideal arrangement for
the complexation of tricationic lanthanides. Finally, the
presence of an additional pendant arm carrying a potential
activated function is especially appealing for bioconjuga-
tion to proteins and biological material. The utility of the
ligands prepared in this study as auxiliaries in the prepa-
ration of luminescent lanthanide complexes is under cur-
rent investigation. From preliminary results obtained in
screening experiments with europium cations the bipy-
ridylcarboxylate frameworks seem to promise good lumi-
A solution of 2 (500 mg, 2.0 mmol) and Pd(PPh3)2Cl2 (50 mg, 0.07
mmol) in a mixture of EtOH (10 mL) and Et3N (3 mL) was heated
to 80 °C for 18 h under a CO atmosphere. After the solution had
cooled to r.t., the solvents were removed under reduced pressure
and the resulting solid was purified by column chromatography
(SiO2 previously deactivated with Et3N; CH2Cl2–hexane, 80:20) to
give 3.
Yield: 475 mg (98%); pale yellow solid; mp 59–60 °C.
IR (KBr): 2980 (w), 2925 (w), 1731 (s), 1577 (m), 1557 (m), 1442
(m), 1423 (m), 1249 (m), 1161 (s) cm–1.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

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Flexible Polydendate Ligands Bearing 5 -Substituted-6-carboxylic-2,2 -bipyridine Subunits
1105
2
N
+
N
Br
N
Br
N
Br
8
NH2
5
(i)
Br
COOEt
Br
EtOOC
N
N
N
N
N
N
N
N
N
N
(ii)
15
16
N
N
N
N
Br
COOEt
(iii)
COOH
HOOC
N
N
N
N
N
17
N
N
COOH
Scheme 4 Reagents and conditions: (i) MeCN, Na2CO3, 5 (2.2 equiv), 80 °C, 86%; (ii) Pd(PPh3)2Cl2 (7.0 mol%), EtOH, Et3N, CO (1 atm),
80 °C, 33%; (iii) MeOH, NaOH, H2O, 90 °C; dilute HCl, 30%.
1H NMR (CDCl3): = 1.38 (t, 3 H, 3J = 5.0 Hz), 2.29 (s, 3 H), 4.41
with irradiation with a conventional desk lamp. The solution was
filtered hot over a thin layer of aluminium oxide, evaporated to dry-
ness and 5 was isolated by column chromatography (SiO2; CH2Cl2–
hexane, 50:50 to 100:0; Rf 0.38, SiO2, CH2Cl2).
3
3
(q, 2 H, J = 5.0 Hz) 7.54 (br d, 1 H, J = 8.0 Hz), 7.84 (t, 1 H,
3J = 8.0 Hz), 8.03 (d, br, 1 H, 3J = 8.0 Hz), 8.32–8.55 (m, 3 H).
13C NMR (CDCl3): = 14.1, 18.2, 61.6, 121.0, 123.6, 124.4, 133.7,
137.3, 137.5, 147.5, 149.4, 152.5, 156.3, 165.1.
Yield: 1.80 g (69%); mp 166–167 °C.
MS (FAB+): m/z = 243.2 ([M + H]+, 100%).
IR (KBr): 1542 (s), 1431 (s), 1391 (m), 1156 (m) cm–1.
3
Anal. Cald for C14H14N2O2 (242.27): C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.31; H, 5.66; N, 11.31.
1H NMR (CDCl3): = 4.53 (s, 2 H), 7.50 (dd, 1 H, J = 8.0 Hz,
4J = 1.0 Hz), 7.67 (t, 1 H, J = 8.0 Hz), 7.85 (dd, 1 H, 3J = 8.0 Hz,
3
4J = 2.5 Hz), 8.37 (dd, 1 H, 3J = 7.5 Hz, 4J = 1.0 Hz), 8.40 (d, 1 H,
3J = 8.5 Hz), 8.67 (d, 1 H, 4J = 2.0 Hz).
5 -Methyl-2,2 -bipyridine-6-carboxylic Acid (4)
A solution of 3 (400 mg, 1.65 mmol) in EtOH (3 mL), concd HCl
(2 mL) and H2O (7 mL) was heated to 100 °C for 12 h. The solvents
were removed under reduced pressure and the solid residue recrys-
tallised from MeOH–THF in the freezer. The crystals were filtered
off and dried under vacuum to give 4.
13C NMR (CDCl3): = 29.5, 119.9, 121.4, 128.3, 134.3, 137.7,
139.3, 141.7, 149.5, 154.5, 156.8.
MS (ESI-ToF): m/z = 326.9 ([M + H]+, 30%), 328.9 ([M + H]+,
83%), 330.9 ([M + H]+, 24%), 348.9 ([M + Na]+, 45%), 350.9 ([M
+ Na]+, 83%), 352.9 ([M + Na]+, 32%).
Yield: 316 mg (89%); pale pink solid; mp 250–251 °C.
IR (KBr): 1744 (s), 1551 (m), 1465 (m), 1345 (s), 1259 (m) cm–1.
Anal. Calcd for C11H8Br2N2 (328.01): C, 40.28; H, 2.46; N, 8.54.
Found: C, 39.91; H, 2.14; N, 8.22.
1H NMR (DMSO-d6): = 2.65 (s, 3 H), 8.16–8.30 (m, 2 H), 8.49
(dd, 1 H, 3J = 8.0 Hz, 4J = 1.5 Hz), 8.56–8.77 (m, 3 H).
6-Bromo-5 -dibromomethyl-2,2 -bipyridine (6)
Compound 6 was obtained in 28% yield as a by-product of the rad-
ical bromination of 2 (Rf 0.57, SiO2, CH2Cl2); mp 106–107 °C.
13C NMR (DMSO-d6): = 18.9, 125.4, 126.8, 128.9, 141.4, 142.2,
143.2, 145.8, 147.8, 149.0, 149.7, 167.8.
IR (KBr): 3013 (w), 2923 (w), 1581 (m), 1546 (s), 1387 (s), 763 (s),
642 (s) cm–1.
MS (ESI-ToF): m/z = 215.1 ([M + H]+, 100%), 237.1 ([M + Na]+,
85%).
3
1H NMR (CDCl3) : = 6.71 (s, 1 H), 7.52 (dd, 1 H, J = 8.0 Hz,
3
6-Bromo-5 -bromomethyl-2,2 -bipyridine (5)
A solution of 2 (2.0 g, 8.0 mmol), NBS (1.79 g, 10.0 mmol) and
AIBN (66 mg, 0.4 mmol) in CCl4 (120 mL) was refluxed for 40 min
4J = 1.0 Hz), 7.69 (t, 1 H, J = 8.0 Hz), 8.08 (dd, 1 H, 3J = 8.0 Hz,
4J = 3.0 Hz), 8.39 (dd, 1 H, 3J = 8.0 Hz, 4J = 1.0 Hz), 8.46 (d, 1 H,
3J = 8.0 Hz), 8.76 (br s, 1 H).
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L. J. Charbonnière et al.
PAPER
NO2
X
N
N
N
N
NO2
N
N
(i)
NH
H2N
N
X
N
18
X
19 X = Br
20 X = COOEt
(ii)
(iii)
NO2
HOOC
N
N
N
N
N
N
N
N
HOOC
HOOC
21
Scheme 5 Reagents and conditions: (i) MeCN, Na2CO3, 5 (3.3 equiv), 80 °C, 74%; (ii) Pd(PPh3)2Cl2 (5 mol% per Br atom), EtOH, Et3N, CO
(1 atm), 80 °C, 36%; (iii) MeOH, H2O, NaOH, 80 °C; dilute HCl, 80%.
3
13C NMR (CDCl3): = 36.9, 120.0, 120.2, 121.5, 128.3, 128.6,
136.0, 138.3, 139.4, 146.4, 149.5.
MS (ESI-ToF): m/z = 406.8 ([M + H]+, 100%), 428.8 ([M + H]+,
1H NMR (CDCl3): = 4.80 (s, 2 H), 7.49 (dd, 1 H, J = 8.0 Hz,
4J = 1.0 Hz), 7.67 (t, 1 H, J = 8.0 Hz), 7.84 (dd, 1 H, 3J = 8.0 Hz,
3
4J = 2.0 Hz), 8.37 (dd, 1 H, 3J = 7.0 Hz, 4J = 1.0 Hz), 8.41 (d, 1 H,
3J = 8.5 Hz), 8.65 (d, 1 H, 4J = 1.5 Hz).
62%).
13C NMR (CDCl3): = 62.6, 119.8, 121.4, 128.1, 135.9, 137.0,
139.4, 141.7, 148.0, 153.9, 157.1.
Anal. Calcd for C11H7Br3N2 (406.90): C, 32.47; H, 1.73; N, 6.88.
Found: C, 32.15; H, 1.41; N, 6.63.
MS (ESI-ToF): m/z = 264.9 ([M + H]+, 35%), 266.9 ([M + H]+,
6-Bromo-5 -hydroxymethyl-2,2 -bipyridine (7)
38%), 286.9 ([M + Na]+, 98%), 288.9 ([M + Na]+, 100%).
A mixture of 5 (866 mg, 2.64 mmol) and NaOAc (5.0 g, 61 mmol)
was dissolved in DMF (20 mL) and heated to 120 °C for 3 h. The
DMF was distilled under reduced pressure and the solid residue was
dissolved in a mixture of MeOH (20 mL) and H2O (20 mL) contain-
ing NaOH (1.5 g, 0.57 mol) and refluxed for 2 h. The pH of the
cooled solution was brought to 7 by careful addition of 10% aq HCl.
The MeOH was evaporated under reduced pressure resulting in the
precipitation of a white solid. The aqueous layer was extracted with
CH2Cl2 (2 75 mL) and the combined organic layer was dried
(MgSO4), filtered and evaporated to dryness. Purification by col-
umn chromatography (aluminium oxide; CH2Cl2–MeOH, 100:0 to
95:5) gave 7.
Anal. Calcd for C11H9BrN2O (265.11): C, 49.84; H, 3.42; N, 10.57.
Found: C, 49.65; H, 3.11, N, 10.36.
6-Bromo-5 -aminomethyl-2,2 -bipyridine (8)
A mixture of 5 (400 mg, 1.22 mmol) and hexamethylenetetramine
(206 mg, 1.47 mmol) in CH2Cl2 (200 mL) was refluxed for 5 h.
Upon cooling the solution to –30 °C, a white precipitate formed,
which was filtered off and dried under vacuum. The solid was dis-
solved in concd HCl (2.8 mL) and EtOH (20 mL) and refluxed for
1 d. Sat aq NaOH (2 mL) was added and the solution was extracted
with CH2Cl2 (2 100 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated to dryness to give 8.
Yield: 622 mg (89%); white solid; mp 112–113 °C.
Yield: 250 mg (78%); white solid; mp >160 °C (decomp).
IR (KBr): 3293 (br s), 2923 (w), 2855 (w), 1595 (m), 1567 (m),
1543 (s), 1432 (s), 1391 (m), 1125 (m), 1051(s) cm–1.
IR (KBr): 3437 (br s), 2922 (w), 2852 (w), 1619 (m), 1583 (br s),
1546 (m), 1430 (m), 1384 (m), 1124 (m), 1074 (br m) cm–1.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Flexible Polydendate Ligands Bearing 5 -Substituted-6-carboxylic-2,2 -bipyridine Subunits
1107
3
1H NMR (CDCl3): = 3.97 (s, 2 H), 7.48 (dd, 1 H, J = 7.5 Hz,
4J = 0.5 Hz), 7.66 (t, 1 H, 3J = 8.0 Hz), 7.80 (dd, 1 H, 3J = 8.5 Hz,
4J = 2.0 Hz), 8.36 (d, 1 H, 3J = 7.5 Hz), 8.38 (d, 1 H, 3J = 8.5 Hz),
8.65 (d, 1 H, 4J = 1.5 Hz).
Yield: 235 mg (65%); white solid; mp >260 °C (decomp).
IR (KBr): 2850 (br s), 1736 (s), 1459 (m), 1345 (s), 1266 (m) cm–1.
1H NMR (D2O–CD3OD, 1:1) : = 4.53 (s, 2 H); 8.18–8.23 (m, 2 H);
8.38–8.50 (m, 1 H), 8.68–8.80 (m, 2 H); 9.02 (s, 1 H).
13C NMR (D2O–CD3OD, 1:1) : = 41.8, 127.2, 128.5, 130.2, 135.3,
143.3, 145.4, 148.6, 149.7, 150.1, 150.4, 169.4.
13C NMR (CDCl3): = 43.5, 119.3, 120.9, 127.5, 135.5, 138.8,
139.0, 141.3, 148.1, 152.9, 157.0.
MS (ESI-ToF): m/z = 263.9 ([M + H]+, 97%), 265.9 ([M + H]+,
MS (ESI-ToF): m/z = 230.1 ([M + H]+, 100%).
100%), 285.9 ([M + Na]+, 29%), 287.9 ([M + Na]+, 29%).
Anal. Calcd for C12H11O2N3 2 HCl (229.24 + 72.92): C, 47.70; H,
4.34; N, 13.91. Found: C, 47.56; H, 4.10; N, 13.78.
Anal. Calcd for C11H10BrN3 (264.13): C, 50.02; H, 3.82; N, 15.91.
Found: C, 49.58; H, 3.63; N, 15.73.
Bis-[(6 -bromo-2,2 -bipyridine-5-yl)methyl] Ether (12)
N-[(6 -Bromo-2,2 -bipyridine-5-yl)methyl]phthalimide (9)
A mixture of potassium phthalimidate (620 mg, 3.35 mmol) and 5
(1.0 g, 3.05 mmol) was heated at 70 °C in a Schlenk tube under an
argon atmosphere for 16 h. The resulting suspension was dissolved
with MeOH (20 mL) and evaporated to dryness. The resulting solid
was purified by column chromatography (SiO2; CH2Cl2–MeOH,
100:0 to 99:1; Rf 0.16, SiO2, CH2Cl2) to give 9.
In a Schlenk tube under argon were added compound 7 (90 mg,
0.34 mmol) and NaH (60% suspension in mineral oil, 19 mg, 0.47
mmol) in freshly distilled THF (15 mL). The mixture was agitated
at r.t. for 1 h. Compound 5 (140 mg, 0.43 mmol) was added and the
temperature raised to 80 °C overnight. After addition of H2O (0.5
mL) the solvents were removed under reduced pressure. MeOH (10
mL) was added to the solid and the mixture was refluxed for 1 h.
Upon slow cooling to 4 °C, a white precipitate formed which was
collected by filtration and dried under vacuum, to give 12.
Yield: 1.08 g (90%); white solid; mp 218–220 °C.
IR (KBr): 1710 (s), 1430 (w), 1389 (m), 1135 (w) cm–1.
3
1H NMR (CDCl3): = 4.91 (s, 2 H), 7.46 (dd, 1 H, J = 7.5 Hz,
Yield: 146 mg (84%); white solid; mp 192–193 °C.
4J = 0.5 Hz), 7.64 (t, 1 H, 3J = 8.0 Hz), 7.71–7.91 (m, 5 H), 8.34 (m,
2 H), 8.74 (d, 1 H, 4J = 2.0 Hz).
13C NMR (CDCl3): = 38.9, 119.8, 121.3, 123.5, 128.0, 131.9,
132.6, 134.2, 137.4, 139.2, 141.6, 149.5, 154.1, 156.9, 167.8.
IR (KBr): 2925 (w), 2867 (w), 1620 (w), 1569 (m), 1545 (m), 1429
(s), 1384 (s), 1125 (m), 1062 (s) cm–1.
1H NMR (CDCl3): = 4.68 (s, 4 H), 7.49 (d, 2 H, 3J = 8.0 Hz), 7.67
(t, 2 H, 3J = 7.5 Hz), 7.84 (dd, 2 H, 3J = 8.0 Hz, 4J = 2.0 Hz), 8.38
(d, 2 H, 3J = 7.0 Hz), 8.42 (d, 2 H, 3J = 8.5 Hz), 8.65 (d, 2 H, 4J = 2.0
Hz).
MS (FAB+): m/z = 394.2, 396.2 ([M + H]+, 100%).
Anal. Calcd for C19H12BrN3O2 (394.23): C, 57.89; H, 3.07; N,
10.66. Found: C, 57.56; H, 2.70; N, 10.44.
13C NMR (CDCl3) : = 69.9, 119.8, 121.4, 128.1, 134.0, 136.6,
139.3, 141.7, 148.7, 154.3, 157.2.
N-[(6 -Carboethoxy-2,2 -bipyridine-5-yl)methyl]phthalimide
(10)
MS (ESI-ToF): m/z = 512.9 ([M + H]+, 53%), 534.9 ([M + Na]+,
100%).
Compound 10 was obtained according to the methodology used for
3, starting from 9 (840 mg, 2.1 mmol) and Pd(PPh3)2Cl2 (90 mg,
0.13 mmol) in EtOH–Et3N (1:1, 70 mL) at 70 °C for 16 h. The re-
sulting solution was evaporated to dryness, dissolved in CH2Cl2 (10
mL), filtered and recrystallised by addition of hexane to give 10.
Anal. Calcd for C22H16Br2N4O (512.21): C, 51.59; H, 3.15; N,
10.94. Found: C, 51.33; H, 2.85; N, 10.58.
Bis-[(6 -carboethoxy-2,2 -bipyridine-5-yl)methyl] Ether (13)
The same procedure as used for synthesis of 3 was employed, start-
ing from 12 (135 mg, 0.26 mmol), Pd(PPh3)2Cl2 (37 mg, 0.053
mmol) in MeOH (20 mL) and Et3N (20 mL). After column chroma-
tography (SiO2; CH2Cl2–MeOH, 99:1) 13 was isolated.
Yield: 544 mg (67%); white solid; mp 198–200 °C.
IR (KBr): 2972 (w), 2932 (w), 1735 (m), 1716 (s), 1428 (m), 1395
(w) cm–1.
3
1H NMR (CDCl3) : = 1.46 (t, 3 H, J = 7.0 Hz), 4.48 (q, 2 H,
Yield: 51 mg, (39%); white solid; mp 221–222 °C; Rf 0.36 (SiO2;
CH2Cl2 with 3% MeOH).
3J = 7.0 Hz), 4.92 (s, 2 H), 7.70–7.98 (m, 6 H), 8.10 (d, 1 H, 3J = 6.5
Hz), 8.49–8.58 (m, 2 H), 8.76 (br s, 1 H).
IR (KBr): 2926 (s), 2855 (s), 1737 (s), 1631 (m), 1590 (m), 1452
(m), 1369 (m), 1279 (s), 1140 (m), 1077 (s) cm–1.
13C NMR (CDCl3): = 14.2, 38.9, 61.6, 121.5, 123.4, 124.1, 124.9,
131.9, 132.4, 134.1, 137.4, 137.8, 147.7, 149.4, 154.8, 155.9, 165.2,
167.7.
3
1H NMR (CDCl3): = 1.41 (t, 6 H, J = 7.0 Hz), 4.44 (q, 4 H,
3J = 7.0 Hz), 4.53 (s, 4 H), 7.82 (d, 2 H, 3J = 8.0 Hz), 7.90 (t, 2 H,
3J = 8.0 Hz), 8.07 (d, 2 H, 3J = 7.5 Hz), 8.47–8.58 (m, 4 H), 8.63 (br
s, 2 H).
MS (FAB+): m/z = 388.3 ([M + H]+, 100%).
Anal. Calcd for C22H17N3O4 (387.40): C, 68.21; H, 4.42; N, 10.85.
Found: C, 67.92; H, 4.14; N, 10.58.
13C NMR (CDCl3): = 14.3, 61.8, 69.8, 121.4, 124.1, 124.9, 133.7,
136.5, 138.0, 147.8, 148.5, 154.9, 156.1, 165.2.
6-Carboxy-5 -aminomethyl-2,2 -bipyridine Dihydrochloride
Salt (11)
MS (ESI-Tof): m/z = 521.2 ([M + Na]+, 100%).
Anal. Calcd for C28H26N4O5 (498.54): C, 67.46; H, 5.26; N, 11.24.
Found: C, 67.32; H, 5.17; N, 11.02.
Compound 10 (526 mg, 1.36 mmol) and hydrazine hydrate (0.27
mL, 5.4 mmol) were dissolved in EtOH (50 mL). The solution was
refluxed for 3 h. The solution was evaporated to dryness and the sol-
id purified by column chromatography (SiO2; CH2Cl2–MeOH–
Et3N, 99:1:0 and 95:3:2) to give 265 mg of a colorless oil (Rf = 0.19;
SiO2 TLC; CH2Cl2–MeOH, 95:5) identified as the free amine by its
NMR. The oily residue was dissolved in aq HCl (3 M, 10 mL) and
heated at 70 °C for 2 h. The solution was cooled to r.t., the insoluble
material filtered off on cotton wool and the solution was evaporated
to dryness to give 11.
Bis-[(6 -carboxy-2,2 -bipyridine-5-yl)methyl] Ether (14)
A mixture of 13 (41 mg, 82 mol) in MeOH (10 mL) and NaOH (69
mg, 1.72 mmol) in H2O (2 mL) was refluxed for 2 h. The pH was
brought to 3 with dilute aq HCl resulting in the precipitation of a
white solid. The solid was isolated by centrifugation, washed with
H2O (5 mL), centrifuged, the aqueous layer was decanted and the
solid dried under vacuum to give 14.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

1108
L. J. Charbonnière et al.
PAPER
Yield: 32 mg (89%); white solid; mp 217–218 °C.
precipitation of a white solid. The residue was isolated by centrifu-
gation, washed with H2O (5 mL), the aq. layer was decanted and the
solid residue dried under vacuum to give 17.
IR (KBr): 2924 (w), 1620 (br s), 1453 (m), 1384 (m), 1121 (br m),
1082 (br m) cm–1.
Yield: 19 mg (30%); white solid; mp >220 °C (decomp).
1H NMR (DMSO-d6): = 4.75 (s, 4 H), 8.02–8.22 (m, 6 H), 8.58 (d,
2 H, 3J = 8.0 Hz), 8.60 (dd, 2 H, 3J = 7.0 Hz, 4J = 2.0 Hz), 8.75 (m,
2 H).
IR (KBr): 3411 (s), 1729 (br m), 1640 (w), 1619 (s), 1556 (m), 1346
(m) cm–1.
13C NMR (DMSO-d6): = 69.0, 121.3, 123.8, 125.1, 135.0, 137.9,
1H NMR (DMSO-d6): = 3.79 (m, 6 H), 8.03–8.12 (m, 9 H), 8.45–
139.0, 147.6, 148.0, 152.8, 153.8, 165.8.
8.58 (m, 6 H), 8.75 (m, 3 H).
MS (ESI-ToF): m/z = 465.1 ([M + Na]+, 19%), 242.3 ([M + 2 H]2+,
13C NMR (DMSO-d6): = 54.6, 121.0, 123.8, 125.1, 135.5, 138.9,
100%).
140.4, 147.9 (2C), 150.7, 153.9, 165.7.
Anal. Calcd for C24H18N4O5 H2O (442.43 + 18.01): C, 62.61; H,
4.38; N, 12.17. Found: C, 62.48; H, 4.42; N, 11.88.
FAB+/MS: m/z = 654.2 ([M + H]+, 100%), 608.2 ([M – COOH +
H]+, 30%), 577.2 ([M –2 COOH]+, 10%).
Anal. Calcd for C36H27N7O6 0.5 H2O (653.66 + 9.00): C, 65.25; H,
4.26; N, 14.80. Found: C, 65.61; H, 4.38; N, 14.64.
Tris-[(6 -bromo-2,2 -bipyridine-5-yl)methyl]amine (15)
Compound 8 (100 mg, 0.38 mmol) and 5 (274 mg, 0.83 mmol) were
dissolved in freshly distilled MeCN (15 mL) containing Na2CO3 (81
mg, 0.764 mmol) under an argon atmosphere. The solution was
heated to 80 °C for 2 days. The residual solid was filtered and dis-
solved in H2O (30 mL) and the aq layer washed with CH2Cl2 (2
50 mL). The mother liquor combined to the CH2Cl2 extracts was
dried (Na2SO4), filtered and evaporated to dryness. Purification by
column chromatography (SiO2; CH2Cl2–MeOH, 100:0 to 99:1)
gave 15.
N-(p-Nitrobenzyl)ethylenediamine (18)
Compound 18 was obtained in a procedure similar to that described
in the literature,25 by slow addition of p-benzylbromide (1.5 g, 6.9
mmol) in CH2Cl2 (20 mL) over a cooled (0 °C) solution of ethylene-
diamine (7 mL, 104 mmol) in CH2Cl2 (25 mL). After 3 h at 0 °C and
2 h at r.t., the organic layer was washed with H2O (2 25 mL). The
aq layer was extracted with CH2Cl2 (50 mL) and the combined or-
ganic layers were dried (Na2SO4), filtered and evaporated to dryness
to give 18.
Yield: 249 mg (86%); mp 146–147 °C.
IR (KBr): 2921 (w), 1635 (br s), 1567 (m), 1545 (m), 1430 (s), 1384
(m), 1124 (m) cm–1.
Yield: 1.3g (96%); light orange oil (which turned brown upon pro-
longed exposure to air).
1H NMR (CDCl3): = 3.68 (s, 6 H), 7.46 (d, 3 H, 3J = 7.5 Hz), 7.65
(t, 3 H, 3J = 7.5 Hz), 7.81 (dd, 3 H, 3J = 8.0 Hz, 4J = 2.0 Hz), 8.33
(d, 3 H, 3J = 7.0 Hz), 8.37 (d, 3 H, 3J = 7.5 Hz), 8.65 (d, 3 H, 4J = 2.0
Hz).
13C NMR (CDCl3): = 55.3, 119.6, 121.3, 128.0, 134.6, 137.4,
139.2, 141.6, 149.6, 153.9, 157.0.
IR (KBr): 3054 (w), 2942 (br m), 2850 (br m), 1605 (m), 1521 (s),
1347 (s), 1265 (s), 738 (s) cm–1.
1H NMR (CDCl3) : = 2.69 (m, 2 H), 2.84 (m, 2 H), 3.91 (s, 2 H),
7.51 (d, 2 H, 3J = 8.0 Hz), 8.17 (d, 2 H, 3J = 8.0 Hz).
13C NMR (CDCl3): = 41.7, 52.0, 53.1, 123.7, 128.7, 148.5, 153.3.
MS (FAB+): m/z = 196.3 ([M + H]+, 100%).
MS (ESI-ToF): m/z = 759.9 ([M + H]+, 6%), 781.9 ([M + Na]+,
22%).
N,N,N -Tris[(6-bromo-2,2 -bipyridine-5 -yl)methyl]-N -p-nitro-
benzylethylenediamine (19)
Anal. Calcd for C33H24N7Br3 (758.32): C, 52.27; H, 3.19; N, 12.93.
Found: C, 52.03; H, 3.07; N, 12.74.
Compound 18 (110 mg, 0.56 mmol), 5 (610 mg, 1.86 mmol) and
K2CO3 (350 mg, 2.5 mmol) were placed in a Schlenk tube under ar-
gon containing dry MeCN (20 mL). The temperature was raised to
80 °C for 19 h. The solvent was evaporated to dryness and the resi-
due dissolved with CH2Cl2 (30 mL) and H2O (20 mL). The aq phase
was washed with CH2Cl2 (20 mL) and the combined organic layers
were dried (Na2SO4), filtered, evaporated to dryness and purified by
column chromatography (SiO2; CH2Cl2–MeOH, 100:0 to 98:2).
Compound 19 was finally obtained after recrystalisation with
CH2Cl2–MeCN.
Tris-[(6 -carboethoxy-2,2 -bipyridine-5-yl)methyl]amine (16)
This compound was obtained according to the procedure described
for 3 starting from 15 (224 mg, 0.29 mmol), PdCl2(PPh3)2 (42 mg,
0.059 mmol) in a mixture of EtOH (30 mL) and Et3N (30 mL). After
column chromatography (SiO2 previously treated with Et3N;
CH2Cl2–MeOH, 100:0 to 99:1) compound 16 was isolated.
Yield: 73 mg (33%); white solid; mp >270 °C (decomp).
IR (KBr): 2964 (m), 2926 (m), 1716 (s), 1588 (m), 1451 (m), 1139
(s) cm–1.
Yield: 390 mg (74%); white microcrystals;. mp 168–170 °C.
IR (KBr): 2800 (br m), 1567 (m), 1542(s), 1515 (m), 1429 (s), 1343
(m), 1124 (m) cm–1.
1H NMR (CDCl3) : = 2.64 (s, 4 H), 3.56 (s, 2 H), 3.58 (s, 6 H), 7.38
(d, 2 H, 3J = 8.5 Hz), 7.44 (dd, 1 H, 3J = 8.0 Hz, 4J = 1.0 Hz), 7.46
(dd, 2 H, 3J = 8.0 Hz, 4J = 1.0 Hz), 7.60–7.69 (m, 6 H), 8.08 (d, 2 H,
3J = 9.0 Hz), 8.26–8.33 (m, 6 H), 8.51 (br s, 3 H).
13C NMR (CDCl3): = 51.8, 52.0, 56.3, 58.3, 119.7, 121.2, 123.7,
128.0, 129.1, 134.9, 135.0, 137.3, 137.4, 139.3, 141.7, 146.9, 147.2,
149.5, 149.6, 153.8, 157.1.
1H NMR (CDCl3) : = 1.47 (t, 9 H, 3J = 7.0 Hz), 3.69 (s, 6 H), 4.49
(q, 6 H, 3J = 7.0 Hz), 7.87 (dd, 3 H, 3J = 8.0 Hz, 4J = 1.5 Hz), 7.94
(t, 3 H, 3J = 8.0 Hz), 8.11 (d, 3 H, 3J = 7.5 Hz), 8.54 (d, 3 H, 3J = 8.0
Hz), 8.56 (d, 3 H, 3J = 7.5 Hz), 8.67 (br s, 3 H).
13C NMR (CDCl3): = 14.3, 55.1, 61.9, 121.6, 124.1, 124.9, 134.6,
137.5, 137.9, 147.8, 149.5, 154.7, 156.1, 165.3.
MS (ESI-ToF): m/z = 738.3 ([M + H]+, 5%), 760.2 ([M + Na]+,
100%).
Anal. Calcd for C42H39N7O6 (737.82): C, 68.37; H, 5.33; N, 13.29.
Found: C, 68.05; H, 5.13; N, 12.95.
MS (FAB+): m/z = 936.2 ([M + H]+, 92%), 938.2 ([M + H]+, 100%),
799.3 {[M
–
(CH2C6H4NO2)]+, 30%}, 801.3 {[M
–
(CH2C6H4NO2)]+, 30%}.
Tris-[(6 -carboxy-2,2 -bipyridine-5-yl)methyl]amine (17)
A mixture of 16 (73 mg, 0.10 mmol) in MeOH (5 mL) and NaOH
(280 mg, 7 mmol) in H2O (5 mL) was refluxed for 2 h. After cooling
to r.t., dilute aq HCl was slowly added until pH 4, resulting in the
Anal. Calcd for C42H34N9O2Br3 (936.51): C, 53.87; H, 3.66; N,
13.46. Found: C, 53.44; H, 3.39; N, 13.09.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Flexible Polydendate Ligands Bearing 5 -Substituted-6-carboxylic-2,2 -bipyridine Subunits
1109
N,N,N -Tris[(6-carboethoxy-2,2 -bipyridine-5 -yl)methyl]-N -p-
nitrobenzylethylenediamine (20)
(3) Montalti, M.; Prodi, L.; Zaccheroni, N.; Charbonnière, L. J.;
Douce, L.; Ziessel, R. J. Am. Chem. Soc. 2001, 123, 12694.
(4) Gao, F. G.; Bard, A. J. J. Am. Chem. Soc. 2000, 122, 7426.
(5) Wang, J.; Wang, R.; Yang, J.; Zheng, Z.; Carducci, M. D.;
Cayou, T.; Peyghambarian, N.; Jabbour, G. E. J. Am. Chem.
Soc. 2001, 123, 6179.
Compound 20 was obtained with a procedure similar to that of 3,
starting from 19 (345 mg, 0.37 mmol) and Pd(PPh3)2Cl2 (39 mg,
0.055 mmol) dissolved in a mixture of CH2Cl2 (5 mL), EtOH (20
mL) and Et3N (20 mL). After 4 d, the solution was evaporated to
dryness, coevaporated three times with CH2Cl2 (20 mL) and puri-
fied by column chromatography (SiO2; CH2Cl2–MeOH, 100:0 to
96.5:3.5; Rf 0.15, SiO2, CH2Cl2–MeOH, 98:2). Fractions corre-
sponding to 20 were evaporated to dryness, dissolved in a mixture
of CH2Cl2 (3 mL) and Et2O (3 mL) and the solution was saturated
with gaseous HCl, resulting in the formation of a white precipitate.
The solid was recovered by centrifugation and dried under reduced
pressure to give 20.
(6) (a) Blackburn, G. F.; Shah, H. P.; Kenten, J. H.; Leland, J.;
Kamin, R. A.; Link, J. Clin. Chem. 1991, 37, 1534. (b) Ege,
D.; Becker, W. G.; Bard, A. J. Anal. Chem. 1984, 56, 2413.
(7) (a) Evangelista, R. A.; Pollak, A.; Allore, B.; Templeton, E.
F.; Morton, R. C.; Diamandis, E. P. Clin. Biochem. 1988, 21,
173. (b) Saha, A. K.; Kross, K.; Kloszewski, E. D.; Upson,
D. A.; Toner, J. L.; Snow, R. A.; Black, C. D. V.; Desai, V.
C. J. Am. Chem. Soc. 1993, 115, 11032. (c) Hemmilä, I.;
Harju, R. In Biological Applications of Labelling
Technologie; Emmilä, I.; Stahlberg, T.; Mottram, P., Eds.;
Wallac Oy and EG&G: Cie, 1995. (d) Vereb, G.; Jares-
Erijman, E.; Selvin, P. R.; Jovin, T. M. Biophys. J. 1998, 74,
2210. (e) Bornhop, D. J.; Hubbard, D. S.; Houlne, M. P.;
Adair, C.; Kiefer, G. E.; Pence, B. C.; Morgan, D. L. Anal.
Chem. 1999, 71, 2607. (f) Griffin, J. M. M.; Skwierawska,
A. M.; Manning, H. C.; Marx, J. N.; Bornhop, D. J.
Tetrahedron Lett. 2001, 42, 3823.
Yield: 133 mg (36%); white solid; mp >130 °C (decomp).
IR (KBr): 2985 (w), 1720 (s), 1630 (m), 1585 (w), 1523 (w), 1347
(w), 1306 (w), 1520 (m) cm–1.
1H NMR (CDCl3, non-protonated form): = 1.46 (t, 3 H, 3J = 7.0
Hz), 1.47 (t, 6 H, 3J = 7.0 Hz), 2.67 (br s, 4 H), 3.60 (s, 6 H), 3.62
(s, 2 H), 4.48 (q, 2 H, 3J = 7.0 Hz), 4.49 (q, 4 H, 3J = 7.0 Hz), 7.40
(d, 2 H, 3J = 9.0 Hz), 7.70–7.79 (m, 3 H), 7.88–7.98 (m, 3 H), 8.07–
8.14 (m, 5 H), 8.46–8.57 (m, 9 H).
(8) Wieder, I. In Immunofluorescence and Related Staining
Techniques. Proceedings of the VIth International
Conference on Immunofluorescence and Related Staining
Techniques; Knapp, W.; Holubar, K.; Wick, G., Eds.;
Elsevier, North-Holland Biomedical Press: Amsterdam,
1978, 67.
13C NMR (CDCl3, non-protonated form): = 14.4, 51.7, 51.9, 56.3
(br), 58.2, 61.9, 121.5, 123.7, 124.1, 125.0, 129.1, 134.9, 137.4,
137.5, 137.9, 146.9, 147.3, 147.9, 149.6, 154.7, 156.2, 165.3.
MS (FAB+): m/z = 916.5 ([M + H]+, 100%), 779.5 {[M –
(CH2C6H4NO2)]+, 20%}.
(9) Soini, E.; Kojola, H. Clin. Chem. 1983, 29, 65.
(10) Charbonnière, L. J.; Guardigli, M.; Cesario, M.; Roda, A.;
Sabbatini, N.; Ziessel, R. J. Am. Chem. Soc. 2001, 123, 2436.
(11) Charbonnière, L. J.; Weibel, N.; Ziessel, R. F. Tetrahedron
Lett. 2001, 42, 659.
(12) Ulrich, G.; Bedel, S.; Picard, C.; Tisnès, P. Tetrahedron Lett.
2001, 42, 6113.
(13) (a) Mukkala, V.-M.; Kwiatkowski, M.; Kankare, J.; Takalo,
H. Helv. Chim. Acta 1993, 76, 893. (b) Takalo, H.;
Hemmilä, I.; Sutela, T.; Latva, M. Helv. Chim. Acta 1996,
79, 789.
(14) Piguet, C.; Bünzli, J.-C. G. Chem. Soc. Rev. 1999, 28, 347.
(15) Charbonnière, L. J.; Weibel, N.; Ziessel, R. F.; J. Org.
Chem., 2001, in press.
(16) Parks, J. E.; Wagner, B. E.; Holm, R. H. J. Organometal.
Chem. 1973, 56, 53.
Anal. Calcd for C51H49N9O8 2 HCl H2O (1006.95 + 72.92 + 18.01):
C, 60.83; H, 5.31; N, 12.52. Found: C, 60.65; H, 5.18; N, 12.39.
N,N,N -Tris[(6-carboxy-2,2 -bipyridine-5 -yl)methyl]-N -p-ni-
trobenzylethylenediamine (21)
Compound 20 (118 mg, 0.12 mmol) was dissolved in MeOH (10
mL). NaOH (40 mg, 1 mmol) in H2O (10 mL) was added resulting
in the formation of a white suspension. The solution was heated at
80 °C for 2 h. MeOH was evaporated under reduced pressure, the
resulting solution was filtered through cotton wool and acidified to
pH 2 with concd aq HCl. The solution was evaporated to dryness,
dissolved in MeOH (3 mL) and Et2O was added until a solid precip-
itated. The solid was collected by centrifugation and dried under re-
duced pressure to give 21.
Yield: 78 mg (80%); white solid; mp > 160 °C (decomp).
(17) King, L. C. J. Am. Chem. Soc. 1944, 66, 894.
(18) Kröhnke, F. Synthesis 1976, 1.
IR (KBr): 2925 (w), 2853 (w), 1720 (br s), 1617 (s), 1588 (s), 1346
(m), 1143 (s) cm–1.
(19) El Ghayoury, A.; Ziessel, R. J. Org. Chem. 2000, 65, 7757.
(20) (a) Savage, S. A.; Smith, A. P.; Fraser, C. L. J. Org. Chem.
1998, 63, 10048. (b) Fraser, C. L.; Anastasi, N. R.; Lamba,
J. J. S. J. Org. Chem. 1997, 62, 9314. (c) Lamba, J. J. S.;
Fraser, C. L. J. Am. Chem. Soc. 1997, 119, 1801.
(21) Ziessel, R.; Hissler, M.; Ulrich, G. Synthesis 1998, 1339.
(22) Weibel, N.; Charbonnière, L. J.; Ziessel, R.F., unpublished
results.
1H NMR (CD3OD–CDCl3, 1:1): = 2.63 (br s, 4 H), 3.56 (br s, 6
H), 3.63 (br s, 2 H), 7.15–7.23 (br d, 2 H), 7.60–7.90 (br m, 11 H),
7.95–8.20 (br m, 6 H), 8.31 (br s, 3 H).
MS (FAB+): m/z = 832.3 ([M + H]+, 100%), 695.5 {[M –
(CH2C6H4NO2)]+, 30%}.
Anal. Calcd for C45H37N9O8 (831.85): C, 64.98; H, 4.48; N, 15.15.
Found: C, 64.61; H, 4.20; N, 14.76.
(23) El-ghayoury, A.; Ziessel, R. Tetrahedron Lett. 1998, 39,
4473, and references cited therein..
(24) (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem.
1974, 39, 3318. (b) Schoenberg, A.; Heck, R. F. J. Org.
Chem. 1974, 39, 3327.
(25) De Almeida, M. V.; Cesar, E. T.; Felicio, E. D. C. A.;
Fontes, A. P. S.; Robert-Gero, M. J. Braz. Chem. Soc. 2000,
11, 154.
(26) Hanan, G. S.; Schubert, U. S.; Volkmer, D.; Rivière, E.;
Lehn, J.-M.; Kyritsakas, N.; Fischer, J. Can. J. Chem. 1997,
75, 169.
References
(1) Ziessel, R. In Photosensitization and Photocatalysis Using
Inorganic and Organometallic Compounds;
Kalyanasundaram, K.; Grätzel, M., Eds.; Kluver: Dordrecht,
1993, 217–240.
(2) Deronzier, A.; Moutet, J.-C. Coord. Chem. Rev. 1996, 147,
339.
Synthesis 2002, No. 8, 1101–1109 ISSN 0039-7881 © Thieme Stuttgart · New York