5′-substituted-6-carboxylic-2,2′-bipyridine acid: A pivotal architecton for building preorganized ligands

Article abstract of DOI:10.1021/jo0200015

A set of ligands bearing 6-bromo-2,2′-bipyridine pendant arms attached in the 5′-position are described. Transformation of the bromo to an ester was performed by a carboethoxylation reaction promoted by low-valent Pd(0), while saponification followed by acidification gave the acids. The introduction of an appended function 3-nitrobenzyl, benzamidomethyl, and tert-butylacetyl opens the way to further functionalize these scaffolds for potential labeling of biological material. The synthetic protocols represent a valuable approach to the rational design of ligands bearing oxophilic and anionic sidearms.

Full text of DOI:10.1021/jo0200015

J . Org. Chem. 2002, 67, 3933-3936
3933
preorganized scaffoldings containing 2,2′-bipyridine-6-
carboxylic acid arms.10 The bipyridine moiety is known
to be very efficient for photon collection and transfer to
lanthanide cations.11 The ionizable 6-carboxylic acid
function affords an anionic function at neutral pH, which
strongly favors the coordination to the metal atom by
purely electrostatic interactions.12 Furthermore, grafting
this carboxylate function at the 6 position further stabi-
lizes the coordination by formation of a second five-
membered ring. All efforts toward the stabilization of the
complex are of particular importance to avoid the release
of the toxic free lanthanide cations, a sine qua non
condition for potential use in biological media. Finally,
assuming a coordination number of nine, a situation
commonly encountered for trivalent lanthanide cations,13
the coordination of three tridentate arms allows for
charge compensation and completion of the first coordi-
nation sphere, thus relegating solvent molecules to the
second sphere and thereby avoiding the nonradiative
deactivation pathways.
5′-Su bstitu ted -6-ca r boxylic-2,2′-bip yr id in e
Acid : A P ivota l Ar ch itecton for Bu ild in g
P r eor ga n ized Liga n d s
Lo¨ıc J . Charbonnie`re,* Nicolas Weibel, and
Raymond F. Ziessel*
Laboratoire de Chimie Mole´culaire, Associe´ au CNRS
UMR-7008, Ecole de Chimie, Polyme`res et Mate´riaux de
Strasbourg (ECPM), 25 rue Becquerel,
67087 Strasbourg Cedex 02, France
ziessel@chimie.u-strasbg.fr.
Received J anuary 3, 2002
Abstr a ct: A set of ligands bearing 6-bromo-2,2′-bipyridine
pendant arms attached in the 5′-position are described.
Transformation of the bromo to an ester was performed by
a carboethoxylation reaction promoted by low-valent Pd(0),
while saponification followed by acidification gave the acids.
The introduction of an appended function 3-nitrobenzyl,
benzamidomethyl, and tert-butylacetyl opens the way to
further functionalize these scaffolds for potential labeling
of biological material. The synthetic protocols represent a
valuable approach to the rational design of ligands bearing
oxophilic and anionic sidearms.
From a chemical point of view, the construction of
bipyridine platforms seems to be a worthy task.14 How-
ever, the chemistry of bipyridine bearing potentially
ionizable groups (e.g., carboxylate, phosphonate, sulfate,
etc.) is significantly underdeveloped due to the lack of
general synthetic methods. Furthermore, the rare exist-
ing ligands bearing such fragments are symmetrically
substituted and offer no synthetic means for attachment
to shaping units.15,16 Here, we partially fill the gap and
describe a general procedure for the synthesis of asym-
metric 5′,6-disubstituted-2,2′-bipyridine architectons, us-
ing an optimized access to the key 5′-bromomethyl-6-
bromo-2,2′-bipyridine building block. We will see in detail
how three tridentate units should be brought together
on acyclic or macrocyclic platforms, some of them offering
potentialities for further grafting on biological com-
pounds. The development of these novel ligands would
expand opportunities for applications of emergent lan-
thanide complexes in the field of time-resolved lumines-
cence microscopy.
In the past few decades, important advances in the
development of optical microscopy and image analysis1
rendered possible the observation of small objects at the
nanometric scale.2 In the field of luminescence micros-
copy,3 a large amount of fluorescent probes are now
commercially available that can easily be bioconjugated
onto biological material. A further step toward the
improvement of sensitivity should be reached by the use
of time-resolved luminescence microscopy.4,5 For such an
application, new luminescent tags have to be created and
the main interests are actually centered around the
synthesis of coordination complexes such as Pt-por-
phine6 or lanthanide complexes.7 Although lanthanide
tags have long been postulated as good candidates for
time-resolved fluoroimmunoassays8 and thereby for time-
resolved luminescence microscopy, the numerous require-
ments that have to be fulfilled by a probe to be efficient9
drastically reduce the number of potential candidates.
As part of a research program aimed at the design and
synthesis of anionic and tridentate ligands and in order
to obtain compounds that fulfill as much as possible the
different requirements for obtaining good probes, we have
been interested in the synthesis of ligands based on
(7) Hemmila¨, I.; Harju, R. In Biological Applications of Labeling
Technologies; Emmila¨, I., Stahlberg, T., Mottram, P., Eds.; Wallac Oy
and EG&G Cie: 1995.
(8) (a) 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; p 67. (b) Soini, E.; Kojola, H. Clin. Chem.
1983, 29, 65. (c) for a recent review see Yam, V. W.-W.; Lo, K. K.-W.
Coord. Chem. Rev. 1998, 184, 157.
(9) (a) Takalo, H.; Hemmila¨, I.; Sutela, T.; Latva, M. Helv. Chim.
Acta 1996, 79, 789. (b) Piguet, C.; Bu¨nzli, J .-C. G. Chem. Soc. Rev.
1999, 28, 347.
(1) (a) Tanke, J . H. J . Microsc. (Oxford) 1989, 155, 405. (b) Cooke,
P. M. Anal. Chem. 1998, 70, 385; 1996, 68, 333; 2000, 72, 169.
(2) De Brabander, M.; Geuens, G.; Nuydens, R.; Moeremans, M.;
de Mey, J . Cytobios 1985, 43, 273.
(3) (a) Mayer, A.; Neuenhofer, S. Angew. Chem., Int. Ed. Engl. 1994,
33, 1044. (b) Hovius, R.; Valloton, P.; Wohland, T.; Vogel, H. Trends
Pharmacol. Sci. 2000, 21, 266.
(4) (a) Mariott, G.; Clegg, R. M.; Arndt-J ovin, D. J .; J ovin, T. M.
Biophys. J . 1991, 60, 1374. (b) Beeby, A.; Botchway, S. W.; Clarkson,
I. M.; Faulkner, S.; Parker, A. W.; Williams, J . A. G. J . Photochem.
Photobiol. B 2000, 57, 83.
(5) Charbonnie`re, L.; Guardigli, M.; Cesario, M.; Roda, A.; Sabbatini,
N.; Ziessel, R. J . Am. Chem. Soc. 2001, 123, 2436.
(10) Charbonnie`re L. J .; Weibel, N.; Ziessel, R. F. Tetrahedron Lett.
2001, 42, 659.
(11) Sabbatini, N.; Guardigli, M.; Lehn, J .-M. Coord. Chem. Rev.
1993, 123, 201.
(12) Bu¨nzli, J .-C. G.; Charbonnie`re, L. J .; Ziessel, R. J . Chem. Soc.,
Dalton Trans. 2000, 1917.
(13) Bu¨nzli J .-C. G. In Lanthanide Probes in Life, Chemical and
Earth Science: Theory and Practice; Bu¨nzli, J .-C. G., Choppin, G. R.,
Eds.; Elsevier Science BV: Amsterdam, 1989.
(14) Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
(15) (a) Whittle, C. P. J . Heterocycl. Chem. 1977, 14, 191. (b)
Newkome, G. R.; Puckett, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia, Y.;
Coreil, M.; Hackney, M. A. J . Org. Chem. 1982, 47, 4116.
(16) Penicaud, V.; Odobel, F.; Bujoli, B. Tetrahedron Lett. 1998, 39,
3689.
(6) Henning, E. J .; de Hass, R.; Verwoerd, N. P.; Tanke, H. J .
Cytometry 1996, 24, 312.
10.1021/jo0200015 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

3934 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
Sch em e 1a
Sch em e 2a
aReaction conditions: (i) C6H5COCl, DMF, Et3N, 5 °C, 72%. (ii)
p-TsCl, pyridine, 0 °C, 69%. (iii) Cs2CO3, DMF, 90 °C, 37%. (iv)
Concd H2SO4, 120 °C, 50%. (v) CH3CN, Na2CO3, 3.3 equiv of 1, 80
°C, 30%.
aReaction conditions: (i) CH3CN, Na2CO3, 80 °C, 96% for 3 and
63% for 6. (ii) [Pd(PPh3)2Cl2] (6.8 mol % per Br atom), EtOH, Et3N,
CO (1 atm), 80 °C, 83% for 4 and 76% for 7. (iii) MeOH, H2O,
NaOH, 80 °C; dil HCl, 78% for 5 and 83% for 8.
antibodies. Furthermore, reaction of 2 with excess 1 gave
the intermediate 6 in excellent yield, which can be easily
converted to the ethyl ester 7 by carboalkoxylation.
Subsequent saponification and acidification afforded the
triacid 8, which is an adequate target for further com-
plexation with lanthanide cations.
Another way to reach the goal of bioconjugation to
protein plants is to envisage a 1,4,7-triazacyclononane
macrocycle carrying a benzamide function with the
viewpoint of releasing the primary amine in strongly
acidic conditions after the alkylation process. Construc-
tion of the modified 1,4,7-triazacyclononane derivative
was carried out as sketched in Scheme 2.
The pivotal 5′-bromomethyl-6-bromo-2,2′-bipyridine
building block 110 required the synthesis of 5′-methyl-6-
bromo-2,2′-bipyridine itself prepared in two steps from
2-acetyl-6-bromopyridine17 according to the methodology
of Kro¨hnke.18 Activation of the 5′-methyl position was a
key step in the development of our envisaged preorga-
nized bipyridine-containing architectures. The target was
reached by the use of a conventional radical bromination
with NBS in refluxing CCl4, using AIBN as an initiator.
The highest yield (69% after purification) was provided
with 1.25 equiv of NBS and 0.05 equiv of AIBN, in hot
CCl4, with irradiation to initiate the reaction.
The first ligand bearing three potentially anionic arms
was prepared by alkylation of the 1,4,7-triazacyclononane
macrocycle followed by a carboethoxylation reaction
catalyzed by low-valent palladium(0)19 to give the corre-
sponding triester 4 in 83% yield (Scheme 1). Upon
saponification with aqueous NaOH in MeOH, followed
by acidification, the triply branched acid 5 was obtained,
which as shown previously is ideally suited for the
formation of mononuclear lanthanide complexes.5 How-
ever, to anchor it onto biomaterials, a functional sidearm
is required. For this purpose, the monoalkylation of
cyclam with 3-nitrobenzylbromide was investigated (81%
yield for 2), according to methods currently used for
monofunctionalization of tetraazamacrocycles consisting
of the use of a large excess of the macrocycle compared
to the alkylating agent.20 The choice of a m-nitrobenzyl-
bromide as the alkylating agent arose from the possibility
of reducing the nitro into the corresponding amino
function, which then can be converted into an isothiocy-
anate function.21 This residue is a good candidate for
coupling to terminal amino residues of proteins or
At first, the aminodiol 9 was acylated selectively at the
primary amine using stoichiometric amounts of benzoyl
chloride, followed by an activation of both alcohol func-
tions with p-toluenesulfonic acid chloride in basic condi-
tions leading to compound 11. Afterward, cyclization
between 11 and the tritosylate of diethylenetriamine 1222
was carried out in the presence of Cs2CO3 as previously
described.23 Detosylation of compound 13 is effective in
concentrated sulfuric acid and provides the macrocycle
14 in 50% yield. When the alkylation reaction is carried
out with a slight excess of derivative 1, the target ligand
bearing only three bipy frameworks could not be isolated,
despite the fact that various experimental conditions
were tested. It appears that the alkylation of the second-
ary amide function takes place readily even in the
absence of added mineral base and provides the tetra-
substituted derivatives 15 in fair yield. Such an undes-
ired side compound was observed even in the early stage
(21) For a recent example, see: Werts, M. H. V.; Woudenberg, R.
H.; Emmerink, P. G.; van Gassel, R.; Hofstraat, J . W.; Verhoeven, J .
W. Angew. Chem., Int. Ed. 2000, 39, 4542.
(22) Comarmond, J .; Plumere´, P.; Lehn, J .-M.; Agnus, Y.; Louis, R.;
Weiss, R.; Kahn, O.; Morgenstern-Badarau, I. J . Am. Chem. Soc. 1982,
104, 6330.
(23) Cox, J . P. L.; Craig, A. S.; Helps, I. M.; J ankowski, K. J .; Parker,
D.; Eaton, M. A. W.; Millican, A. T.; Millar, K.; Beeley, N. R.; Boyce,
B. A. J . Chem. Soc., Perkin Trans. 1 1990, 2567.
(17) Parks, J . E.; Wagner, B. E.; Holm, R. H. J . Organomet. Chem.
1973, 56, 53.
(18) Kro¨hnke, F. Synthesis 1976, 1.
(19) El Ghayoury, A.; Ziessel, R. J . Org. Chem. 2000, 65, 7757.
(20) Kimura, E. Pure Appl. Chem. 1989, 61, 823.

Notes
J . Org. Chem., Vol. 67, No. 11, 2002 3935
Sch em e 3a
The presence of a bromine atom at the 6 position
facilitates a Pd-assisted carboethoxylation reaction lead-
ing to esters and carboxylic acids and potentially to amide
functions. In addition, the optimized synthesis of 5′-
bromomethyl-6-bromo-2,2′-bipyridine makes this com-
pound an attractive and more available template for
ligand synthesis. We succeeded in preparing a large
variety of preorganized platforms spanning from triaza-
cyclononane to tetraazacyclotetradecane, all of them
carrying polytridentate subunits. The chosen protocols
allow an amalgamation of several distinct functionalities
and properties. The basic architecture of the target
molecules is the presence of three anionic N,N,O donor
fragments, which is an ideal situation for the complex-
ation of tricationic cations. The complexation of lanthani-
de(III) cations with these 6-carboxylic-2,2′-bipyridyl acid
functionalized ligands is currently in progress in our
laboratory and has already shown remarkable photo-
physical properties for the europium and terbium com-
plexes generated with ligand 5.5 Finally, in some cases,
the presence of an additional pendant arm carrying a
potential activated function is auspicious for bioconju-
gation to proteins and biological analogues.
a
(i) CH3CN, Na2CO3, 80 °C, 3.3 equiv of 1, 85%. (ii) [Pd(PPh3)2-
Cl2] (5.0 mol % per Br atom), EtOH, Et3N, CO (1 atm), 80 °C, 80%.
(iii) MeOH, H2O, NaOH, 80 °C; dil HCl, 57%.
Exp er im en ta l Section
Ma ter ia ls. 6-Bromo-2-acetylpyridine,17 bis[2-(tosylamino)-
ethyl]tosylamine 12,22 (2-amino-ethylamino)acetic acid-tert-
butylester 16,24 and 6-bromo-5′-methyl-2,2′-bipyridine10,25 were
prepared according to literature procedures. All other reagents
were used as commercially supplied.
of the reaction and would give disappointingly low yields
of the target tris-substituted derivatives under typical
reaction conditions. This is a rather surprising result
because it was previously shown that alkylation of
similar compounds does not occur even in the presence
of a large excess of alkylating agent.23 From these
observations, it appears that the use of a short methylene
linker between the amide nitrogen and the macrocycle
might favor intramolecular hydrogen bonding between
the amide proton and the endocyclic NH fragments
leading to six- or five-membered rings and also to an
indirect increase of the nucleophilicity of the amide
nitrogen atom. Such an unexpected alkylation reaction
on the amide function will be detrimental for the selective
formation of lanthanide complexes and brings us to
consider other ways to introduce the branching sidearm.
To induce more flexibility and solubility within the
central polyamine frame but also introduce an additional
pendant arm that could ultimately be functionalized to
a targeted anchoring point, we have protected one
nitrogen atom of ethylenediamine with a tert-butylbro-
moacetate24 affording the product 16 as outlined in
Scheme 3. Further alkylation of the remaining three
positions with 1 afforded ligand 17 in 85% isolated yield.
This tribromo-substituted derivative was esterified under
smooth conditions as described above to afford the
tetraester 18 in 80% yield. Saponification of this com-
pound under basic conditions and subsequent acidifica-
tion provide the tetraacid 19.
6-Br om o-5′-br om om eth yl-2,2′-bip yr id in e (1). 69%; TLC:
1
Rf ) 0.38, SiO2, CH2Cl2). H NMR (CDCl3): δ 4.53 (s, 2H), 7.50
(dd, 1H, 3J ) 8.0 Hz, 4J ) 1.0 Hz), 7.67 (t, 1H, 3J ) 8.0 Hz),
7.85 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.4 Hz), 8.37 (dd, 1H, 3J ) 7.5
Hz, 4J ) 1.0 Hz), 8.40 (d, 1H, 3J ) 8.5 Hz), 8.67 (d, 1H, 4J ) 2.0
Hz). 13C NMR (CDCl3): δ 29.5, 119.9, 121.4, 128.3, 134.3, 137.7,
139.3, 141.7, 149.5, 154.5, 156.8. FT-IR (KBr, cm-1): 1541 (s),
1430 (s), 1391 (m), 1156 (m). Anal. Calcd for C11H8Br2N2: C,
40.30; H, 2.46; N, 8.54. Found: C, 39.91; H, 2.14; N, 8.22. Mp:
166-167 °C. ESI-ToF/MS m/z: 326.902 ([M + H]+, 30%), 328.901
([M + H]+, 83%), 330.980 ([M + H]+, 24%), 348.874 ([M + Na]+,
45%), 350.876 ([M + Na]+, 83%), 352.874 ([M + Na]+, 32%).
1-(3-Nitr oben zyl)-1,4,8,11-tetr a a za cyclotetr a d eca n e (2).
81%. 1H NMR (CDCl3): δ 1.56-1.90 (m, 4H), 2.36-2.88 (m, 16H),
3
3
3.58 (s, 2H), 7.37 (t, 1H, J ) 7.5 Hz), 7.52 (d, 1H, J ) 7.5 Hz),
8.02 (d, br, 1H, J ) 8.5 Hz), 8.34 (s, br, 1H). 13C NMR (CDCl3):
3
δ 26.1, 28.8, 47.2, 47.9, 48.8, 49.3, 49.9, 51.9, 53.3, 55.2, 57.5,
122.1, 123.2, 128.9, 134.7, 135.0, 141.8. Rf ) 0.51, deactivated
SiO2, CH2Cl2/MeOH, 90/10. FT-IR (KBr, cm-1): 3293 (m), 2806
(s), 1527 (s), 1463 (m), 1352 (m). Anal. Calcd for C17H29N5O2:
C, 60.85; H, 8.71; N, 20.88. Found: C, 60.41; H, 8.46; N, 20.37.
Mp: 58-59 °C. FAB+/MS: 336.4 ([M + H]+, 100%).
1,4,7-Tr is[(6-b r om o-2,2′-b ip yr id in e-5′-yl)m et h yl]-1,4,7-
tr ia za cyclon on a n e (3). 96%. 1H NMR (CDCl3): δ 2.81 (s, 12H,
br), 3.68 (s, 6H, br), 7.48 (dd, 3H, 3J ) 7.8 Hz, 4J ) 1.0 Hz), 7.67
(t, 3H, 3J ) 8.0 Hz), 7.78 (dd, 3H, 3J ) 8.0 Hz, 4J ) 2.0 Hz),
8.35 (d, 3H, 3J ) 8.0 Hz), 8.37 (dd, 3H, 3J ) 8.0 Hz, 4J ) 1.0
Hz), 8.60 (s, 3H, br). 13C NMR (CDCl3): δ 55.5, 60.2, 119.6, 121.0,
127.7, 136.3, 137.7, 139.2, 141.5, 149.8, 153.3, 157.3. Rf ) 0.44,
deactivated SiO2, CH2Cl2. FT-IR (KBr, cm-1): 1647 (s), 1541 (m),
1430 (s). Anal. Calcd for C39H36N9Br3: C, 53.81; H, 4.17; N,
14.48. Found: C, 53.62; H, 3.91; N, 14.24. Mp: 150-151 °C.
FAB+/MS: 870.3 ([M + H]+, 96%), 872.3 ([M + H]+, 100%), 620.2
([M - CH2bipyBr)], 20%), 622.2 ([M - CH2bipyBr)], 50%), 624.2
([M - CH2bipyBr)], 28%).
In summary, we have presented a logical and expedient
protocol for the synthesis of different 2,2′-bipyridyl
derivatives asymmetrically substituted at the 5′ and 6
positions with various functions. The engineering of a
reactive bromomethyl group in the 5′ position allowed
nucleophilic substitution by primary or secondary amines.
1,4,7-Tr is[(6-ca r boeth oxy-2,2′-bip yr id in e-5′-yl)m eth yl]-
1,4,7-tr ia za cyclon on a n e (4). 83%. 1H NMR (CDCl3): δ 1.46 (t,
9H, 3J ) 7.0 Hz), 2.93 (s, 12H, br), 3.77 (s, 6H, br), 4.49 (qd, 6H,
3J ) 7.5 Hz), 7.89-8.02 (m, 6H), 8.11 (dd, 3H, 3J ) 7.5 Hz, 4J )
1.0 Hz), 8.51-8.64 (m, 9H). 13C NMR (CDCl3): δ 14.6, 55.8, 60.5,
(24) Thompson, S. A.; J osey, J . A.; Cadilla, R.; Gaul, M. D.;
Hassmann, C. F.; Luzzio, M. J .; Pipe, A. J .; Reed, K. L.; Ricca, D. J .;
Wiethe, R. W.; Noble, S. A. Tetrahedron 1995, 51, 6179.
(25) Hanan, G. S.; Schubert, U. S.; Volkmer, D.; Rivie`re, E.; Lehn,
J .-M.; Kyritsakas, N.; Fischer, J . Can. J . Chem. 1997, 75, 169.

3936 J . Org. Chem., Vol. 67, No. 11, 2002
Notes
62.0, 121.5, 124.3, 125.0, 132.2, 136.5, 138.0, 148.0, 150.0, 154.4,
156.6, 165.5. Rf ) 0.66, deactivated SiO2, CH2Cl2/MeOH, 99.5/
0.5. FT-IR (KBr, cm-1): 2929 (m), 1732 (s), 1719 (s), 1450 (m),
1240 (s), 1139 (s). Anal. Calcd for C48H51N9O6: C, 67.83; H, 6.05;
N, 14.83. Found: C, 67.67; H, 5.81; N, 14.66. Mp: >150 °C dec.
FAB+/MS: 850.7 ([M + H]+, 100%).
96/4. FT-IR (KBr, cm-1): 2921 (m), 2873 (w), 1651 (m), 1343 (s),
1155 (s). Anal. Calcd for C35H40N4O7S3: C, 58.00; H, 5.56; N, 7.73.
Found: C, 57.78; H, 5.25; N, 7.46. ESI-ToF/MS: 725.311 ([M +
H]+, 100%), 747.282 ([M + Na]+, 50%).
2-(Ben za m id om eth yl)-1,4,7-tr ia za cyclon on a n e (14). 50%.
1H NMR (CDCl3): δ 2.58-2.85 (m, 10H), 3.65-4.15 (m, 2H), 4.81
(m, 1H), 7.25-7.48 (m, 4H), 7.90 (d, 2H, J ) 8.5 Hz). 13C NMR
1,4,7-Tr is[(6-ca r boxy-2,2′-bip yr id in e-5′-yl)m eth yl]-1,4,7-
tr ia za cyclon on a n e (5). 78%. 1H NMR (DMSO-d6): δ 3.99 (s,
12H, br), 4.04 (s, 6H, br), 7.83 (d, 3H, br, 3J ) 8.0 Hz), 8.05-
8.10 (m, 6H), 8.53-8.56 (m, 6H), 8.59 (s, 3H, br). 13C NMR (D2O/
NaOD): δ 55.7, 60.4, 123.8, 124.7, 125.8, 137.0, 140.5, 140.9,
151.3, 155.3, 155.6, 156.0, 174.4. FT-IR (KBr, cm-1): 1720 (s),
1630 (s), 1460 (m), 1352 (s), 1262 (m). Mp: >220 °C dec. Anal.
Calcd for C42H39N9O6‚H2O: C, 64.36; H, 5.27; N, 16.08. Found:
C, 64.26; H, 5.15; N, 16.14. FAB+/MS: 766.5 ([M + H]+, 30%).
1-(3-Nitr oben zyl)-4,8,11-tr is[(6-br om o-2,2′-bip yr id in e-5′-
yl)m eth yl]-1,4,8,11-tetr a a za cyclotetr a d eca n e (6). 63%. 1H
NMR (CDCl3): δ 1.66-1.86 (m, 4H), 2.40-2.72 (m, 16H), 3.43
(s, br, 8H), 7.31-7.48 (m, 4H), 7.52-7.80 (m, 7H), 8.05 (d, br,
1H, 3J ) 8.0 Hz), 8.16-8.35 (m, 7H), 8.47-8.58 (m, 3H). 13C
NMR (CDCl3): δ 24.7, 29.8, 50.5, 50.6, 50.7, 50.9, 51.4, 51.6,
56.1, 56.3, 56.4, 58.0, 119.7 (2C), 121.0, 121.1, 122.1, 123.7, 127.9,
129.0, 134.8, 136.2, 136.3, 137.6, 139.3, 141.6, 142.7, 148.3, 149.8,
153.4, 157.4, 157.5. Rf ) 0.26, SiO2, CH2Cl2/MeOH, 95/5. Mp:
>200 °C dec. FT-IR (KBr, cm-1): 2936 (m), 2800 (m), 1544 (s),
1526 (s), 1384 (m), 1347 (m). Anal. Calcd for C50H50N11O2Br3:
C, 55.78; H, 4.68; N, 14.31. Found: C, 55.41; H, 4.32; N, 13.92.
FAB+/MS: 1076.3 ([M + H]+, 100%), 1078.3 ([M + H]+, 100%),
940.5 ([M - CH2PhNO2 + H]+, 30%), 942.5 ([M - CH2PhNO2 +
H]+, 10%).
3
(CDCl3): δ 29.8, 41.9, 49.3, 49.6, 52.6, 58.4, 79.6, 127.9, 128.2,
128.4, 131.4. FT-IR (KBr, cm-1): 2925 (m), 1645 (s), 1538 (m),
1308 (m). HRMS (ES): calcd for C14H22N4O, 263.1871 (MH);
found, 263.1875.
2-[N-((6-Br om o-2,2′-bipyr idin e-5′-yl)m eth yl)ben zam idom -
et h yl)-1,4,7-t r is-[(6-b r om o-2,2′-b ip yr id in e-5′-yl)m et h yl]-
1,4,7-tr ia za cyclon on a n e (15). 30%. 1H NMR (CDCl3): δ 2.40-
2.79 (m, 10H), 3.43-3.65 (m, 9H), 3.93-4.05 (m, 1H), 4.62-4.78
(m, 1H), 7.28-7.70 (m, 15H), 7.84 (d, br, 2H, 3J ) 7.5 Hz), 8.15-
8.58 (m, 12H). 13C NMR (CDCl3): δ 51.7, 52.6, 52.8, 53.0, 56.0
(br), 56.7, 56.9, 58.3, 58.5, 78.6, 119.5, 120.9, 121.0, 127.6, 127.7,
127.8, 128.0, 128.3, 128.6, 131.3, 135.0, 135.1, 135.4 (br), 137.1,
137.2, 137.3, 139.1, 141.5 (br), 149.4, 149.5, 153.4, 153.5 (br),
157.0, 157.1, 163.6. Rf ) 0.49, SiO2, CH2Cl2/MeOH, 90/10. FT-
IR (KBr, cm-1): 2927 (m), 2817 (m), 1647 (s), 1543 (m), 1430 (s),
1124 (m). Mp: >220 °C dec. Anal. Calcd for C58H50N12OBr4: C,
53.46; H, 4.23; N, 14.12. Found: C, 55.42; H, 3.74; N, 13.15. ESI-
ToF/MS: 1273.035 ([M + Na]+, 100%).
N,N,N′-Tr is[(6-br om o-2,2′-bip yr id in e-5′-yl)m eth yl]-N′-t-
1
bu tyla cetyl-eth ylen ed ia m in e (17). 85%. H NMR (CDCl3): δ
1.41 (s, 9H), 2.61 (t, br, 2H, 3J ) 6.0 Hz), 2.85 (t, br, 2H, 3J )
6.0 Hz), 3.20 (s, 2H), 3.62 (s, 4H), 3.80 (s, 2H), 7.40-7.47 (m,
3H), 7.58-7.76 (m, 6H), 8.22-8.38 (m, 6H), 8.51 (d, 1H, 4J )
1.5 Hz), 8.56 (d, 2H, 4J ) 1.5 Hz). 13C NMR (CDCl3): δ 28.1,
29.6, 51.4, 51.9, 55.2, 55.8 (2C), 81.2, 119.6, 121.1, 127.8, 135.2
(2C), 137.3, 137.4, 139.1, 141.5, 149.5, 149.6, 153.6, 157.1, 157.2,
170.3. Rf ) 0.80, deactivated SiO2, CH2Cl2/MeOH, 98/2. FT-IR
(KBr, cm-1): 1731 (m), 1569 (m), 1544 (m), 1430 (s), 1153 (m),
1124 (m). Mp: >180 °C dec. Anal. Calcd for C41H39N8O2Br3: C,
53.79; H, 4.29; N, 12.24. Found: C, 53.61; H, 4.02; N, 12.00.
FAB+/MS: 916.2, 917.2, 918.2, 919.2 (40, 100, 45, and 40%,
respectively, [M + H]+).
1-(3-Nitr oben zyl)-4,8,11-tr is[(6-car beth oxy-2,2′-bipyr idin e-
5′-yl)m eth yl]-1,4,8,11-tetr a a za cyclotetr a d eca n e (7). 76%. 1H
NMR (CDCl3): δ 1.41 (t, br, 9H, 3J ) 7.0 Hz), 1.79 (m, 4H), 2.32-
3
2.75 (m, 16H), 3.40 (s, br, 8H), 4.44 (q, 6H, J ) 7.0 Hz), 7.10-
8.58 (m, 22H). 13C NMR (CDCl3): δ 14.4, 24.6, 50.5 (2C), 50.8,
51.3, 51.4, 51.5, 56.2, 56.3, 56.4, 58.0, 61.9, 119.7, 121.2, 121.3,
122.0, 123.7, 124.1, 124.8, 127.8, 128.4, 128.7, 129.0, 132.0 (2C),
132.2, 134.8, 136.0, 136.2, 137.6 (2C), 137.8, 139.3, 141.6, 142.7,
147.8, 148.3, 149.8, 154.2, 156.4, 156.5 (2C), 165.4. Rf ) 0.35,
deactivated SiO2, CH2Cl2/hexane, 70/30. FT-IR (KBr, cm-1):
2939 (m), 2793 (m), 1717 (s), 1527 (m), 1348 (m). Anal. Calcd
for C59H65N11O8: C, 67.08; H, 6.20; N, 14.59. Found: C, 66.74;
H, 5.94; N, 14.38. Mp: 51-52 °C. FAB+/MS: 1056.2 ([M + H]+,
100%), 814.2 ([M - (CH2bipyCO2Et)], 47%).
N,N,N′-Tr is[(6-car boeth oxy-2,2′-bipyr idin e-5′-yl)m eth yl]-
N′-t-bu tyla cetyl-eth ylen ed ia m in e (18). 80%. 1H NMR
3
(CDCl3): δ 1.40 (s, 9H), 1.44 (t, br, 9H, J ) 7.0 Hz), 2.63 (t, br,
3
3
2H, J ) 6.0 Hz), 2.88 (t, br, 2H, J ) 6.0 Hz), 3.20 (s, 2H), 3.64
(s, 4H), 3.80 (s, 2H), 4.45 (q, 6H, 3J ) 7.5 Hz), 7.72-7.95 (m,
6H), 8.04-8.10 (m, 3H), 8.41-8.60 (m, 9H). 13C NMR (CDCl3):
δ 14.4, 28.24, 29.7, 45.9, 51.5, 51.9, 55.2, 55.8, 61.9 (2C), 81.2,
121.5, 124.1, 124.2, 124.8, 135.2, 137.5, 137.7, 137.8, 147.8, 149.6,
149.7, 154.5, 156.3, 156.4, 165.4, 170.5. Rf ) 0.47, deactivated
SiO2, CH2Cl2. Mp: >200 °C dec. HRMS (ES): calcd for
C50H54N8O8, 895.4142 (MH); found, 895.4145.
1-(3-Nitr oben zyl)-4,8,11-tr is[(6-ca r boxy-2,2′-bip yr id in e-
5′-yl)m eth yl]-1,4,8,11-tetr a a za cyclotetr a d eca n e (8). 83%. 1H
NMR (DMSO-d6): δ 1.90-2.25 (m, br, 4H), 2.60-3.50 (m, 16H),
3.70-4.30 (m, br, 8H), 7.50-8.80 (m, 22H). FT-IR (KBr, cm-1):
2980 (m), 1637 (s), 1384 (m). Anal. Calcd for C53H53N11O8‚H2O:
C, 64.30; H, 5.60; N, 15.56. Found: C, 64.20; H, 5.76; N, 15.48.
Mp >190 °C dec. FAB+/MS: 972.3 ([M + H]+, 23%), 759.3 ([M
- (CH2bipyCO2H) + H]+, 100%).
N-(2,3-Dih yd r oxyp r op yl)ben za m id e (10). 72%. 1H NMR
(CDCl3): δ 3.35-3.61 (m, 4H), 3.83 (m, 1H), 4.82 (s, br, 2H),
N,N,N′-Tr is[(6-ca r boxy-2,2′-bip yr id in e-5′-yl)m eth yl]-N′-
a cetoxy-eth ylen ed ia m in e (19). 57%. 1H NMR (DMSO-d6): δ
3.37 (s, br, 2H), 3.58 (s, br, 2H), 3.75-3.95 (m, br, 2H), 4.35 (s,
br, 2H), 4.53 (s, br, 4H), 8.05-8.20 (m, br, 6H), 8.25-9.10 (m,
br, 12H). 13C NMR (DMSO-d6): δ 48.8, 53.0, 53.3, 53.8, 54.3,
121.4, 122.0, 124.1, 124.4, 125.3, 125.5, 128.1, 128.8, 129.4, 132.1,
137.2, 139.1, 139.3, 141.8, 142.3, 147.8, 149.8, 151.4, 152.7, 165.4
(2C), 169.7. FT-IR (KBr, cm-1): 1736 (s), 1630 (s), 1350 (m), 1264
(m). Mp: >220 °C dec. Anal. Calcd for C40H34N8O8: C, 63.65;
H, 4.54; N, 14.85. Found: C, 63.30; H, 4.27; N, 14.69. FAB+/MS:
755.3 ([M + H]+, 90%), 777.3 ([M + Na]+, 100%).
3
3
7.20-7.42 (m, 3H), 7.60 (t, 1H, br, J ) 5.5 Hz), 7.70 (d, 2H, J
) 7.5 Hz). 13C NMR (CDCl3): δ 42.8, 64.0, 71.1, 127.2, 128.6,
131.8, 133.7, 169.3. Rf ) 0.34, SiO2, CH2Cl2/MeOH, 95/5. FT-IR
(KBr, cm-1): 2933 (s), 2878 (m), 1637 (s), 1541 (s), 1310 (m). Anal.
Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.18. Found: C, 61.50;
H, 6.51; N, 6.84. FAB+/MS: 196.3 ([M + H]+, 100%).
N-[2,3-(Bis-tolu en e-p-su lfon a to)p r op yl]ben za m id e (11).
69%. 1H NMR (CDCl3): δ 2.31 (s, 3H), 2.43 (s, 3H), 3.45-3.85
(m, 2H), 4.10-4.25 (m, 2H), 4.83 (sx, 1H, 3J ) 8.0 Hz), 6.70 (t,
3
br, 1H, J ) 6.0 Hz), 7.18-7.51 (m, 7H), 7.65-7.73 (m, 6H). 13C
NMR (CDCl3): δ 21.6 (2C), 40.3, 68.3, 77.1, 127.0, 127.9, 128.0,
128.5, 129.9, 130.0, 131.8, 131.9, 132.4, 133.2, 145.3, 145.4, 167.5.
Rf ) 0.14, SiO2, CH2Cl2/MeOH, 99/1. FT-IR (KBr, cm-1): 3428
(s), 1663 (s), 1537 (s), 1347 (s), 1192 (s), 1176 (s). Anal. Calcd
for C24H25NO7S2: C, 57.20; H, 5.00; N, 2.78. Found: C, 57.11;
H, 4.92; N, 2.63. FAB+/MS: 504.6 ([M + H]+, 100%).
Ack n ow led gm en t. This work was supported by the
Centre National de la Recherche Scientifique and
Engineer School of Chemistry of Strasbourg, ECPM, in
France.
N-(Ben zam idom eth yl)-1,4,7-tr is(tolu en e-p-su lfon yl)-1,4,7-
tr ia za cyclon on a n e (13). 37%. 1H NMR (CDCl3): δ 2.36 (s, 3H),
2.37 (s, 3H), 2.40 (s, 3H), 3.00-3.50 (m, 10H), 3.67-4.18 (m,
2H), 4.80-5.00 (m, 1H), 5.19 (t, 1H, 3J ) 5.5 Hz), 7.18-7.50 (m,
9H), 7.56 (d, 2H, 3J ) 8.5 Hz), 7.68 (d, 2H, 3J ) 8.0 Hz), 7.72 (d,
2H, 3J ) 8.5 Hz), 7.86 (d, 2H, 3J ) 8.0 Hz). 13C NMR (CDCl3):
δ 21.4 (3C), 29.6, 42.3, 49.6, 49.8, 49.9, 57.9, 78.4, 127.0, 127.1,
127.2 (2C), 128.1, 128.3, 129.6, 129.8, 129.9, 131.4, 134.7, 135.0,
136.5, 143.3, 143.8, 143.9, 163.5. Rf ) 0.31, SiO2, CH2Cl2/MeOH,
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the radical bromination of 6-bromo-5′-methyl-2,2′-
bipyridine, synthesis and detailed characterization of analo-
gous linear dipodal and start tripodal ligands, and experimental
methods for all compounds synthesized. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0200015