A convenient preparative method for anionic tris(substituted pyrazolyl)methane ligands

Article abstract of DOI:10.1016/S0040-4039(03)01506-5

The synthesis of tris[3-(6-carboxypyridin-2-yl)pyrazol-1-yl]methane is described in a linear multi-step protocol. The pyridyl-pyrazolyl arms are first constructed before being condensed with chloroform. Careful study of the condensation reaction shows the presence of an isomeric form of the tris(pyrazolyl)methane derivative in which one of the pyrazolyl substituents is linked through the nitrogen atom at the 2 position of the pyrazol. After acid-catalysed isomerisation to the desired isomer, the intermediate compound was subjected to a carboalkoxylation reaction and a subsequent hydrolysis. These are some rare examples of reactions directly occurring on the tris(pyrazolyl)methane platforms.

Full text of DOI:10.1016/S0040-4039(03)01506-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6305–6307
A convenient preparative method for anionic tris(substituted
pyrazolyl)methane ligands
Lo ¨ı c J. Charbonni e` re* and Raymond Ziessel*
Laboratoire de Chimie Mol e´ culaire associ e´ au CNRS, Ecole de Chimie, Polym e` res et Mat e´ riaux, 25 rue Becquerel,
67087 Strasbourg Cedex 02, France
Received 10 April 2003; revised 17 June 2003; accepted 17 June 2003
Abstract—The synthesis of tris[3-(6-carboxypyridin-2-yl)pyrazol-1-yl]methane is described in a linear multi-step protocol. The
pyridyl-pyrazolyl arms are first constructed before being condensed with chloroform. Careful study of the condensation reaction
shows the presence of an isomeric form of the tris(pyrazolyl)methane derivative in which one of the pyrazolyl substituents is linked
through the nitrogen atom at the 2 position of the pyrazol. After acid-catalysed isomerisation to the desired isomer, the
intermediate compound was subjected to a carboalkoxylation reaction and a subsequent hydrolysis. These are some rare examples
of reactions directly occurring on the tris(pyrazolyl)methane platforms.
©
2003 Elsevier Ltd. All rights reserved.
1
Tris(pyrazolyl)methane (TPM) and the isoelectronic
resolved luminescent probes in particular in the case of
terbium complexes. Whatever their application, the
main drawback of these polyheteroaromatic ligands
and their complexes is their low solubility and instabil-
ity in water solutions.
2
9
tris(pyrazolyl)borate (TPB) have raised a lot of interest
in the field of coordination chemistry due to their
shape and pre-organised structure and to relatively easy
synthetic access. From these so called scorpionates,
numerous derivatives were developed by functionalisa-
tion of the pyrazolyl rings, some of them being used as
3
The present work describes the synthesis of ligand LH3,
which combines the basic tris(pyrazolyl)methane (TPM)
framework, three pyridyl-pyrazolyl chromophores and
carboxylate functions attached on the pyridine moi-
eties. The combination of these three functions is
expected to provide a ligand with a pre-organised com-
plexation pocket well suited for lanthanide complexa-
tion. These complexes should exhibit interesting
photo-physical properties and thermodynamic stability
in aqueous solvents.
4
artificial enzymes. For coordination purposes, the
functionalisation of the position 3 of pyrazols was
particularly attractive as it may lead to the introduction
of further coordinating functionalities such as methyl-
sulfanylphenyl, carboxylic acids or pyridyl rings. In
this last case, the chelating arms have been shown to be
very efficient chromophores for providing an antenna
5
6
7
8
effect with lanthanide cations. Such ligands are thus
expected to be relevant targets for the design of time-
Keywords: tris(pyrazolyl)methane; bipyridine carboxylate; scorpionate; water solubility.
*
Corresponding authors. Tel./fax: 33 3 90 24 26 89; e-mail: ziessel@chimie.u-strasbg.fr
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01506-5

6
306
L. J. Charbonni e` re, R. Ziessel / Tetrahedron Letters 44 (2003) 6305–6307
Our first attempt to synthesise LH was based on the
The condensation was conducted under conditions sim-
14
3
preparation of an ester precursor 5, which should then
ilar to previously reported results, in which 4 was first
be condensed with chloroform to afford an ester pre-
suspended in water in the presence of Na CO , resulting
2
3
cursor of LH . Starting from the commercially avail-
in an exothermal reaction probably due to deprotona-
tion of the pyrazol. This mixture was then added to
3
able 2,6-dibromopyridine 1, 2-acetyl-6-bromopyridine
10
2, was obtained according to a literature procedure.
CHCl containing triethylbenzyl ammonium chloride as
3
Reaction of 2 with neat N,N-dimethylformamide
dimethylacetal gave 3-dimethylamino-1-(6-bromopy-
ridin-2-yl)prop-2-en-1-one 3 in 77% yield. When 3 is
reacted with hydrazine hydrate in hot methanol in a
Schlenk tube, the pyrazolyl ring is formed in quantita-
tive yield, leading to 4 (Scheme 1). Unfortunately, all
our efforts to obtain compound 5 by a conventional
carboalkoxylation procedure, in which 5 was reacted
a phase transfer catalyst. The biphasic mixture was then
refluxed, resulting in the slow formation of two new
compounds, as evidenced by TLC analysis of the
organic layer (Scheme 2, protocol ii).
After column chromatography, the second eluting
product (R =0.54, SiO , CH Cl /MeOH 97/3) was
f
2
2
2
characterised as the expected TPM adduct 6. On the
1
13
13
with bubbling CO in a hot EtOH/Et N mixture using
basis of its H and C NMR spectra and according to
14,15
3
1
1
5
% [Pd(PPh ) Cl ] as catalyst, remained unsuccessful.
literature data,
the first eluting compound (R =
f
3
2
2
This disappointing result was nevertheless in agreement
0.59, same conditions) was identified as being 7, an
isomeric form of 6 in which one of the pyrazolyl ring is
linked through the N2 nitrogen atom.
1
2
with previous findings, in which this kind of reaction
was showed to be poorly efficient in the presence of
secondary aliphatic amines. In order to overcome this
drawback, it was decided to realise the condensation of
compound 4 with chloroform leading to the TPM
framework 6.
Treatment of 7 with p-toluenesulfonic acid in toluene
led to isomerisation to 6, but during this process, the
product partly decomposed with the formation of the
10
Scheme 1. Reagents and conditions: (i) n-BuLi, THF, −78°C then CH C(O)NMe ; (ii) neat Me NCH(OMe) , 100°C, 2 h, 77%;
3
2
2
2
(
iii) H NNH ·H O, MeOH, 80°C, 45 min, quantitative; (iv) [Pd(PPh ) Cl ], EtOH, Et N, CO (1 atm.), 70°C, 15 h.
2 2 2 3 2 2 3
Scheme 2. Reagents and conditions: Protocol (i) H O, Na CO , CHCl , Bz(Et) NCl, reflux, 19 h; extraction; PhMe, CF COOH,
2
2
3
3
3
3
1
10°C, 1 day, 38% overall yield for compound 6. Protocol (ii) H O, Na CO , CHCl , Bz(Et) NCl, reflux, 19 h; purification by
2 2 3 3 3
chromatography. (iii) PhMe, p-TsOH, reflux 15 h, 18%.

L. J. Charbonni e` re, R. Ziessel / Tetrahedron Letters 44 (2003) 6305–6307
6307
Scheme 3. Reagents and conditions: (i) [Pd(PPh ) Cl ], EtOH, Et N, CO (1 atm.), 70°C, 15 h, 68%; (ii) NaOH, EtOH, H O, 70°C,
3
2
2
3
2
3
h then conc. HCl, 88%.
starting material 4, and 6 was recovered in only 18%
after purification (protocol iii). The presence of traces
of water in the p-toluenesulfonic acid used probably
plays an important rule in this decomposition process.
As a result of the difficulties encountered during the
purification process, we decided to run the isomerisa-
tion process directly on the crude reaction mixture
obtained after aqueous work-up and to change p-TsOH
to CF CO H (protocol i). In these conditions, the iso-
Merbach, A. E.; B u¨ nzli, J.-C. G. J. Am. Chem. Soc. 2000,
122, 10810.
7. Reeves, Z. R.; Mann, K. L. V.; Jeffery, J. C.; McClev-
erty, J. A.; Ward, M. D.; Barigeletti, F.; Armaroli, N. J.
Chem. Soc., Dalton Trans. 1999, 349.
8. Sabbatini, N.; Guardigli, M.; Lehn, J.-M. Coord. Chem.
Rev. 1993, 123, 201.
9. (a) Armaroli, N.; Accorsi, G.; Barigelletti, F.; Couchman,
S. M.; Fleming, J. S.; Harden, N. C.; Jeffery, J. C.;
Mann, K. L. V.; McCleverty, J. A.; Rees, L. H.; Starling,
S. R.; Ward, M. D. Inorg. Chem. 1999, 38, 5769; (b)
Armaroli, N.; Barigelletti, F.; Ward, M. D.; McCleverty,
J. A. Chem. Phys. Let. 1997, 276, 435.
3
2
mer 7 is not isolated before the acidic treatment and 6
can be obtained in 38% overall yield after purification.
When 6 was submitted to a carboethoxylation reaction
promoted by palladium(0), the triethyl ester 8 was
isolated in fair yield, without any major side-reaction
10. Parks, J. E.; Wagner, B. E.; Holm, R. H. J. Organomet.
Chem. 1973, 56, 53.
11. ElGhayoury, A.; Ziessel, R. J. Org. Chem. 2000, 65, 7757.
12. Weibel, N.; Charbonni e` re, L. J.; Ziessel, R. F. J. Org.
(
Scheme 3). Such mild synthetic conditions are of great
interest as the use of more conventional procedures
such as halogen–metal exchanges often require the use
of hard bases which may led to deprotonation of the
Chem. 2002, 67, 7876.
13. Selected data for compound 7: H NMR (CDCl , 200
1
3
1
6
3
3
central carbon atom.
MHz): l 6.77 (d, 1H, J=2.0 Hz), 7.00 (d, 2H, J=2.5
3
4
Hz), 7.36 (dd, 2H, J=7.5 Hz, J=1.0 Hz), 7.41–7.44 (m,
3
In a final step, the ester functions were saponified in a
1
H), 7.52 (t, 2H, J=7.5 Hz), 7.59–7.69 (m, 3H), 7.84 (d,
3
3
4
methanol/water mixture containing NaOH and LH3
2H, J=2.5 Hz), 7.93 (dd, 2H, J=7.5 Hz, J=1.0 Hz),
.84 (s, 1H). C NMR (CDCl , 50 MHz): l 82.0, 106.3,
08.6, 119.3, 121.2, 127.1, 127.7, 131.8, 138.8, 139.6,
40.2, 140.9, 141.6, 141.7, 148.9, 152.0, 152.9. For com-
17
13
was recovered by acidification with concentrated HCl.
9
1
1
3
Preliminary experiments with lanthanide cations
showed the ligand to form stable [LnL] water soluble
complexes. In the case of europium and terbium, bright
red and green emissions were respectively observed
upon UV irradiation, indicative of a ligand to metal
energy transfer. The measured excited state lifetimes are
respectively of 0.28 and 1.00 ms for europium and
terbium in water with quantum yields of 2 and 15%,
respectively. Further experiments are currently in pro-
gress for a full characterisation of the photo-physical
1
parison, compound 6: H NMR (CDCl , 200 MHz): l
3
3
3
4
7
.07 (d, 3H, J=3 Hz), 7.42 (dd, 3H, J=8.0 Hz, J=1.0
3
3
Hz), 7.57 (t, 3H, J=7.5 Hz), 7.65 (d, 3H, J=2.5 Hz),
.93 (dd, 3H, J=7.5 Hz, J=1.0 Hz), 8.52 (s, 1H).
3
4
13
7
C
NMR (CDCl , 50 MHz): l 84.0, 107.0, 119.2, 127.5,
3
131.1, 139.0, 141.8, 152.4, 152.9.
1
1
4. Reger, D. L.; Grattan, T. C.; Brown, K. J.; Little, C. A.;
Lamba, J. J. S.; Rheingold, A. L.; Sommer, R. D. J.
Organomet. Chem. 2000, 607, 120.
5. Lee, C. S.; Allwine, D. A.; Barbachyn, M. R.; Grega, K.
C.; Dolak, L. A.; Ford, C. W.; Jensen, R. M.; Seest, E.
P.; Hamel, J. C.; Schaadt, R. D.; Stapert, D.; Yagi, B. H.;
Zurenko, G. E.; Genin, M. J. Bioorg. Med. Chem. 2001,
18
properties of the ligand and complexes.
References
9
, 3243.
1
. (a) H u¨ ckel, W.; Bretschneidner, H. Ber. Dtsch. Chem.
Ges. 1937, 70, 2024; (b) Juli a` , S.; del Mazo, J. M.; Avila,
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1
1
6. Kl a¨ ui, W.; Berghahn, M.; Rheinwald, G.; Lang, H.
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7. Selected data for LH : H NMR (d -DMSO): l 7.19 (d,
1
2
3
3
6
3
3
H, J=2.5 Hz), 7.99–8.10 (m, 6H), 8.15–8.20 (m, 3H),
3
13
8.22 (d, 3H, J=2.5 Hz), 9.35 (s, 1H). C NMR (d -ace-
6
tone): l 84.4, 107.6, 124.3, 126.8, 133.2, 139.8, 147.9,
151.7, 153.5, 165.6. FABMS: m/z 578.3 (100%, M+H ),
533.2
C H N O ·2HCl: C, 51.71; H, 3.25; N, 19.38. Found:
C, 51.59; H, 3.16; N, 19.29. IR: 2972, 2926, 2890, 1720,
1587, 1447, 1341, 1248, 1083, 1050.
+
+
4
5
. Kitajima, N.; Moro-Oka, Y. Chem. Rev. 1994, 94, 737.
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Behrendt, A.; Jeffery, J. C.; Maher, J. P.; McCleverty, J.
A.; Ward, M. D. New J. Chem. 1999, 23, 417.
(15,
M−CO
2
+H ).
Anal.
calcd
for
28 19 9 6
6. Fatin-Rouge, N.; T o´ th, E.; Perret, D.; Backer, R. H.;
18. Charbonni e` re, L.; Ziessel, R. manuscript in preparation.