Direct functionalisation of group 10 N-heterocyclic carbene complexes for diversity enhancement

Article abstract of DOI:10.1039/c1cc11391g

The synthesis of alkyne-substituted N-heterocyclic carbene complexes of Pd(ii) and Pt(ii) is reported. Catalyzed 1,3-dipolar cycloaddition with azides has been applied as a modular way of functionalisation of group 10 transition metal NHC complexes to gen

Full text of DOI:10.1039/c1cc11391g

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COMMUNICATION
Direct functionalisation of group 10 N-heterocyclic carbene complexes
for diversity enhancementw
Edith Chardon,ab Gian Luigi Puleo, Georges Dahm, Gilles Guichard* and
Ste
´
a
a
b
phane Bellemin-Laponnaz*a
Received 10th March 2011, Accepted 1st April 2011
DOI: 10.1039/c1cc11391g
The synthesis of alkyne-substituted N-heterocyclic carbene
complexes of Pd(II) and Pt(II) is reported. Catalyzed 1,3-dipolar
cycloaddition with azides has been applied as a modular way of
functionalisation of group 10 transition metal NHC complexes
to generate potentially new metallodrugs.
Cisplatin which is effective against many forms of cancer is the
quintessential transition metal-based chemotherapeutic
agent. The formation of covalent crosslinks with DNA and
subsequent disruption of the DNA structure are believed to
account for its cytotoxic activity against cancer cells. Despite
considerable benefits, the clinical use of cisplatin is limited by
adverse side effects and resistance. Several approaches have
been explored to overcome these hurdles. The search for new
platinum complexes with different DNA binding properties
and/or improved pharmacological profile has attracted
Scheme 1 Group 10 NHC complexes exhibiting cytoxicity against
cancer cells (cell lines in brackets).
fluorescence. . .) and ultimately facilitate the development of
this emerging class of cytotoxic molecules. However, the
unavoidable strategy in organometallic synthesis, which con-
sists in the coordination of the transition metal at the very last
step of the synthesis, suffers from serious drawbacks: (i)
forcing reaction conditions, (ii) low modularity and most
importantly (iii) incompatibility with a large number of che-
1
6
considerable attention.
mical functions (i.e. alcohols, amides. . .). Although attractive,
Very recently, several groups pointed to the importance of
2
N-heterocyclic carbene (NHC) ligand as a new structure
the chemoselective functionalisation of the NHC complex of
late transition metals remains a challenging route and these
transition metal complexes are potentially reactive molecules
for the development of transition metal-containing drug
7
,8
candidates. Remarkably, Ghosh et al. established that
that usually do not tolerate further manipulation.
palladium complexes of general formula trans-(NHC)
or trans-(NHC)PdX (pyridine) are potent inhibitors of the
2
PdX
2
We reasoned that catalyzed 1,3-dipolar cycloadditions of
terminal alkynes to azides could be the solution of choice for
that purpose. However, the copper(I)-catalyzed alkyne–azide
2
3
proliferation of cancer cells, whereas Marinetti et al. showed
the efficiency of trans-configured platinum complexes of
9
cycloaddition (CuAAC) is not compatible with the presence
general formula (NHC)PtX (L) (with L = amine) towards
2
of halogens on a group 10 transition metal as shown in
Scheme 2. Indeed, the reaction of dihalocomplexes of palla-
dium (or platinum) with terminal alkyne in the presence of a
copper(I) catalyst and an amine base is known as a method for
4
,5
cisplatin-resistant cell lines (Scheme 1). Nevertheless, there
is still a significant gap to be filled between this NHC-proof of
concept and (pre)clinical developments. At this stage, a
modular approach allowing the synthesis of functionalised
and conjugated NHC metal complexes would be an asset to
increase chemical diversity, introduce specific features (i.e.
water solubility, specific cell recognition elements, delivery,
a
Institute of Physics and Chemistry of Materials of Strasbourg
(
2
IPCMS), University of Strasbourg – CNRS UMR7504,
3 rue du Loess, 67034 Strasbourg, France.
E-mail: bellemin@unistra.fr; Fax: +33 (0)388107246;
Tel: +33 (0)388107166
European Institute of Chemistry and Biology (IECB),
University of Bordeaux – CNRS UMR5248, 2 rue Escarpit,
b
33607 Pessac, France. E-mail: g.guichard@iecb.u-bordeaux.fr;
Fax: +33 (0)540002200; Tel: +33 (0)540003020
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c1cc11391g
Scheme 2 The incompatibility of CuAAC: the reaction conditions
lead to the formation of alkynyl complexes.
5
864 Chem. Commun., 2011, 47, 5864–5866
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1
0
the preparation of dialkynyl complexes. So far, the organic
functionalisation of a sensitive group 10 transition metal
complex (i.e. with potentially exchangeable ligands) in the
1
1
presence of a transition metal catalyst remains elusive.
Herein, we report the successful functionalisation of alkyne-
substituted NHC complexes of Pd(II) and Pt(II) with diverse
azides as a direct and modular method for the development of
elaborated NHC-based cytotoxic molecules.
The reaction of N-alkyne (TMS protected) functionalised
imidazolium salt 1 with 0.5 equivalent of palladium acetate
leads to the trans-bis(NHC) palladium complex in 63%
1
2,13
yield.
Optimal deprotection of the TMS-alkyne was
obtained with fluoride on a macroporous polymer support
À1
(
2.0–3.0 mmol g loading). The unmasked alkyne 2 was then
subjected to reaction with 2.2 equivalents of benzyl azide
in the presence of classical copper catalysts. Screening of
various experimental conditions (copper source, solvent,
temperature. . .) led to the conclusion that the reaction is not
compatible with the presence of the Pd(II) complex derivative.
Investigation of the reaction product composition revealed the
presence of palladium black with insoluble orange/brown
solids that may be assigned to coordination polymers by
alkynyl complexes formation. Fortunately, an attempt
to conduct the reaction with the ruthenium catalyst
Cp*RuCl(PPh ) afforded the long-awaited bis-cycloaddition
Scheme 4 Double functionalisation of trans-(NHC) PdBr
2
2
complex
4. (1) Fluoride on Amberlyst A-26, THF, rt; (2) 8 mol% catalyst,
THF, 60 1C, overnight.
3
2
challenging azides like PEG derivatives was also possible.
product 3 (1,5-regioisomer), albeit in modest yield as shown in
Scheme 3.
Noteworthily, compounds 6 and 7 were both obtained in good
16
yields (74% and 72% respectively).
The ruthenium-catalyzed azide–alkyne cycloaddition
Further investigation of the 1,3 dipolar cycloaddition
reaction with platinum derivatives also proved the efficiency
of ruthenium vs. copper catalysts towards square-planar
1
RuAAC) was then successfully applied to the bis-N-hetero-
4
(
cyclic carbene palladium complex 4 with remote TMS-alkyne
tether in the backbone of the carbene ligand that accordingly
17
NHC–platinum complexes such as 8. The cycloaddition
1
5
offers a more significant degree of diversity (Scheme 4). The
double cycloaddition reaction with benzyl azide in the
presence of 8 mol% of a Ru catalyst gave the desired
product (5) in 87% isolated yield. Functionalisation with more
products were obtained in 82% and in 70% with benzyl
azide when L was pyridine (9) and cyclohexylamine (10)
respectively. Following the same procedure the complex 8
gave the L-lysine derivative 11 in 59% yield (Scheme 5).
Finally, in order to possibly enhance selectivity and specificity
towards cancer cells, we designed the oestrogen functionalised
Pt(II) complex 13 as a possible candidate to target hormone-
1
8
dependent diseases (e.g. breast cancer). Complex 13 was
obtained in 24% yield by reaction of 8 with the oestrogen
Scheme 3 Synthesis of complex 2 and 1,3-dipolar cycloaddition
studies: (1) THF, D, 2 h; (2) fluoride on Amberlyst A-26, THF, rt;
RuAAC: Cp*RuCl(PPh
3
)
2
as a catalyst; CuAAC: various copper
Scheme 5 Functionalisation of platinum complex 8 (L = pyridine or
sources, solvents and temperatures have been screened.
2 3
cyclohexylamine). (1) K CO , MeOH, rt; (2) 8 mol% catalyst, THF, D.
This journal is c The Royal Society of Chemistry 2011
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3
(
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7
8
Only few examples of functionalisation of transition metal
complexes were reported in the literature, see for example:
(
a) L. Raszeja, A. Maghnouj, S. Hahn and N. Metzler-Nolte,
ChemBioChem, 2011, 12, 1; (b) F. Noor, R. Kinscherf,
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Cesar and co-workers reported the possibility to functionalise
anionic NHCs on rhodium and copper complexes by reaction
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N. Lugan and G. Lavigne, Chem. Commun., 2009,
¨
´
´
4
2
720; (b) V. Ce
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010, 16, 11432; (c) L. Benhamou, N. Vujkovic, V. Ce
sar, N. Lugan and G. Lavigne, Chem.–Eur. J.,
sar,
´
H. Gornitzka, N. Lugan and G. Lavigne, Organometallics, 2010,
9, 2616.
2
9
For reviews, see: (a) M. Meldal and C. W. Tornøe, Chem. Rev.,
2008, 108, 2952; (b) H. C. Kolb, M. G. Finn and K. B. Sharpless,
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Scheme 6 Functionalisation of platinum complex 8 (L = pyridine)
with oestrogen derivative 13 (8 mol% catalyst, THF, D).
1
0 (a) K. Osakada, M. Hamada and T. Yamamoto, Organometallics,
000, 19, 458; (b) M. J. Irwin, G. Jia, J. J. Vittal and
R. J. Puddephatt, Organometallics, 1996, 15, 5321;
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2
derived azide 12 (Scheme 6) despite the presence of a 1,3-diol
function in 12 susceptible to react either with the platinum
complex or with the ruthenium catalyst.
(
Sci., 1981, 41, 149; (d) S. Kotani, K. Shiina and K. Sonogashira,
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1 Note that the CuAAC has been achieved with few single
palladium(II) and platinum(II) derivatives. In these particular
cases, the complexes were stabilized by ligands that have been found
to produce relatively unreactive metal species, see: (a) D. Urankar and
In this work, we have investigated a modular approach to
the functionalisation of a sensitive group 10 transition
metal NHC complex using ruthenium-catalyzed azide–alkyne
cycloaddition. Encouraged by these preliminary results, we are
currently extending the scope of this method to a more diverse
set of azides with the aim to generate chemical libraries and
later to endow cytotoxic NHC complexes of transition metals
with new properties (e.g. specific cell recognition, delivery,
fluorescence. . .).
1
J. Kosmrlj, Inorg. Chim. Acta, 2010, 363, 3817; (b) S. Warsink,
ˇ
R. M. Drost, M. Lutz, A. L. Spek and C. J. Elsevier, Organometallics,
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2 Note that the alkyne has to be protected for the metal complexation
with the NHC ligand.
The authors gratefully acknowledge the CNRS (France)
and the Ministere de l’Enseignement Superieur et de la
` ´
1
1
Recherche (MESR) for a PhD grant to E.C. The authors also
thank Dr B. Kauffmann for X-ray diffraction studies. The
crystallographic data have been collected at the IECB X-ray
3 The trans-configuration of the palladium complex was established
by NMR studies. The H NMR of the trans-bis(NHC) palladium
1
3
complex (in CDCl at RT) gives rise to two sets of signals due to
facility (UMS3033, CNRS and Universite
´
de Bordeaux,
the presence of rotational isomers. The interconversion between
them has been confirmed by variable-temperature investigation
US001 INSERM).
(
see ESIw).
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4 (a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
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15 The trans-configuration of complex 4 was established by NMR
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1
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3
4
17 We found that the alkyne in 8 was optimally unmasked by
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ˆ
5
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´
´
ˆ
´
´
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6
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´
5
866 Chem. Commun., 2011, 47, 5864–5866
This journal is c The Royal Society of Chemistry 2011