Gem-bisphosphonate-ended group dendrimers: Design and gadolinium complexing properties

Article abstract of DOI:10.1002/ejoc.200900458

The synthesis of the first gem-bisphosphonate-ended group dendrimers is described using nucleophilic substitution of terminal P(S)Cl₂ units of phosphorus dendrimers of generation 1 to 3 with protected aminophenols followed by deprotection of am

Full text of DOI:10.1002/ejoc.200900458

FULL PAPER
DOI: 10.1002/ejoc.200900458
gem-Bisphosphonate-Ended Group Dendrimers: Design and Gadolinium
Complexing Properties
Grégory Franc,[a,b] Cédric-Olivier Turrin,[a,b] Emma Cavero,[a,b]
Jean-Pierre Costes,*[a,b] Carine Duhayon,[a,b] Anne-Marie Caminade,*[a,b] and
Jean-Pierre Majoral*[a,b]
Keywords: Dendrimers / Gadolinium / Magnetic properties / Michael addition / Bisphosphonate
The synthesis of the first gem-bisphosphonate-ended group
dendrimers is described using nucleophilic substitution of
terminal P(S)Cl2 units of phosphorus dendrimers of genera-
tion 1 to 3 with protected aminophenols followed by depro-
tection of amino groups and Michael addition with vinyl-
idene tetraisopropyl bisphosphonate. These dendrimers
were found to act as chelating agents towards Gd ions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
the activation of human monocytes and the selective multi-
plication of human Natural Killer (NK) cells.[27–29] These
phosphonate groups were also found useful for the grafting
to TiO2 surfaces and the elaboration of chemical sensors.[30]
In marked contrast nothing is reported concerning the de-
sign and consequently the use of dendrimers bearing gem-
bisphosphonates or 1,1-bisphosphonic acids of type B,
these monomers being known for their exceptionally high
affinity for the bone mineral hydroxy-apatite and their role
against osteoroporosis.[31] To the best of our knowledge
only a dendron of generation one C (Figure 1) composed
of four bisphosphonic acid moieties was designed for im-
proved targeting of proteins to bone.[32]
Introduction
Dendrimers are monodisperse and three-dimensional
nanometre-sized structures built from monomers around a
plurifunctional core by an iterative process permitting a
perfect control of their size and topology.[1] They allow a
multivalent presentation of a given active molecular motif
in a highly defined fashion. The ability to synthesize such
architectures in such a rigorous way opens large avenues for
their applications in different fields ranging from biology
and medicine to material sciences and catalysis. Among the
different types of dendrimers, those incorporating phos-
phorus[2–6] were found to be extremely versatile “soft mat-
ter” bringing specific properties for example as two photons
tracers for in vivo imaging,[7–10] for gene transfection[11,12]
or antiprion activity.[13–15] Their crucial role for the elabora-
tion of new materials as dendronized nanolatexes,[16] nano-
tubes,[17,18] fibres,[19] antiviral supramolecular assembl-
ies,[20,21] DNA chips,[22,23] microcapsules,[24] chemical sen-
sors[25] was also pointed out while enhanced catalytic per-
formance of ligands were observed when multiple copies
of these monomers were incorporated on the surface of P-
dendrimers.[26]
Phosphorus-containing dendrimers capped with amino
bismethylene phosphonates or phosphonic acids of type A
were found to induce a remarkable bioactivity promoting
[a] Laboratoire de Chimie de Coordination du CNRS, UPR 8241,
205 route de Narbonne, 31077 Toulouse, France
Fax: +33-5-61553003
Figure 1. Amino bis-methylene phosphonate (A), gem-bisphos-
phonate (B) and multivalent gem-bisphosphonate dendron (C).
E-mail: majoral@lcc-toulouse.fr
caminade@lcc-toulouse.fr
costes@lcc-toulouse.fr
[b] Université de Toulouse, UPS, INPT, LCC,
31077 Toulouse, France
On the basis of these observations we report hereafter
several ways of synthesis of unique phosphorus dendrimers
capped with gem-bisphosphonates, and their behaviour as
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900458.
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gem-Bisphosphonate-Ended Group Dendrimers
efficient multi-pincers for gadolinium as preliminary illus- group to afford, after purification, the first phosphorus
tration of their complexing properties. Discussion regarding dendrimer capped with N-gem-bisphosphonate units 5-[G1]
the magnetic properties of these novel macromolecular spe- in 64% yield (Scheme 2). The slow reaction needed two
cies will be also addressed.
days to go to completion and was monitored by 31P NMR
which shows the partial disappearance of the signal due to 1
(δ31P = 10.9 ppm) in behalf of a new signal at δ = 19.9 ppm
characteristic of the gem-bisphosphonate moieties in 5-[G1].
Results and Discussion
We already demonstrated that P(S)Cl2 end groups of 1H and 13C NMR spectroscopic data also corroborate the
dendrimers easily react with phenols in the presence of structure of 5-[G1]. Typically the signal of the carbon in α
base.[2] Indeed this is one of the key reactions used for the position to phosphorus appears as a triplet (1JCP
=
preparation of phosphorus dendrimers. Therefore our first 132.1 Hz) at δ = 37.76 ppm (δ = 134.56 ppm, 1JCP = 168 Hz
efforts were directed to the synthesis of phenols bearing bis- in 1) and the C(Ar)N signal shifts from 132.3 ppm in 9-[G1]
phosphonate moieties. To this end, Michael type additions to 145.1 ppm in 5-[G1] in 13C NMR spectroscopy.
between 4-aminophenol or 4-(hydroxyphenyl)piperazine
Subsequently we extended this method to the use of the
and vinylidene tetraisopropyl bisphosphonate 1 were under- Boc-protected 4-(hydroxyphenyl)piperazine 10. Grafting
taken (Scheme 1). Phenol N-bisphosphonate monomers 2 was undertaken under the same conditions (Scheme 3) lead-
and 3 were obtained readily as a viscous oil (2, 95% yield) ing successively to generation-one dendrimers, 11-[G1], 12-
or a crystalline solid (3, 84% yield). Unfortunately nucleo- [G1] and finally 6-[G1] bearing twelve aza-gem-bisphos-
philic substitution on terminal P(S)Cl2 groups of the den- phonate end groups. As expected three signals were ob-
drimer of generation 1, 4-[G1] either with 2 or 3 does not tained in 31P NMR for 6-[G1] at respectively 9.2 (P=N
1
afford the desired dendrimers 5-[G1] and 6-[G1]. A retro core), 20.5 (P=O, surface), 64.3. (P=S, branches) ppm. H
Michael addition takes place, regardless of the experimental and 13C NMR spectroscopic data validate the complete
conditions used.
functionalization of the periphery for 6-[G1].
To overcome these difficulties a different divergent strat-
The same successful strategy was also applied for the
egy was used consisting of the protection of the amino construction of generation-two dendrimers. 11-[G2], 12-[G2]
group of 4 aminophenol with classical Boc leading to the and 6-[G2] (24 terminal gem-bisphosphonate units) starting
phenol 7 which was grafted onto the surface of 4-[G1] in from 4-[G2] (Scheme 4), and finally for dendrimers of gener-
basic conditions (Cs2CO3, THF, overnight, yield of 81%). ation 3, 11-[G3], 12-[G3] and 6-[G3] [48 terminal gem-bis-
Deprotection of the Boc groups on the resulting dendrimer phosphonate units (see Supporting Information)].
8-[G1] using standard conditions leads readily to the poly-
Having in hand these new dendrimers we started prelimi-
cationic dendrimer 9-[G1] with a yield of 100%. Disappear- nary experiments concerning their complexing properties.
1
ance of the signal of the tert-butyl groups in H NMR at δ For several reasons, we decided to investigate the complex-
= 1.48 ppm confirms complete deprotection. Dendrimer 9- ation with gadolinium salts. First, the gadolinium ion with
8
[G1] is then left to react in presence of caesium carbonate its half-filled 4f orbitals and its S7/2 ground state (S = 7/2,
and 4 equiv. of the vinylidene bisphosphonate 1 per amino L = 0) is the only 4f ion without first-order orbital momen-
Scheme 1. Synthesis of gem-bisphosphonate containing phenols 2 and 3. Grafting failures on 4-[G1].
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Scheme 3. Synthesis of the piperazino gem-bisphosphonate den-
drimer 6-[G1].
Scheme 2. Multistep synthesis of the dendrimer 5-[G1].
tum. This huge advantage makes the Gd ion a key element of structural data and the interaction parameters are easily
to solve several magnetic problems. It can be used as a mag- deduced from the experimental data by use of an isotropic
netic probe to give supporting information in the absence Hamiltonian. The second reason lies to the fact that most
Scheme 4. Synthesis of the piperazino bisphosphonate dendrimers of generation 2 and 3: 6-[G2], 6-[G3].
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gem-Bisphosphonate-Ended Group Dendrimers
of the used contrast agents are based on gadolinium ion
Gd3+. In the field of dendrimers, there are a few reports
dealing with complexation with Gd,[33,34] the group of Wie-
ner was the first to describe a dendrimer-based contrast
agent for magnetic resonance imaging (MRI), using a
[Gd(DTPA)] complex covalently bound to polyamidoamine
dendrimers
(DTPA:
diethylenetriaminepentacetic
acid),[35,36] while other reports described the use of a den-
drimer-based MRI contrast agent consisting on a trimesic
acid core on which second-generation lysine dendrons bear-
ing 24 Gd ions are anchored.[37–39] Another reason for the
choice of complexation of Gd is the ability of phosphonate
and bisphosphonate monomers to complex such an ele-
ment.[40] Therefore it was tempting to undertake such ex-
periments with the unique gem-bisphosphonate dendrimers
reported in this work.
Dendrimers 6-[G1], 6-[G2] and 6-[G3] possess 12, 24 and
48 gem-bisphosphonate functions, respectively. Their com-
plexation by gadolinium ions was accomplished according
to the same experimental protocol, which is briefly de-
scribed hereafter. Supposing that each phosphonate pair is
able to coordinate one gadolinium ion, an acetonitrile solu-
tion containing a slight excess of gadolinium triflate
[Gd(SO3CF3)3·6H2O, 13] was added dropwise to an aceto-
nitrile solution of the dendrimer. The resulting solution was
stirred for 48 h leading after work-up to a powder that was
filtered off and dried (yield 32–40%). IR data confirm the
presence of water with large bands at 3461 (6-[G1] Gd12),
3437 (6-[G2] Gd24) and 3436 cm–1 (6-[G3] Gd48). Strong C–
F stretching bands due to triflate counterions (1225,
1197 cm–1) appear in a region where several bands (mainly
P=O) from the dendrimers are present (1224–1103 cm–1).
Nevertheless strong bands at 1027 and 634 cm–1 do confirm
Figure 2. Temperature dependence of the magnetic moment µ for
6-[G1] Gd12.
From these magnetic data, it is clear that antiferromag-
netic Gd–Gd interactions are a common feature of the three
Gd dendrimer entities. Such interactions can have an intra-
or inter-dendrimer origin. In order to better understand the
magnetic behaviour of these Gd dendrimers, a simple syn-
thon 14 corresponding to the terminal dendrimer arms has
been prepared and reacted with Gd ions. After several
attempts using different Gd salts, crystals were isolated in
presence of gadolinium acetate and gadolinium hexafluo-
roacetylacetonate Gd(hfa)3·2H2O. The molecular structure
of the resulting complex 15 is shown in Figure 3.
Obviously the molecular entity is binuclear, with four
their presence in the different dendrimer-Gd entities. It is acetato or trifluoroacetato anions acting as bridging ligands
well established that the gadolinium magnetic interactions through their carboxylato groups, hfa and bisphosphonate
in entities containing Gd ions are weak and only active at ligands chelating each gadolinium ion (Gd and Gdi). Two
low temperature. So, measurement of the magnetic suscep- acetate functions are in the usual η1:η1:µ mode while the
tibility at room temperature gives information on the two others form bridges in the less common η2:η1:µ fash-
amount of Gd ions present per dendrimer. If we consider ion.[41] In the η1:η1:µ mode, the bridging acetates are a mix
that 12 gadolinium ions are linked to dendrimer 6-[G1], the up of trifluoroacetate and acetate anions in the 0.25:0.75
expected value of the χMT product, χM being the magnetic ratio, trifluoroacetate coming from hexafluoroacetylacetone
susceptibility and
T
temperature, must be equal to decomposition. In the latter case, η2:η1:µ bridge, one oxy-
94.5 cm3 mol–1 K (27.5 BM). The experimental χMT product gen atom (O19, O19i) is terminally bound to the related
of 94.0 cm3mol–1 (27.4 BM) at 300 K is in good agreement gadolinium ion (Gd, Gdi) and the second oxygen (O18,
with the expected value, as shown in Figure 2. This product O18i) is involved in a monoatomic bridge between the two
decreases slightly from 300 to 50 K (85.1 cm3 mol–1 K, 26.1 lanthanide ions. Due to the inversion centre the Gd(O18,
BM) and more abruptly between 25 and 2 K O18i)Gdi double bridging network is perfectly planar. The
(45.1 cm3 mol–1 K, 19.0 BM). This last decrease corresponds second bridge through the atoms Gd, O16, C16, O17, Gdi,
to antiferromagnetic Gd–Gd interactions and confirms that O16i, C16i and O17i is not planar. The dihedral angle be-
at least some of the Gd ions do interact, surely through tween the two planes, Gd(O18, O18i)Gdi and mean
Gd–O–Gd bridges.
Gd(O16, C16, O17)Gdi plane, is equal to 87.75(6)° while
Very similar curves have been obtained with Gd com- the nine-coordinated gadolinium ions are separated by
plexes of the second and third generation. They are given 3.9816(3) Å. There are two dinuclear units in the unit cell
in Figures S1 and S2 (S). This is particularly true for the 6- distinguished by their η2:η1:µ acetate bridges and the six-
[G3] Gd48 entity, where the magnetic moment varies from membered Gd-bisphosphonate cycles. The six-membered
55.6 BM at 300 K to 44.7 BM at 2 K. A theoretical value Gd-bisphosphonate cycles are in a boat conformation in
of 55.0 BM was expected for 48 Gd ions in the isolated one unit and in a skew boat conformation in the second
species (Figure S2).
unit, with very similar bond lengths. On the contrary, the
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Figure 3. Molecular structure of complex 15 with the thermal ellipsoids drawn at the 30% probability level. Hydrogen atoms are omitted
for clarity. Selected bond lengths and distance [Å]: Gd1–O18 2.329(2), Gd1–O18i 2.580(2), Gd1–O19 2.460(2), Gd1–O16 2.443(2), Gd1–
O17 2.387(2), Gd1–O14 2.449(2), Gd1–O15 2.447(2), Gd1–O11 2.397(2), Gd1–O21 2.451(2), Gd1···Gd1i 3.9816(3).
Gd–O bond lengths of the η2:η1:µ acetate bridge do vary, 6-[G1] Gd12, the equation[42] defined above gives an interac-
2.358(2) and 2.507(2) Å instead of 2.329(2) and 2.580(2) Å tion parameter J equal to –0.11 cm–1, in perfect agreement
for the η2 oxygen atom and 2.492(2) against 2.460(2) Å for with expected J values.[45] As we know that solutions of
the η1 oxygen atom. So the Gd···Gdi distance in the skew- positive ions are acidic in protic solvents[46] and that Ln
boat conformation is slightly shorter, 3.9582(3) Å, than in salts contain water molecules, we can easily imagine that
the boat conformation [3.9816(3) Å] shown in Figure 3. The some water molecules give hydroxo anions able to bridge
dinuclear units are well isolated from each other, with inter- the Gd ions and to replace an equivalent number of non
molecular distances greater than 11.2 Å. The main interest coordinating triflate anions.
of this dinuclear structure consists in showing that the bis-
phosphonate pincer does not act as a bridging ligand but
prefers to act as a chelate for each gadolinium ion.
The magnetic behavior of the dinuclear complex is quite
reminiscent of what was observed for the Gd dendrimer
entities. At 300 K, χMT (Figure 4) is equal to
15.8 cm3 mol–1 K which is the value attributable to two non-
interacting spin carriers, each being characterized by S = 7/
2 and g = 2.0. Lowering of the temperature causes χMT to
decrease to 14.6 cm3 mol–1 K at 2 K. Fitting the experimen-
tal data to the equation[42] deduced from the isotropic spin
Hamiltonian H = –JSGd1·SGd2 yields J = –0.01 cm–1 and g
= 2.00, with an agreement factor R equal to 2.0 10–4 (R =
Figure 4. Temperature dependence of the χMT product for complex
Σ[(χMT)obs – (χMT)calc]2/Σ[(χMT)obs]2). The weak J param-
15.
eter results from a delicate balance between two contri-
butions of opposite signs and slightly different magnitudes.
All these data suggest that the Gd dendrimers chelates
Indeed, the double usual η1:η1:µ bridging mode[43] is known are better represented as polymeric networks, the Gd units
to favour antiferromagnetic interactions while the less com- acting as anchoring centres for dendrimers. The poor solu-
mon η2:η1:µ bridge is associated to ferromagnetic interac- bility observed for the complexes seems to be in agreement
tions.[44] Supposing that Gd ions are associated by pairs in with the existence of such polymeric networks.
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gem-Bisphosphonate-Ended Group Dendrimers
1
(CDCl3, 121.5 MHz): δ = 10.84 (s, P=O) ppm. H NMR (CDCl3,
Conclusions
200.13 MHz): δ = 1.21–1.34 [m, 24 H, CH(CH3)2], 4.63–4.77 [m, 4
H, CH(CH3)2], 6.88 (distorted dd, JHP = 33.6, 34.0 Hz, 2 H,
CH2=C) ppm. 13C{1H} NMR (CDCl3, 75.46 MHz): δ = 23.76 [d,
Synthetic strategies leading to the first gem-bisphosphon-
ate-ended dendrimers are reported. They imply nucleophilic
substitutions of the terminal P(S)Cl2 groups of phosphorus
dendrimers of generation 1 to 3 with protected aminophe-
nols followed by deprotection of amino groups and Michael
type addition with vinylidene tetraisopropyl bisphosphon-
ate. Preliminary experiments show that the novel dendri-
mers studied in this work are able to coordinate Gd ions
thanks to the presence of gem-bisphosphonate functions.
Contrary to the phosphonic acids that can introduce brid-
ges between Gd ions,[47] these synthons act as unique chelat-
ing agents toward the Gd ions. Furthermore, it appears that
the number of Gd ions introduced in the isolated units is
equal to the number of gem-bisphosphonate pairs. Eventu-
ally, the magnetic measurements demonstrate clearly that
the Gd ions are not coordinated to these pairs as isolated
ions but that at least some of these ions are bridged through
oxygen atoms that are not P=O functions, as shown by the
structural determination given in the paper. Studies con-
cerning properties of these Gd dendrimers complexes are
under active investigation.
3JCP = 15.8 Hz, CH(CH3)2], 71.24 [s, CH(CH3)2], 134.56 (t, 1JCP
=
2
168 Hz, CH2=C), 147.25 (d, JCP = 7.5 Hz, CH2=C) ppm.
2: 4-Hydroxyaniline (150 mg, 1.37 mmol) and 1 (0.5 g, 1.40 mmol)
were left to react in THF (4 mL) at 50 °C for 2 h. After reaction
completion (31P NMR monitoring), the solution was filtered
through celite to remove any residual insoluble starting material.
After removal of the residual solvent, an oil was obtained and
washed twice with pentane (5 mL) to afford 2 as black oil in 95%
yield (606 mg). 31P{1H} NMR (CDCl3, 101.25 MHz): δ = 20.08 (s,
1
P=O) ppm. H NMR (CDCl3, 250.13 MHz): δ = 1.26–1.31 [m, 24
H, CH(CH3)2], 2.54 (tt, 3JHH = 5.7, 2JHP = 23.5 Hz, 1 H, CH2CH),
3
3
3.60 (td, JHH = 5.7, JHP = 15.7 Hz, 2 H, CH2CH), 4.63–4.81 [m,
3
3
4 H, CH(CH3)2], 6.51 (d, JHH = 6.75 Hz, 2 H, C0 H), 6.71 (d,
3JHH = 6.75 Hz, 2 H, C0 H) ppm. 13C{1H} NMR (CDCl3,
2
1
75.46 MHz): δ = 23.76–24.07 [m, CH(CH3)], 37.53 (t, JCP
134 Hz, CH2CH), 41.87 (s, CH2CH), 71.57–71.83 [m, CH(CH3)2],
115.68 (s, C0 ), 116.23 (s, C0 ), 139.41 (s, C0 ), 150.17 (s, C0 ) ppm.
=
2
3
1
4
3: (4-Hydroxyphenol)piperazine (150 mg, 0.841 mmol) and
1
(305 mg, 0.855 mmol) were left to react in THF (4 mL) at 50 °C
during 5 h. After reaction completion (31P NMR monitoring), the
solution was filtered through celite to remove any residual insoluble
starting material. After removal of the residual solvent, solid ob-
tained was washed twice with pentane (5 mL) and then crystallized
with a mixture n-pentane/diethyl ether (3:1, with the minimum
amount of ether) 3 times to afford 3 as a rose-tinted crystalline
powder in 84% yield (378 mg). 31P{1H} NMR (CDCl3,
81.015 MHz): δ = 23.93 (s, P=O) ppm. 1H NMR (CDCl3,
Experimental Section
General: All manipulations were carried out with standard high-
vacuum and dry-argon techniques. Chemicals were purchased from
Sigma–Aldrich or Strem and used without further purification; sol-
vents were dried and distilled by routine procedures. H, 13C, and
3
1
250.133 MHz): δ = 1.26–1.31 [m, 24 H, CH(CH3)2], 2.58 (tt, JHH
31P NMR spectra were recorded at 25 °C with Bruker AC 200,
ARX 250, AV 300, DPX 300, AMX 400 or AV500 spectrometers.
References for NMR chemical shifts are 85% H3PO4 for 31P NMR,
2
3
= 6.5, JHP = 30.6 Hz, 1 H, CH2CH), 2.65 (t, JHH = 4.2 Hz, 2 H,
CbH), 2.93 (dt, JHH = 6.5, JHP = 15.0 Hz, 2 H, CH2CH), 2.98 (t,
3JHH = 4.2 Hz, 2 H, CaH), 4.70–4.87 [m, 4 H, CH(CH3)2], 6.74–
6.85 (m, 4 H, Har) ppm. 13C{1H} NMR (CDCl3, 75.46 MHz): δ =
3
3
1
and SiMe4 for H and 13C NMR spectroscopy. The attribution of
13C NMR signals has been done using Jmod, two-dimensional 1H-
13C HSQC, 1H-13C HMBC, and 1H-31P HMQC, Broad Band or
CW 31P decoupling experiments when necessary. The numbering
scheme used for NMR is depicted on Figure 5.
1
23.95–24.02 [m, CH(CH3)], 37.64 (t, JCP = 134.5 Hz, CH2CH),
50.76 (s, Ca), 53.10 (s, Cb), 54.33 (s, CH2CH), 71.17–71.49 [m,
2
3
1
CH(CH3)2], 115.93 (s, C0 ), 118.28 (s, C0 ), 144.77 (s, C0 ), 151.20
4
(s, C0 ) ppm. MS (DCI): m/z = 535 [MH]+. MP: 87–91 °C.
Magnetic susceptibility data were collected on powdered samples
with a Quantum Design MPMS SQUID magnetometer under a
0.1 T applied magnetic field. All data were corrected for diamagne-
tism of the ligands estimated from Pascal’s constants.[48]
7: At 0 °C (ice bath), Boc2O (6.54 g, 29.96 mmol) was solubilised in
THF (50 mL) then 4-hydroxyaniline (2 g, 18.32 mmol) was added
gently. The reaction mixture was allowed to reach room tempera-
ture and was left to react for 36 h. Solvent was removed and the
residual oil was solubilised in AcOEt. Organic phase was washed
three times with brine, then dried with MgSO4 and filtered. After
Compound 1 was a gift from Rhodia PPD and was purified by
chromatography (SiO2, acetone/pentane, 1:1): 31P{1H} NMR
Figure 5. Numbering scheme used for NMR assignment.
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removal of the residual solvents, compound 7 was obtained as a
white crystalline solid in 92% yield (3.527 g). 1H NMR (CDCl3,
250.33 MHz): δ = 1.50 (s, 9 H, CH3), 5.38 (s, 1 H, NH), 6.34 (s, 1
132.1 Hz, CH2CH), 40.82 (s, CH2CH), 70.54–71.42 [m, CH(CH3)],
3
2
2
3
113.53 (s, C1 ), 121.19 (s, C0 ), 122.06 (s, C1 ), 128.23 (s, C0 ),
4
3
2
132.73 (s, C0 ), 139.05 (d, JCP = 13.8 Hz, CH=N), 142.02 (d, JCP
3
2
3
1
4
1
H, OH), 6.73 (d, JHH = 10.0 Hz, 2 H, C0 H), 7.14 (d, JHH
=
= 6.3 Hz, C1 ), 145.10 (s, C1 ), 150.95 (s, C0 ) ppm.
3
10.0 Hz, 2 H, C0 H) ppm. 13C{1H} NMR (CDCl3, 62.89 MHz): δ
10: At 0 °C (ice bath), Boc2O (4.40 g, 20.16 mmol) was solubilised
in THF (50 mL) then 4-hydroxypiperazine (3.08 g, 17.28 mmol)
was added gently. The reaction mixture was allowed to reach room
temperature and was left to react during 4 h. Solvent was removed
and the residual oil was solubilised in AcOEt (150 mL). Organic
phase was washed once with a saturated solution of NaHCO3,
twice with brine, then dried with MgSO4 and filtered. After re-
moval of the residual solvents, compound 10 was obtained as a
brownish crystalline solid in 98% yield (4.714 g). 1H NMR (CDCl3,
2
3
= 28.32 (s, CH3), 80.45 [s, C(CH3)3], 118.52 (s, C0 ), 122.98 (s, C0 ),
4
1
128.93 (s, C0 ), 138.32 (s, C0 ), 152.7 (s, C=O) ppm. MP: 132–
133 °C.
8-[G1]: Dendrimer 4-[G1] (200 mg, 0.11 mmol),
7 (297 mg,
1.42 mmol) and Cs2CO3 (913 mg, 2.80 mmol) were left to react in
THF (5 mL) at room temperature for 5 d. After reaction comple-
tion, salts were removed by centrifugation and the clear solution
was concentrated under reduced pressure. The residue was then
dissolved in the minimum amount of THF (ca. 1 mL) and precipi-
tated with pentane/diethyl ether. The resulting powder was filtered
off and the procedure was repeated twice to afford 8-[G1] as a
brownish powder in 81% yield (348 mg). 31P{1H} NMR (CDCl3,
3
300.13 MHz): δ = 1.50 (s, 9 H, CH3), 2.98 (t, JHH = 5.1 Hz, 2 H,
3
CaH), 3.58 (t, JHH = 5.1 Hz, 2 H, CbH), 6.55 (br. s, 1 H, OH),
2
3
6.77–6.86 (m, 4 H, C0 H, C0 H) ppm. 13C{1H} NMR (CDCl3,
62.89 MHz): δ = 28.46 (s, CH3), 43.50 (s, Cb), 51.17 (s, Ca), 80.28
[s, C(CH3)3], 116.00 (s, C0 ), 129.23 (s, C0 ), 145.03 (s, C0 ), 150.95
(s, C0 ), 154.98 (s, C=O) ppm. MP: 170–173 °C.
2
3
1
121.5 MHz): δ = 8.60 (s, P=N), 63.75 (s, P=S) ppm. 1H NMR
4
3
(CDCl3, 300.13 MHz): δ = 1.48 (s, 108 H, CH3), 3.21 (d, JHP
=
10.2 Hz, 18 H, CH3NP), 6.75 (s, 12 H, NH), 6.98 (d, 3JHH = 8.4 Hz,
11-[G1]: Dendrimer 4-[G1] (0.635 g, 0.347 mmol), 10 (1.2 g,
4.31 mmol) and Cs2CO3 (2.81 g, 8.62 mmol) were left to react in
THF (5 mL) at room temperature overnight. After reaction com-
pletion, salts were removed by centrifugation and the clear solution
was concentrated under reduced pressure. The residue was then
dissolved in the minimum amount of THF (ca. 3 mL) and precipi-
tated with pentane/diethyl ether. The resulting powder was filtered
off and the procedure was repeated twice to afford 11-[G1] as a
brownish powder in 87% yield (1.428 g). 31P{1H} NMR (CDCl3,
2
3
2
3
12 H, C0 H), 7.08 (d, JHH = 7.8 Hz, 24 H, C1 H), 7.26 (d, JHH
3
3
= 7.8 Hz, 24 H, C1 H), 7.59 (s, 6 H, CH=N), 7.63 (d, JHH
=
3
8.4 Hz, 12 H, C0 H) ppm. 13C{1H} NMR (CDCl3, 75.46 MHz): δ
2
= 28.34 (s, CH3), 33.10 (d, JCP = 12.3 Hz, CH3NP1), 80.57 [s,
3
2
2
C(CH3)3], 119.64 (s, C1 ), 121.49 (br. s, C0 ), 121.82 (d, JCP
=
=
=
2
4
4
3
4.4 Hz, C1 ), 128.30 (s, C1 ), 132.17 (s, C0 ), 135.83 (d, JCP
3
3
2
1.7 Hz, C1 ), 138.55 (d, JCP = 13.8 Hz, CH=N), 145.77 (d, JCP
1
2
1
7.1 Hz, C1 ), 151.21 (d, JCP = 5.0 Hz, C0 ), 152.87 (s, C=O) ppm.
81.015 MHz): δ = 12.16 (s, P=N), 67.81 (s, P=S) ppm. 1H NMR
9-[G1]: Dendrimer 8-[G1] (211 mg, 0.054 mmol) was solubilised at
room temperature in a mixture DCM/TFA (3 mL/1 mL) for 20 min
then residual solvents were removed. The procedure was repeated
once. The residue obtained was solubilised in MeOH, and then
solvents were removed under reduced pressure to eliminate the ex-
cess of TFA by co-evaporation. The procedure was repeated twice.
Final compound 9-[G1] was obtained as yellowish powder in 100%
yield (218 mg). 31P{1H} NMR (CD3OD, 121.49 MHz): δ = 8.63 (s,
3
(CDCl3, 200.13 MHz): δ = 1.45 (s, 108 H, CH3), 2.98 (t, JHH
=
4.8 Hz, 48 H, CbH2), 3.20 (d, JHP = 10 Hz, 18 H, CH3NP1), 3.49
3
(t, 3JHH = 4.8 Hz, 48 H, CaH2), 6.74 (d, 3JHH = 9 Hz, 24 H, C1 H),
3
2
6.93 (d, 3JHH = 8.4 Hz, 12 H, C0 H), 7.04 (dd, 3JHH = 9 Hz, 24 H,
C1 H), 7.56–7.64 (m, 18 H, CH=N, C0 H) ppm. 13C{1H} NMR
2
3
2
(CDCl3, 62.89 MHz): δ = 28.42 (s, CH3), 33.13 (d, JCP = 11.7 Hz,
CH3NP1), 43.53 (br. s, Cb), 49.55 (s, Ca), 79.89 [s, C(CH3)3], 117.39
3
2
2
3
(s, C1 ), 121.42 (s, C0 ), 121.94 (s, C1 ), 128.24 (s, C0 ), 132.40 (s,
C0 ), 138.6 (d, JCP = 14.1 Hz, CH=N), 143.88 (d, JCP = 7.0 Hz,
1
P=N), 62.93 (s, P=S) ppm. H NMR (CD3OD, 300.13 MHz): δ =
4
3
2
2
3.32 (m, 18 H, CH3NP), 7.03 (d, 3JHH = 8.4 Hz, 12 H, C0 H), 7.31
1
4
1
C1 ), 148.84 (s, C1 ), 151.10 (s, C0 ), 154.65 (s, C=O) ppm.
2
3
3
3
(s, 48 H, C1 H, C1 H), 7.65 (d, JHH = 8.4 Hz, 12 H, C0 H), 7.82
11-[G2]: Dendrimer 4-[G2] (0.250 g, 0.052 mmol),
1
(0.36 g,
(s, 6 H, CH=N) ppm. 13C{1H} NMR (CD3OD, 75.46 MHz): δ =
32.11 (d, JCP = 12.1 Hz, CH3NP), 121.00 (s, C0 ), 122.62 (d, JCP
1.29 mmol) and Cs2CO3 (0.850 g, 2.60 mmol) were left to react in
THF (2 mL) at room temperature overnight. After reaction com-
pletion, salts were removed by centrifugation and the clear solution
was concentrated under reduced pressure. The residue was then
dissolved in the minimum amount of THF (ca. 1 mL) and precipi-
2
2
3
2
3
3
4
= 4.5 Hz, C1 ), 123.42 (s, C1 ), 128.13 (s, C0 ), 129.82 (s, C0 ),
4
3
2
132.32 (s, C1 ), 140.11 (d, JCP = 14.3 Hz, CH=N), 149.81 (d, JCP
1
1
= 6.8 Hz, C1 ), 151.20 (s, C0 ) ppm.
5-[G1]: Dendrimer 9-[G1] (108 mg, 0.027 mmol) and Cs2CO3 tated with pentane/diethyl ether. The resulting powder was filtered
(215 mg, 0.66 mmol) were mixed in CH3CN (1 mL) for 30 min at off and the procedure was repeated twice to afford 11-[G2] as a
room temperature. Compound
1
(491 mg, 1.377 mmol) was
brownish powder in 79% yield (435 mg). 31P{1H} NMR (CDCl3,
121.49 MHz): δ = 8.61 (s, P=N), 62.50 (s, P1=S), 64.55 (s, P2=S)
ppm. 1H NMR (CDCl3, 300.13 MHz): δ = 1.46 [s, 216 H, C(CH3)],
dropped in and the reaction mixture was left to react for 3 d. After
reaction completion (1H and 31P monitoring), 20 mL of DCM were
added and the organic phase was washed with water (20 mL) twice.
Residue was dried with MgSO4, filtered, concentrated and precipi-
tated with pentane. The resulting powder was filtered off and the
procedure was repeated twice to afford 5-[G1] as a white powder in
64% yield (121 mg). 31P{1H} NMR (CDCl3, 81.015 MHz): δ = 8.09
3
3.00 (br. s, 96 H, CbH2), 3.17 (d, JHP = 10.5 Hz, 18 H, CH3NP1),
3
3.20 (d, JHP = 9.9 Hz, 18 H, CH3NP2), 3.50 (br. s, 96 H, CaH2),
3
3
2
6.70–6.81 (m, 48 H, C2 H), 6.86 (d, JHH = 8.1 Hz, 12 H, C0 H),
3
2
3
7.05 (d, JHH = 7.8 Hz, 48 H, C2 H), 7.16 (d, JHH = 8.1 Hz, 24
2
3
H, C1 H), 7.54 (s, 12 H, CH=NNP1), 7.62 (d, JHH = 7.8 Hz, 48
1
3
(s, P=N), 19.91 (s, P=O), 65.17 (s, P=S) ppm. H NMR (CDCl3,
H, C1 H, CH=NNP2) ppm. 13C{1H} NMR (CDCl3, 75.46 MHz):
3
300.13 MHz): δ = 1.31–1.40 [m, 288 H, CH(CH3)], 2.52 (tt, JHH δ = 28.44 [s, CH(CH3)], 32.85–33.17 (m, CH3NP1, CH3NP2), 43.52
2
3
3
= 5.4, JHP = 23.4 Hz, 12 H, CH2CH), 3.27 (d, JHP = 9.9 Hz, 18 (br. s, Cb), 49.56 (s, Ca), 79.88 [s, C(CH3)3], 117.39 (s, C2 ), 121.48
3
3
2
2
3
3
3
H, CH3NP), 3.62 (td, JHH = 5.4, JHP = 15.6 Hz, 12 H, CH2CH), (s, C0 ), 121.83 (s, C1 ), 122.07 (s, C1 ), 128.27 (s, C0 and C1 ),
3
2
4
4
3
4.77 [m, 48 H, CH(CH3)], 6.57 (d, JHH = 8.1 Hz, 24 H, C1 H),
132.18 (s, C0 ), 132.55 (s, C1 ), 138.29 (d, JCP = 13.8 Hz,
2
3
3
3
7.00–7.09 (m, 36 H, C0 H, C1 H), 7.61–7.65 (m, 18 H, C0 H,
CH=NNP2), 139.17 (d, JCP = 14 Hz, CH=NNP1), 143.82 (d, 2JCP
= 7.0 Hz, C2 ), 148.84 (s, C2 ), 151.09 (d, JCP = 7.2 Hz, C0 , C1 ),
CH=N) ppm. 13C{1H} NMR (CD3CN, 125.80 MHz): δ = 23.28
1
4
2
1
1
2
1
[m, CH(CH3)], 32.85 (d, JCP = 11.3 Hz, CH3NP), 37.76 (t, JCP
=
154.65 (s, C=O) ppm.
4296
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4290–4299

gem-Bisphosphonate-Ended Group Dendrimers
11-[G3]: Dendrimer 4-[G3] (0.180 g, 0.016 mmol), 10 (0.250 g,
7.5 mL) for 20 min then residual solvents were removed. The pro-
0.897 mmol) and Cs2CO3 (0.575 g, 1.764 mmol) were left to react cedure was repeated twice. Residue obtained was solubilised in
in THF (2 mL) at room temperature overnight. After reaction com-
pletion, salts were removed by centrifugation and the clear solution
was concentrated under reduced pressure. The residue was then
dissolved in the minimum amount of THF (ca. 1 mL) and precipi-
tated with pentane/diethyl ether. The resulting powder was filtered
off and the procedure was repeated twice to afford 11-[G3] as a
brownish powder in 82% yield (293 mg). 31P{1H} NMR (CDCl3,
121.49 MHz): δ = 8.17 (s, P=N), 62.56 (s, P2=S), 63.62 (s, P1=S),
64.27 (s, P3=S) ppm. 1H NMR (CDCl3, 300.13 MHz): δ = 1.46 [br.
s, 432 H, C(CH3)], 2.99 (br. s, 192 H, CbH2), 3.23 (m, 126 H,
MeOH, and then solvents were removed under reduced pressure to
eliminate the excess of TFA by co-evaporation. The procedure was
repeated twice. Final compound 12-[G3] was obtained as yellowish
powder in 97% yield (375 mg). 31P{1H} NMR (CD3COD3 + D2O,
121.49 MHz): δ = 8.62 (s, P=N), 62.71 (br. s, P1=S, P2=S), 64.27
(s, P3=S) ppm. 1H NMR (CD3COD3 + D2O, 200.13 MHz): δ =
2.90–3.70 (br. s, 498 H, CaH2, CbH2, CH3N), 6.80–8.00 (m, 402 H,
Har, CH=N) ppm. 13C{1H} NMR (CD3COD3 + D2O, 75.46 MHz):
δ = 32.00 (m, CH3-N), 43.28 (br. s, CH2NH2+), 46.47 (s, CH2NAr),
116.26 (q, 1JCF = 291 Hz, CF3), 117.82 (s, C3 ), 121.89 (s, C0 , C1 ,
3
2
2
CH3NP1, CH3NP2, CH3NP3), 3.50 (br. s, 192 H, CaH2), 6.60–6.85 C2 , C3 ), 128.32 (br. s, C0 , C1 , C2 ), 132.50 (s, C0 , C1 , C2 ),
2
2
3
3
3
4
4
4
3
2
2
2
2
1
4
(m, 96 H, C3 H), 6.85–7.25 (m, 180 H, C0 H, C1 H, C2 H, C3 H), 139.50–134.00 (m, CH=N), 144.50 (br. s, C3 ), 147.97 (br. s, C3 ),
7.50–7.80 (m, 126 H, CH=N, C0 H, C1 H, C2 H) ppm. 13C{1H} 151.00 (m, C0 , C1 , C2 ), 161.00 (q, JCP = 36.0 Hz, CF3C=O)
NMR (CDCl3, 75.46 MHz): δ = 28.44 [s, CH(CH3)], 32.85–33.2 ppm.
3
3
3
1
1
1
3
(m, CH3NP), 43.41 (br. s, Cb), 49.56 (s, Ca), 79.86 [s, C(CH3)3],
6-[G1]: Dendrimer 12-[G1] (220 mg, 0.044 mmol) and Cs2CO3
3
2
2
2
2
3
3
117.39 (s, C3 ), 121.98 (m, C0 , C1 , C2 , C3 ), 128.26 (m, C0 , C1 ,
(350 mg, 1.074 mmol) were mixed in CH3CN (1 mL) for 30 min at
room temperature. Compound 1 (800 mg, 2.24 mmol) was dropped
in and the reaction mixture was left to react for 3 d. After reaction
completion (31P monitoring), 20 mL of DCM were added and the
organic phase was washed with water (20 mL) twice. The residue
was dried with MgSO4, filtered and the solvents evaporated. It was
then solubilised in ether and precipitated with pentane. The re-
sulting powder was filtered off and the procedure was repeated
twice to afford 6-[G1] as a brownish powder in 65% yield (223 mg).
31P{1H} NMR (CD3CN, 121.50 MHz): δ = 9.19 (s, P=N), 20.54 (s,
3
4
4
4
3
C2 ), 132.50 (m, C0 ,C1 , C2 ), 138.33 (d, JCP
= 15.4 Hz,
2
CH=NNP3), 139.01 (m, CH=NNP1, CH=NNP2), 143.91 (d, JCP
1
4
1
1
1
= 7.1 Hz, C3 ), 148.81 (s, C3 ), 151.09 (m, C0 , C1 , C2 ), 154.65 (s,
C=O) ppm.
12-[G1]: Dendrimer 11-[G1] (0.6 mg, 0.126 mmol) was solubilised at
room temperature in a mixture TFA/DCM (2 mL/ 8 mL) for
20 min then residual solvents were removed. The procedure was
repeated twice. Residue obtained was solubilised in MeOH, and
then solvents were removed under reduced pressure to eliminate
the excess of TFA by co-evaporation. The procedure was repeated
twice. Final compound 12-[G1] was obtained as a yellowish powder
in 95% yield (586 mg). 31P{1H} NMR (CD3OD, 121.49 MHz): δ =
9.34 (s, P=N), 63.93 (s, P=S) ppm. 1H NMR (CD3OD,
200.13 MHz): δ = 3.30 (m, 18 H, CaH2, CbH2, CH3NP1), 6.87 (d,
1
P=O), 64.29 (s, P=S) ppm. H NMR (CD3CN, 300.13 MHz): δ =
3
2
1.28–1.34 [m, 288 H, CH(CH3)], 2.46 (tt, JHH = 5.4, JHP
=
=
24.0 Hz, 12 H, CH2CH), 2.54 (br. s, 48 H, CbH2), 2.81 (td, 3JHH
5.4, JHP = 15.0 Hz, 24 H, CH2CH), 3.00 (br. s, 48 H, CaH2), 3.20
3
3
(d, JHP = 9.6 Hz, 18 H, CH3NP1), 4.65–4.78 [m, CH(CH3)], 6.74
3
2
(d, 3JHH = 8.4 Hz, 24 H, C1 H), 6.91 (s, 12 H, C0 H), 7.00 (d, 3JHH
3
2
2
3
3JHH = 9 Hz, 36 H, JHH = 8.7 Hz, C0 H, C1 -H), 7.08 (d, JHH
=
2
3
3
9 Hz, 24 H, C1 H), 7.75 (s, 6 H, CH=N) ppm. 13C{1H} NMR
3
= 8.4 Hz, 24 H, C1 H), 7.59 (d, JHH = 7.8 Hz, 12 H, C0 H), 7.67
(s, 6 H, CH=NNP1) ppm. 13C{1H} NMR (CDCl3, 125.80 MHz):
δ = 23.13–23.67 [m, CH(CH3)], 32.96 (d, 2JCP = 11.3 Hz, CH3NP1),
2
(CD3OD, 75.46 MHz): δ = 32.42 (d, JCP = 11.5 Hz, CH3NP),
43.28 (s, CH2NH2+), 46.68 (s, CH2NAr), 117.74 (s, C1 ), 121.19 (s,
3
37.67 (t, JCP = 133.3 Hz, CH2CH), 48.86 (s, Ca), 52.87 (s, Cb),
2
C0 ), 121.74 (d, 3JCP = 4.5 Hz, C1 ), 128.12 (s, C0 ), 132.74 (s, C0 ),
2
2
3
4
3
138.83 (d, 3JCP = 14.4 Hz, CH=N), 144.68 (d, JCP = 7.1 Hz, C1 ),
2
1
54.47 (s, CH2CH), 70.52–71.20 [m, CH(CH3)], 116.37 (s, C1 ),
121.37 (s, C0 ), 121.67 (s, C1 ), 128.25 (s, C0 ), 132.74 (s, C0 ),
139.00 (m, CH=N), 143.10 (d, JCP = 7.0 Hz, C1 ), 149.12 (s, C1 ),
2
2
3
4
4
1
3
147.89 (s, C1 ), 150.89 (s, C0 ), 161.40 (d, JCP = 34.5 Hz, CF3-
C=O) ppm. (CF3 could not be attributed).
2
1
4
1
150.91 (s, C0 ) ppm.
12-[G2]: Dendrimer 11-[G2] (0.391 mg, 0.036 mmol) was solubilised
at room temperature in a mixture TFA/DCM (2 mL/ 8 mL) for
20 min then residual solvents were removed. The procedure was
repeated twice. Residue obtained was solubilised in MeOH, and
then solvents were removed under reduced pressure to eliminate
the excess of TFA by co-evaporation. The procedure was repeated
twice. Final compound 12-[G2] was obtained as yellowish powder
in 97% yield (382 mg). 31P{1H} NMR [CD3COD3 + D2O (4:1),
121.49 MHz]: δ = 9.02 (s, P=N), 62.36 (br. s, P1=S), 64.46 (br. s,
P2=S) ppm. 1H NMR (CD3COD3 + D2O, 200.13 MHz): δ = 3.10–
3.50 (br. s, 236 H, CaH2, CbH2, CH3NP1, CH3NP2), 6.88–7.25 (m,
6-[G2]: Dendrimer 12-[G2] (226 mg, 0.021 mmol) and Cs2CO3
(328 mg, 1.006 mmol) were mixed in CH3CN (1 mL) for 30 min at
room temperature. Compound 1 (600 mg, 1.68 mmol) was dropped
in and the reaction mixture was left to react for 3 d. After reaction
completion (31P monitoring), 20 mL of DCM were added and the
organic phase was washed with water (20 mL) twice. Residue was
dried with MgSO4, filtered and the solvents evaporated. It was then
solubilised in ether and precipitated with pentane. The resulting
powder was filtered off and the procedure was repeated twice to
afford 6-[G2] as a brownish powder in 56% yield (197 mg). 31P{1H}
NMR (CD3CN, 121.50 MHz): δ = 9.11 (s, P=N), 20.54 (s, P=O),
62.27 (s, P1=S), 64.80 (br. s, P2=S) ppm. 1H NMR (CD3CN,
300.13 MHz): δ = 1.25–1.40 [m, 576 H, CH(CH3)], 2.46 (br. t, 3JHP
= 24.0 Hz, 24 H, CH2CH), 2.63 (br. s, 96 H, CbH2), 2.91 (br. t,
3JHP = 14.4 Hz, 48 H, CH2CH), 3.09 (br. s, 96 H, CaH2), 3.28 (m,
54 H, CH3N), 4.78 [br. s, 96 H, CH(CH3)], 6.70–6.85 (m, 48 H,
2
2
2
3
3
3
132 H, C0 H, C1 H, C2 H, C2 H), 7.55–7.80 (m, 54 H, C0 H, C1 H,
CH=NNP1, CH=NNP2) ppm. 13C{1H} NMR (CD3COD3 + D2O,
75.46 MHz): δ = 32.55–32.84 (m, CH3NP1, CH3NP2), 43.27 (s,
CH2NH2+), 46.47 (s, CH2NAr), 116.26 (q, JCF = 291 Hz, CF3),
1
3
2
2
2
118.02 (s, C2 ), 121.05 (s, C0 ), 121.14 (s, C1 ), 121.27 (s, C2 ),
3
3
4
4
128.41 (br. s, C0 , C1 ), 132.50 (s, C0 ), 132.80 (s, C1 ), 139.50–
3
2
2
2
C2 H), 6.95–7.30 (m, 84 H, C0 H, C1 H, C2 H), 7.55–7.70 (m, 54
139.80 (m, CH=NNP1, CH=NNP2), 144.27 (d, 2JCP = 4.5 Hz, C2 ),
1
3
3
H, CH=N, C0 H, C1 H) ppm. 13C{1H} NMR (CDCl3,
4
1
1
3
147.96 (s, C2 ), 150.91 (m, C0 , C1 ), 161.40 (d, JCP = 36.2 Hz,
CF3C=O) ppm.
75.46 MHz): δ = 23.80–24.30 [m, CH(CH3)], 33.14 (m, CH3-N),
2
37.80 (t, JCP = 133.9 Hz, CH2CH), 49.32 (s, Ca), 52.93 (s, Cb),
3
12-[G3]: Dendrimer 11-[G3] (0.399 mg, 0.0168 mmol) was solu-
bilised at room temperature in a mixture TFA/DCM (2.5 mL/
54.36 (s, CH2CH), 70.52–71.25 [m, CH(CH3)], 116.70 (s, C1 ),
2
2
2
3
3
121.41 (m, C0 ), 121.92 (br. s, C1 , C2 ), 128.26 (s, C0 , C1 ), 132.18
Eur. J. Org. Chem. 2009, 4290–4299
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4297

J.-P. Costes, A.-M. Caminade, J.-P. Majoral et al.
FULL PAPER
(s, C0 ), 132.62 (s, C1 ), 138.24 (m, CH=NNP2), 139.06 (m,
CH=NNP2), 143.53 (m, C2 ), 148.90 (s, C2 ), 150.22 (s, C0 , C1 )
ppm.
Complex 15: Addition of Gd(CH3COO)3 (0.007 g, 0.20 10–4 mol)
and Gd(hfa)3·2H2O (0.077 g, 0.95 10–4 mol) to a stirred solution of
ligand 14 (0.06 g, 1.15 10–4 mol) in diethyl ether (5 mL) yielded a
yellow oil 48 h later, after solvent evaporation. Pentane addition
induced precipitation of a colorless powder, which was dissolved in
dichloromethane and saturated by pentane vapors to give colorless
crystals suitable for X-ray analysis.
4
4
1
4
1
1
6-[G3]: Dendrimer 12-[G3] (410 mg, 0.0155 mmol) and Cs2CO3
(483 mg, 1.48 mmol) were mixed in CH3CN (1 mL) for 30 min at
room temperature. Compound 1 (883 mg, 2.48 mmol) was dropped
in and the reaction mixture was left to react for 2 d. After reaction
completion (31P monitoring), 20 mL of DCM were added and the
organic phase was washed with water (20 mL) twice. Residue was
dried with MgSO4, filtered and the solvents evaporated. It was then
solubilised in ether and precipitated with pentane. The resulting
powder was filtered off and the procedure was repeated twice to
afford 6-[G3] as a brownish powder in 61% yield (327 mg). 31P{1H}
NMR (CD3CN, 121.50 MHz): δ = 20.57 (s, P=O), 62.69 (s, P1=S,
P2=S), 64.58 (s, P3=S) ppm (P=N could not be attributed). 1H
NMR (CD3CN, 300.13 MHz): δ = 1.34 [br. s, 1152 H, CH(CH3)],
Crystal Structure Determination: CCDC-727232 (for 15) contains
the supplementary crystallographic data for the complex reported
in this paper. The data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Crystal Data for 15: C66H100.5F13.5Gd2N4O24P4, M = 2028.88, tri-
clinic, a = 12.1180(6), b = 19.9790(10), c = 22.1570(12) Å, α =
114.825(2), β = 92.508(3), γ = 101.168(2)°, V = 4729.1(4) Å3, T =
–1
¯
180 K, space group P1, Z = 2, µ (Mo-Kα) = 1.549 mm , 166117
3
2.41 (br. t, JHP = 24.0 Hz, 48 H, CH2CH), 2.63 (br. s, 192 H,
reflections collected, 23318 independent (Rint = 0.027). The final R
values were R(F) = 0.0321 for 20169 reflections with I Ͼ 2σI and
wR(F2) = 0.1098 for all data.
3
CbH2), 2.91 (br. t, JHP = 14.4 Hz, 96 H, CH2CH), 3.09 (br. s, 192
H, CaH2), 3.28 (m, 126 H, CH3N), 4.78 [br. s, 192 H, CH(CH3)],
3
2
2
2
6.80 (br. s, 96 H, C3 H), 6.95–7.30 (m, 180 H, C0 H, C1 H, C2 H,
Supporting Information (see also the footnote on the first page of
this article): Crystallographic data collection and structure determi-
nation for 15, temperature dependence of the magnetic moment µ
for 6-[G2] and 6-[G3].
2
3
3
3
C3 H), 7.55–7.70 (m, 126 H, CH=N, C0 H, C1 H, C2 -H) ppm.
13C{1H} NMR (CDCl3, 75.46 MHz):
δ = 23.8–24.31 [m,
2
CH(CH3)], 32.97 (m, CH3N), 37.80 (t, JCP = 133.9 Hz, CH2CH),
49.32 (s, Ca), 52.92 (s, Cb), 54.34 (s, CH2CH), 70.52–71.35 [m,
3
2
2
2
2
CH(CH3)], 116.70 (s, C3 ), 121.90 (m, C0 , C1 , C2 , C3 ), 128.26
3
3
3
4
4
4
(s, C0 , C1 , C1 ), 132.54 (s, C0 , C1 , C2 ), 138.26 (m, CH=NNP3),
Acknowledgments
1
4
139.06 (m, CH=NNP2, CH=NNP1), 143.50 (m, C3 ), 148.8 (s, C3 ),
1
1
1
151.22 (s, C0 , C1 , C2 ) ppm.
We thank the European Community for a PhD grant to G. F.
(Fond Social Européen). E. C. thanks the Fundacion Ramon
Areces for financial support.
6-[G1] Gd12: To a solution of 6-[G1] (20.3 mg, 2.6ϫ10–6 mol) in
CH3CN (3 mL) was added dropwise a solution containing a slight
excess of Gd(trifl)3·6H2O (13) (25 mg, 3.5ϫ10–5 mol). The re-
sulting solution was stirred at room temperature for 48 h. Then the
solvent was removed and the solid was washed with CH2Cl2 (5 mL)
to eliminate the excess of gadolinium triflate. Addition of diethyl
ether to the solid yielded a powder product that was filtered off
and dried. Yield 12.7 mg, 31.5%. The same procedure was applied
to obtain 6-[G2] Gd24 and 6-[G3] Gd48.
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(41 mg, 5.7ϫ10–5 mol). Yield 21.7 mg, 38%.
14: Phenylpiperazine (136 mg, 0.841 mmol) and
1 (302 mg,
0.855 mmol) were left to react in THF (4 mL) at 50 °C during 5 h.
After reaction completion (31P NMR monitoring), the solution was
filtered through celite to remove any residual insoluble starting ma-
terial. After removal of the residual solvent, solid obtained was
washed 2 times with pentane (5 mL) and then crystallized with a
mixture n-pentane/diethyl ether (3:1, with the minimum amount of
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ppm. 1H NMR (CDCl3, 300.13 MHz): δ = 1.11–1.25 [m, 24 H,
3
2
CH(CH3)2], 2.36 (tt, JHH = 6.0, JHP = 274.3 Hz, 1 H, CH2CH), [11] C. Loup, M. A. Zanta, A. M. Caminade, J. P. Majoral, B.
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15.0 Hz, 2 H, CH2CH), 2.99 (t, JHH = 4.6 Hz, 2 H, CaH), 4.57–
3
1
4.69 [m, 4 H, CH(CH3)2], 6.64 (t, 3JHH = 7.2 Hz, 1 H, C0 -H), 6.72
3
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3
3
(d, JHH = 8.1 Hz, 2 H, C0 -H), 7.06 (dd, JHH = JHH = 8.4 Hz,
2
2 H, C0 -H) ppm. 13C{1H} NMR (CDCl3, 75.47 MHz): δ = 23.47–
1
24.17 [m, CH(CH3)], 37.68 (t, JCP = 133.5 Hz, CH2CH), 48.86 (s,
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2
1
3
4
115.75 (s, C0 ), 119.36 (s, C0 ), 128.86 (s, C0 ), 151.17 (s, C0 ) ppm.
MS (DCI): m/z = 519 [MH]+.
4298
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4290–4299

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Received: April 28, 2009
Published Online: July 22, 2009
Eur. J. Org. Chem. 2009, 4290–4299
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4299