Synthesis of dendritic β-diketones and their application in copper-catalyzed diaryl ether formation

Article abstract of DOI:10.1002/ejoc.201101521

Phosphorus-based dendrimers decorated with β-diketones were prepared and fully characterized. These macromolecules, which are the first examples of multivalent dendrimeric β-diketones, were tested as ligands for copper in O-arylations of 3,5-dimethylpheno

Full text of DOI:10.1002/ejoc.201101521

FULL PAPER
DOI: 10.1002/ejoc.201101521
Synthesis of Dendritic β-Diketones and Their Application in Copper-Catalyzed
Diaryl Ether Formation
Michel Keller,[a,b] Mykhailo Ianchuk,[a,b] Sonia Ladeira,[a,b] Marc Taillefer,[c]
Anne-Marie Caminade,*[a,b] Jean-Pierre Majoral,*[a,b] and Armelle Ouali*[a,b]
Keywords: Diketone ligands / Dendrimers / Copper / Phosphorus / Arylation / Phenols
Phosphorus-based dendrimers decorated with β-diketones
were prepared and fully characterized. These macromole- amounts of copper precursor (1 mol-% instead of 5–10 mol-
cules, which are the first examples of multivalent dendrim- %), diketone (4 mol-% instead of 25–80 mol-%), and base
eric β-diketones, were tested as ligands for copper in O-aryl- (1.2 equiv. of cesium carbonate instead of 2 or more). More-
O coupling can be efficiently performed by using low
ations of 3,5-dimethylphenol by aryl bromides. Although no
dendrimer effect was observed, we were able to highlight a
very efficient catalytic system that involved a monomeric β-
diketone as the ligand. The proposed conditions are very
competitive in terms of catalyst and base loading as the C–
over, the absence of the dendrimer effect is explained by the
decomposition of the dendrimer under the reaction condi-
tions, which led to the release of the peripheral diketone moi-
eties.
ones as end groups. Among the numerous potential appli-
cations for these multivalent diketones, we chose to study
catalysis, which was one of the first published uses of den-
drimers.[8] To the best of our knowledge, although catalysis
now constitutes one of the major applications of dendri-
mers,[9] the rare examples of diketone-functionalized den-
drimers mentioned above have not been studied for this
purpose. Owing to the success of diketone ligands in the
copper-catalyzed arylation of nucleophiles,[10] the dendrim-
eric diketones were tested as ligands for copper in coupling
reactions that involved aryl halides and phenols.[11] The re-
sulting diaryl ethers constitute important intermediates and
targets in the fields of life sciences and polymers.[12]
Introduction
β-Diketones, which are important building blocks for the
construction of a wide range of natural products,[1] consti-
tute efficient ligands for main group and transition metals
as well as for lanthanides.[2] Owing to their interesting cata-
lytic, photophysical, photochemical, and electrochemical
properties, their complexes have been grafted onto different
supports, such as organic polymers or hybrid silica, and the
resulting materials also constitute attractive targets in nu-
merous applications, which include catalysis and lumines-
cent materials.[3–5] Surprisingly, dendrimers that incorporate
diketone moieties have been scarcely studied and, to the
best of our knowledge, the described examples only concern
diketones that are used as the cores of dendrons.[6] These
diketones and their corresponding complexes have been
studied for their optical and electrochemical properties,[6a]
light-harvesting capability,[6b] and photoluminescent prop-
erties.[6c] Taking into account the great diversity of reported
properties of dendrimers in many areas, such as catalysis,
materials science, nanotechnology, biology, and medicine,[7]
we designed phosphorus dendrimers that incorporate diket-
Results and Discussion
Synthesis and Characterization of Diketone-Decorated
Dendrimers
The synthesis of the starting phosphorus dendrimers was
achieved by a classical two-step method, i.e. the nucleo-
philic substitution of P(S)Cl2 by hydroxybenzaldehyde in
the presence of a base followed by a condensation reaction
[a] Laboratoire de Chimie de Coordination UPR 8241 CNRS,
BP 44099, 205 route de Narbonne, 31077 Toulouse Cedex 04, of the aldehyde unit with H2NNMeP(S)Cl2.[13] These reac-
France
Fax: +33-5-61553003
tions were applied to the cyclotriphosphazene core to afford
a series of dendrimers, 1-Gn (n = 1–4). Phenol 2-OH was
prepared in one step from 4-hydroxyacetophenone and
methyl pivalate in 82% yield (Scheme 1). Compound 2-OH
was then allowed to react with the terminal PCl2 groups
of N3P3Cl6 and 1-Gn (Scheme 2) in the presence of cesium
carbonate in tetrahydrofuran (THF) at room temperature.
The resulting diketone-decorated dendrimers 2-Gn (n = 0–
E-mail: anne-marie.caminade@lcc-toulouse.fr
jean-pierre.majoral@lcc-toulouse.fr
armelle.ouali@lcc-toulouse.fr
[b] Université de Toulouse, UPS, INPT, LCC,
31077 Toulouse, France
[c] CNRS, UMR 5253, ICG, AM2N, ENSCM,
8, rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101521.
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Dendritic β-Diketones and Cu-Catalyzed Diaryl Ether Formation
4, Schemes 2 and 3), which bear 6, 12, 24, 48, and 96 pe-
The monomeric model ligand 2-OMe (Scheme 1) and a
ripheral diketone moieties, respectively, were obtained in mimic for the branches of the phosphorus dendrimers 2-
very high yields (85–94%).
B (Scheme 2) were also prepared in order to compare the
activities they confer to copper with those of the dendri-
mers.
The β-diketone moieties underwent intramolecular hy-
drogen transfer, which led to keto and enol tautomers.[14]
Hence, several tautomeric structures can be proposed for
monomeric 2-OH and 2-OMe and dendrimeric 2-Gn: one
keto form (a, Scheme 4) and two enol forms (b and c).[15]
Scheme 1. Synthesis of 2-OH and 2-OMe.
Scheme 2. Synthesis of 2-Gn (n = 0–4) and 2-B. (a) Cs2CO3, THF, room temperature.
Scheme 3. Schematic representations of 2-Gn (n = 0–4).
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A.-M. Caminade, J.-P. Majoral, A. Ouali, et al.
FULL PAPER
Scheme 4. Possible tautomers of β-dicarbonyl compounds.
Compounds 2-OH, 2-OMe, 2-B, and 2-Gn were analyzed which is in the range found for other β-dicarbonyl com-
by 1H, 13C, and 31P NMR spectroscopy in deuterated pounds.[14a,14c,14d] The crystallized tautomer thus corre-
dichloromethane. The keto form a and the enol forms b/c sponds to 2-OH-b. In 2-B, both diketone moieties were also
gave rise to two distinct sets of signals whatever the den- found to exist as enol forms, and, according to the C(16)–
drimer generation and the nucleus, whereas the enols b and O(4), C(18)–O(5), C(29)–O(6), and C(31)–O(7) distances
c only exhibited one set of signals.[14a,16,17] In dichlorometh- (1.273, 1.307, 1.311, and 1.253 Å, respectively), 2-B dis-
ane, the enol forms were found to be highly favored (87– played one b-type enol and one c-type enol.
96%) compared to the keto tautomer. To the best of our
knowledge, although 1H, 13C, 15N, and 16O NMR spec-
troscopy has been used extensively to study tautomerism in
diketones,[14b] 31P NMR spectroscopy has not been yet ap-
plied to the observation of different diketone tautomers in
solution. The 31P NMR spectrum of 2-B displayed two sin-
glets: a minor one at δ = 61.16 ppm, which corresponds to
P(S) units linked to one keto form and one enol form, and
a major one at δ = 61.41 ppm, which corresponds to P(S)
units linked to two enol tautomers.[16] Compound 2-G0 ex-
hibited a minor singlet at δ = 8.11 ppm and a major one at
δ = 8.17 ppm for phosphorus atoms that belong to P3N3
units that are bound to one keto form and one enol form
or to two enol tautomers, respectively. In the case of 2-Gn
(n = 1–4), magnetically nonequivalent peripheral phosphor-
Figure 2. Structure of 2-B.
us atoms also exhibited two signals according to their
neighboring tautomers.[16,18] In addition, the IR spectra of
2-OH, 2-OMe, 2-B, and 2-Gn (n = 0–4) as solids and solu-
tions (in CH2Cl2) displayed the expected broad band be-
tween 1600 and 1550 cm–1, which is assigned to C=C–C=O
stretching, O–H stretching, and C–H in-plane bending of
the enol ring.[14c] In CH2Cl2, an additional sharp band at
1710 cm–1, which corresponds to the diketone moiety, con-
firmed the coexistence of both tautomers in solution.[14c]
Single crystals were grown of 2-OH and 2-B, and their
structures were determined by X-ray crystallography (Fig-
ures 1 and 2, respectively). In 2-OH, the C(8)–O(2) and
C(9)–O(3) distances are 1.2735 and 1.3238 Å, respectively,
The catalytic activity conferred to copper by these dif-
ferent diketones was evaluated.
Copper-Catalyzed Arylation of Phenols in the Presence of
Monomeric and Dendrimeric Diketone Ligands
Diaryl ethers constitute structural units found in many
intermediates and targets of life sciences and in polymer
industry.[12] One of the most convenient synthetic methods
to prepare these compounds consists of arylation of phen-
ols by aryl halides, which is mediated by transition metals,
principally palladium and cheaper, less toxic copper. Diket-
one ligands and, in particular, diketones that involve one or
two tert-butyl substituents have been shown to confer a very
good activity to copper,[11] even if these systems still suffer
from limitations such as the high amount of copper used
(10 mol-% generally) and the high diketone/copper ratio re-
quired (2.5–8).[10] We have already reported that the cata-
lytic activity of copper in related arylations of N- and O-
nucleophiles that involve iminopyridine ligands was dra-
matically enhanced by using dendrimeric rather than mono-
meric ligands.[19] Therefore, dendrimeric diketones 2-Gn
appeared to be good candidates to be tested as ligands in
copper-catalyzed C–O couplings, and we hoped that the
above-mentioned limitations would be overcome.
Figure 1. Structure of 2-OH.
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Dendritic β-Diketones and Cu-Catalyzed Diaryl Ether Formation
The copper-catalyzed arylation of 3,5-dimethylphenol by no dendrimer effect was observed as both the monomeric
bromobenzene in the presence of cesium carbonate 2-OMe and the dendrimeric 2-Gn (n = 1–3) ligands con-
(1.2 equiv.) and a small amount of copper precursor CuI ferred a similar activity to Cu.
(1 mol-%) associated with monomeric or dendrimeric dike-
We were pleased to find that good to very good yields
tone ligands was chosen as the model reaction (Table 1). To were reached by increasing the reaction temperature to
the best of our knowledge, except in some rare cases that 120 °C. Indeed, 3 was obtained in 82–94% yield in the pres-
involve more reactive aryl iodides as arylating agents and ence of 2-OMe, 2-B, and 2-Gn (n = 0–4, Table 2, Entries 1–
nitrogen ligands,[11b,20] 5–10 mol-% of copper is generally 7). Acetylacetonate conferred a much lower activity to cop-
used to efficiently achieve arylations by aryl bromides. At per, and a yield of only 56% was reached under similar
110 °C in N,N-dimethylformamide (DMF) with a diketone conditions (Entry 8).
moiety/copper ratio of 2:1, the expected diaryl ether 3 was
Moreover, the coupling of two substituted aryl bromides
obtained in low yields (35–39% within 24 h) whatever the was also explored. As expected in this type of coupling, aryl
monomeric or dendrimeric nature of the ligand (Table 1, bromides substituted by electron-donating groups such as
Entries 2–5). The performance was improved to 60% by in- 4-bromoanisole were found to be less reactive than bromo-
creasing the diketone moiety/copper ratio to 4:1 (Table 1, benzene, and the corresponding diaryl ether was obtained
Entries 6–9). Whatever the diketone/copper ratio (2 or 4), in 75% yield with 2-OMe and 56% with 2-G2 (Table 2, En-
Table 1. Copper-catalyzed arylation of 3,5-dimethylphenol by bromobenzene in the presence of monomeric or dendrimeric diketones.[a]
Entry
Ligand
Amount of ligand [mol-%]
Number of diketone moieties per Cu
Yield [%][b]
1
2
3
4
5
6
7
8
9
–
–
2
–
2
2
2
2
4
4
4
4
14
38
35
38
39
56
53
60
51
2-OMe
2-G1
0.17
0.08
0.04
4
0.33
0.17
0.08
2-G2
2-G3
2-OMe
2-G1
2-G2
2-G3
[a] CuI (0.04 mmol), diketone [0.08 (two diketone units per Cu) or 0.16 (four diketone units per Cu) mmol], PhBr (4 mmol), 3,5-dimeth-
1
ylphenol (5.6 mmol), Cs2CO3 (4.8 mmol), DMF (2 mL). [b] Yields determined by H NMR spectroscopy with 1,3-dimethoxybenzene as
standard.
Table 2. Copper-catalyzed arylation of 3,5-dimethylphenol by aryl bromides in the presence of monomeric or dendrimeric diketones.[a]
Entry
R
Product
Ligand
Amount of ligand [mol-%]
Yield [%][b]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
3
3
3
3
3
3
3
3
4
4
5
5
2-OMe
2-B
4
8
94
82
92
83
92
89
90
56
75
56
93
95
2-G0
0.67
0.33
0.17
0.08
0.04
4
4
0.17
4
2-G1
2-G2
2-G3
2-G4
acetylacetone
2-OMe
2-G2
4-OMe
4-OMe
4-COMe
4-COMe
10
11
12
2-OMe
2-G2
0.17
[a] CuI (0.04 mmol), diketone (0.16 mmol), PhBr (4 mmol), 3,5-dimethylphenol (5.6 mmol), Cs2CO3 (4.8 mmol), DMF (2 mL). [b] Yields
1
determined by H NMR spectroscopy with 1,3-dimethoxybenzene as standard.
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FULL PAPER
Scheme 5. Nucleophilic substitution by 3,5-dimethylphenol onto P–O bonds of the dendrimer periphery (release of free diketones 2-OH
and subsequent copper-catalyzed arylation into 2-OPh) and of the dendrimer interior (release of 2-B-OH and subsequent copper-catalyzed
arylation into 2-B-OPh).
tries 9–10). On the contrary, activated 4-acetylbromobenz- are stable in DMF at 120 °C for 48 h. Therefore, the pres-
ene was converted in higher yields (93% with 2-OMe and ence of all these compounds indicated that 3,5-dimethyl-
95% with 2-G2, Table 2, Entries 11–12).
phenoxide was able to perform nucleophilic substitutions
Although no dendrimer effect was observed, the condi- onto both the peripheral and internal P–O bonds, which led
tions tested with 2-OMe constitute an improvement to the to the release of 2-OH and 2-B-OH, respectively, in DMF
existing methods. Indeed, very small amounts of copper at 120 °C.[23,24] These observations were made for all gener-
precursor CuI (1 mol-% instead of 10), diketone ligands ations of dendrimers. The nucleophilic substitutions onto
(4 mol-% instead of 25–80%), and base (1.2 equiv. of ce- the P–O bonds were found to be fast, and the dendrimeric
sium carbonate instead of 2 or more) allowed the efficient diketones were quantitatively converted into monomers
catalysis of C–O coupling with aryl bromides.[10,11] More within 3 h. This could probably account for the similar
generally, as mentioned before, examples of copper-cata- yields of diaryl ethers obtained whatever the monomeric
lyzed arylations of N-, C-, or O-nucleophiles that involve (2-OMe) or dendrimeric (2-Gn) nature of the diketone.
less than 5 mol-% of copper precursors are very rare.[11,20]
From a general point of view, a potential and well-known
advantage of using dendrimers in catalysis is the possibility
of recovery and reuse of the nanosized catalysts from reac-
Conclusions
tion mixtures. The main techniques to recover and recycle
We have prepared and characterized phosphorus-based
catalysts involve filtration through membranes, precipi- dendrimers decorated with diketones. To the best of our
tation, or column chromatography.[7,9f] We have already knowledge, these macromolecules represent the first exam-
shown that phosphorus-based dendrimers (with, for exam- ples of multivalent dendrimeric diketones 2-Gn. We evalu-
ple, phosphane end-groups instead of diketones) can be eas- ated the catalytic activities conferred to copper by these li-
ily separated from a reaction mixture by precipitation with gands in copper-catalyzed O-arylations of 3,5-dimethyl-
an apolar solvent such as pentane and recycled in various phenol by aryl bromides. Although no dendrimer effect was
catalytic reactions.[21] We thus attempted recovery experi- observed, we were able to highlight a very efficient catalytic
ments with 2-Gn (n = 0–4) as ligands (under the conditions system that involved 2-OMe as the ligand and required very
given in Table 2),[22] but the obtained precipitates were not low copper precursor (1 mol-% instead of 5–10 mol-%), di-
able to catalyze the reaction. We then analyzed the compo- ketone (4 mol-% instead of 25–80 mol-%) and base
sition of the filtrates that contained 3 carefully[22] and de- (1.2 equiv. of cesium carbonate instead of 2 or more) load-
tected and successfully isolated unexpected compounds ing.[11,20] Moreover, an explanation for the absence of a
(Scheme 5). For example, when the reaction was performed dendrimer effect, a phenomenon widely encountered in the
with 2-G2 (under the conditions given in Table 2), almost literature but generally not explained,[7] was provided. In-
90% of the introducted diketone moieties initially grafted deed, in DMF at 120 °C, nucleophilic substitution by phen-
on this dendrimer were recovered in the form of 2-OH (ca. oxides led to the release of peripheral diketone moieties,
75%) and the corresponding arylated diketone 2-OPh (ca. which act as monomeric ligands. Therefore, the dendrimeric
15%). The latter was probably obtained by a copper-cata- diketones will now be tested as ligands for copper and other
lyzed arylation of 2-OH by PhBr. Moreover, dendrimer metals in reactions that require milder temperatures and
branches 2-B-OH and the arylated version 2-B-OPh were different solvent conditions. Moreover, we are also currently
also identified and characterized. The diketone dendrimers evaluating the properties of these compounds in other
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Dendritic β-Diketones and Cu-Catalyzed Diaryl Ether Formation
fields, such as materials science and biphotonic absorption.
In addition, because of environmental laws and regulations
that demand environmentally more friendly products, many
efforts are currently being dedicated to the design of de-
gradable materials. To this end, the observed decomposition
of the phosphorus dendrimer interiors could give an oppor-
tunity to render them environmentally more friendly, thus
opening new uses.
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Experimental Section
General: The procedures for the syntheses of 2-OH, 2-OMe, 2-B,
1
and 2-Gn (n = 0–4), their characterization and corresponding H,
13C, and 31P NMR spectra (if applicable) are detailed in the Sup-
porting Information.
General Procedure for Catalytic Tests (4 mmol Scale): After stan-
dard cycles of evacuation and back-filling with argon, an oven-
dried Radley tube (Carousel “reaction stations RR98030”)
equipped with a magnetic stirring bar was charged with CuI
(0.04 mmol), ligand (0.16 mmol for monomeric ligands, 0.08 mmol
for 2-B, 0.027 mmol for 2-G0, 0.013 mmol for 2-G1, 0.0067 mmol
for 2-G2, 0.0033 mmol for 2-G3, and 0.0017 mmol for 2-G4), 3,5-
dimethylphenol (1.4 equiv.), aryl bromide (1 equiv.), if a solid, and
cesium carbonate (1.2 equiv.). The tube was evacuated and back-
filled with argon. If a liquid, aryl bromide was added under a
stream of argon by syringe at room temperature followed by DMF
(2.0 mL). The tube was sealed under a positive pressure of argon,
stirred, and heated to the required temperature for the required
time period. After cooling to room temperature, 1,3-dimethoxy-
benzene (standard, 230 μL) and dichloromethane (5 mL) were
added. A small amount of the reaction mixture was filtered through
a plug of Celite®, and the filter cake was washed with dichloro-
methane. The filtrate was washed once with water, which was reex-
tracted twice with dichloromethane. The organic layers were com-
bined, concentrated in vacuo, and characterized by NMR spec-
troscopy. To isolate 3, the filtrate was purified by flash chromatog-
raphy on silica gel (eluent: pentane/dichloromethane, 80:20) and
obtained as a colorless oil (673 mg, 85% if using 2-OMe and
595 mg, 75% if using 2-G1). Whatever the nature of the ligand
(either monomeric or dendrimeric), 3 was obtained in high purity
(see Supporting Information for 1H NMR spectra). See the Sup-
porting Information for the isolation (column chromatography)
and characterization of 2-OPh, 2-B-OH, and 2-B-OPh.
[5]
[6]
[7]
[8]
[9]
CCDC-835337 (for 2-OH), -835336 (for 2-B), and -835338 (for
2-OPh) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Procedures for the syntheses of 2-OH, 2-OMe, 2-B, and 2-Gn
(n = 0–4), their characterization and corresponding 1H, 13C, and
31P NMR spectra; isolation (column chromatography) and charac-
terization of 2-OPh, 2-B-OH, and 2-B-OPh.
Acknowledgments
We thank the Ministère de l’Education Nationale for a PhD grant
and financial support, the Centre National de la Recherche Sci-
entifique (CNRS) and the Agence Nationale de la Recherche
(ANR H2OFerCat) for funding.
Eur. J. Org. Chem. 2012, 1056–1062
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1061

A.-M. Caminade, J.-P. Majoral, A. Ouali, et al.
FULL PAPER
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range δ = 6.2–6.3 ppm for the olefinic proton and a broader
singlet in the range δ = 16.3–16.8 ppm for the enol proton
(OH).[14a,14b] 13C NMR spectra: most of the signals occur at
similar chemical shifts for both tautomers. Only the carbonyl
carbon atoms that give rise to two distinct singlets at δ = 190–
192 and 209–211 ppm in the keto form are shifted to δ = 183–
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and 61.38 (major) ppm for 2-G2, at δ = 61.01 (minor) and 61.28
(major) ppm for 2-G3, at δ = 61.04 (minor) and 61.24 (major)
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[22] For that purpose, pentane was added to the cooled reaction
mixtures, which enabled the precipitation of solids in each case.
These were filtered and rinsed several times with cold pentane.
The filtrates were concentrated to dryness to give a crude oil
that contained the expected diaryl ether as the major com-
pound (1H NMR). Recycling experiments were then attempted.
For that purpose, each precipitate was allowed to react with
a mixture of bromobenzene, 3,5-dimethylphenol, and cesium
carbonate, but whatever the dendrimer generation (0–4), the
coupling failed to occur. See Experimental Section and Sup-
porting Information for details.
[23] Taking into account the excess of phenol and base, and even if
the expected diaryl ether was obtained in the maximum yield
(92% for dendrimeric catalysts), we checked that there was
enough phenoxide left to substitute all the peripheral diketone
moieties and all the P–O bonds involved within the dendrimer
skeleton.
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[15] The trans-enol forms have been shown to be highly un-
stable,[14a] so we did not take them into account.
[16] 1H, 13C, and 31P NMR (if applicable) spectra of 2-OH, 2-OMe,
2-B and 2-Gn (n = 0–4) are given in the Supporting Information
[17] 1H and 13C NMR spectra display the expected characteristic
patterns for both tautomers. 1H NMR spectrum for the keto
form: a singlet at δ = 4.1–4.2 ppm for the methylene group. 1H
[24] Such a nucleophilic attack onto the P–O bonds was not ob-
served under milder conditions such as those described earlier
(acetonitrile, 20–80 °C).[19]
Received: October 18, 2011
Published Online: December 14, 2011
1062
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1056–1062