'Click' Dendritic phosphines: Design, synthesis, application in Suzuki coupling, and recycling by nanofiltration

Article abstract of DOI:10.1002/adsc.200900058

A new synthetic route towards stable molecular-weight enlarged monodentate phosphine ligands via 'click' chemistry was developed. These ligands were applied in the Pd-catalyzed Suzuki-Miyaura coupling of aryl halides and phenyl boronic acid. The supported systems show very similar activities compared to the unsupported analogues. Moreover, recycling experiments by means of nanofiltration using ceramic nanofiltration membranes demonstrate that these systems can be recovered and reused efficiently.

Full text of DOI:10.1002/adsc.200900058

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DOI: 10.1002/adsc.200900058
ꢀClickꢁ Dendritic Phosphines: Design, Synthesis, Application in
Suzuki Coupling, and Recycling by Nanofiltration
Michꢀle Janssen,a Christian Mꢁller,a and Dieter Vogta,*
a
A Schuit Institute for Catalysis, Eindhoven University of Technology, P.O.Box 513, 5600 MB Eindhoven, The Netherlands
Fax : (+31)-40-245-5054; phone: (+31)-40-247-2483; e-mail: D.Vogt@tue.nl
Received: December 5, 2008; Revised: January 27, 2009; Published online: February 9, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900058.
Abstract: A new synthetic route towards stable mo-
lecular-weight enlarged monodentate phosphine li-
gands via ꢂclickꢃ chemistry was developed. These li-
gands were applied in the Pd-catalyzed Suzuki–
Miyaura coupling of aryl halides and phenyl boron-
ic acid. The supported systems show very similar ac-
tivities compared to the unsupported analogues.
Moreover, recycling experiments by means of nano-
filtration using ceramic nanofiltration membranes
demonstrate that these systems can be recovered
and reused efficiently.
zation) and soluble supports (molecular weight en-
largement, MWE).[6–8]
MWE catalysts can, in principle, be recovered by
means of precipitation, ultracentrifugation or nanofil-
tration.[9–16] Although there are numerous examples of
catalyst recovery, especially via precipitation, the field
of nanofiltration in homogeneous catalysis is still
rather unexploited, because advanced membrane re-
actor technology is usually needed.[7,17–20] Recently,
Rothenberg et al. demonstrated, however, that this is
not necessarily required and that a Ru-based transfer
hydrogenation catalyst can efficiently be recovered
with a relatively simple set-up.[21]
Keywords: catalyst recycling; ceramic membranes;
cross-coupling; dendrimers; homogeneous catalysis
We report here on the synthesis of multiple phos-
phine ligands attached to a dendritic support via
ꢂclickꢃ chemistry. Their application in the Pd-catalyzed
Suzuki coupling and their facile recovery and reuse
by means of nanofiltration has been investigated.
In order to attach a ligand to a soluble support,
Homogeneously catalyzed reactions play an increas-
ingly important role in organic synthesis.[1] However, both ligand and support need to be decorated with an
a major drawback of homogeneous catalysts over het- anchoring group. In this respect, we started to focus
erogeneous systems is the difficulty of their recovery on ꢂclickꢃ chemistry, since it is an elegant way to
and recycling.[2] A range of approaches have been attach ligands to a support (Figure 1). The ꢂclickꢃ reac-
studied over the years, all with their own strengths tion, officially referred to as Huisgen 1,3-dipolar cy-
and weaknesses, leading to the conclusion that one ul- cloaddition reaction, has received a lot of attention
timate solution does not exist. This is inherently due due to the work by Sharpless and co-workers.[22,23]
to the vast variety of applications, each with its own This reaction between an alkyne and an organic azide
specific requirements and conditions. Hence, there is exhibits several attractive features, such as high and
a great need for the development of complementary often quantitative yields as well as a high functional
generic methods – a toolbox for practical application. group tolerance. These interesting characteristics have
These methods can be roughly divided in biphasic cat- already been widely exploited in polymer and materi-
alysis[3–5] and immobilization on insoluble (heterogeni- als science,[24,25] while examples in the field of catalysis
are still in their infancy.[26–28]
Figure 1. ꢂClickꢃ reaction for the attachment of a ligand to a support.
Adv. Synth. Catal. 2009, 351, 313 – 318
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Despite the above-mentioned advantages, a few
practical points have to be considered. First, either
the support or the ligand has to be decorated with the
azide functionality. For safety reasons we chose to
functionalize the ligand with an azide anchoring
group, avoiding several azide moieties in one mole-
cule. Second, azides and free phosphines would un-
dergo a Staudinger reaction under formation of dini-
trogen and an iminophosphorane.[29] For this reason,
the phosphine moiety has to be protected as its oxide,
sulfide, or BH3 adduct, until the triazole ring is
formed.
For a suitable support we chose tetrakis(4-ethynyl-
Scheme 2. Synthesis of azide-functionalized phosphine
phenyl)methane, since this results in a rigid, spherical oxides 8 and 9.
molecule after ligand attachment. These structures
are known to display better retention and less mem-
brane fouling than linear shaped or flat macromole-
Compound 6 was then reduced to its corresponding
benzylamine and protected as its phosphine oxide 7,
cules.[30]
Based on literature data, triphenylphosphine (A), necessary to prevent Staudinger reaction once the
dicyclohexylphenylphosphine (B) and 2-dicyclohexyl- azide is formed. This was followed by a copper-medi-
phosphinobiphenyl (C) were chosen. These ligands ated diazo transfer reaction to obtain the azide-func-
are among the best and most frequently used mono- tionalized phosphine oxides 8 and 9 in 64 and 71%
dentate phosphines for the Pd-catalyzed Suzuki– overall yield, respectively (Scheme 2).[37]
Miyaura coupling reaction.[31–33]
The synthesis of the azido-functionalized phosphine
Support 4 was prepared according to a literature oxide 14 was achieved by a slightly modified proce-
procedure.[34] Commercially available tetraphenylme- dure. After a Suzuki coupling between 1-bromo-2-io-
thane 1 was selectively brominated in the para posi- dobenzene and 4-cyanophenyl boronic acid, 11 was
tions using bromine in the presence of iron filings.[35] obtained in 80% yield, which was lithiated and subse-
The tetra-(4-bromophenyl)-methane 2 was coupled quently reacted with chlorodicyclohexylphosphine to
with TMS-protected acetylene in a Sonogashira reac- yield compound 12.[38,39] Nitrile 12 was reduced to the
tion. After deprotection, support 4 was obtained in corresponding benzylamine and protected by reaction
65% overall yield (Scheme 1).
with H2O2. After the copper-mediated diazo transfer
The synthesis of the azide-functionalized ligands reaction, the azide-functionalized Buchwald phos-
started with the deprotonation of diphenyl- or dicy- phine oxide 14 was obtained in 60% overall yield
clohexylphosphine with potassium or PhLi, respec- (Scheme 3).
tively. The obtained phosphide was reacted with 4-flu-
The azide-functionalized phosphine oxides were
orobenzonitrile in a nucleophilic aromatic substitution then attached to support 4 by means of a copper-
reaction yielding the cyano-functionalized phosphine mediated 1,3-dipolar cycloaddition reaction (ꢂclickꢃ re-
6 in high yield.[36]
action). After deprotection of the phosphine with
excess HSiCl3, the desired molecular-weight enlarged
Scheme 1. Synthesis of support 4.
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ꢂClickꢃ Dendritic Phosphines: Design, Synthesis, Application in Suzuki Coupling
COMMUNICATIONS
Scheme 5. Suzuki–Miyaura coupling between aryl halide and
phenyl boronic acid.
ligands L1–L3 were obtained in good yields
(Scheme 4).[40]
In order to justify immobilization of homogeneous
catalysts, they should be easy to prepare and should
show high activity as well as high total turnover
number (ttn). We chose to investigate the Suzuki re-
action, since single monodentate phosphine ligands
are frequently applied. Thus, ligands L1–L3 were ex-
plored in the Pd-catalyzed coupling of phenylboronic
acid and aryl halides (Scheme 5).
First, the activities of the Pd catalysts containing li-
gands L1–L3 were compared with those of their origi-
nal unsupported counterparts A–C. The results are
summarized in Table 1. The conversion followed in
time is depicted in Figure 2 exemplarily for the cata-
lyst system Pd/L3 in comparison with Pd/C. Both
Table 1 and Figure 2 clearly demonstrate that the sup-
ported systems show essentially identical activities as
the original ones, indicating that the four catalysts on
a dendrimer act truly independently. No Pd black for-
mation was observed in any of the catalytic runs.
Moreover, NMR studies on the MWE ligands before
and after the catalysis experiments showed no degra-
dation of the triazole ring.
Scheme 3. Synthesis of azide-functionalized Buchwald phos-
phine oxide 14.
Subsequently, the total turnover numbers (ttn) of
the three ꢂclickꢃ dendritic systems were determined.
The ttnꢃs turned out to be high (~15,000) for all three
MWE systems and, moreover, comparable with
values reported in the literature.[41]
Since the ꢂclickꢃ dendritic catalysts fulfilled the re-
quirements discussed above, (straightforward synthe-
sis, high ttn and high activity), we applied these sys-
Table 1. Comparison of activities of ꢂclickꢃ dendritic ligands
and their unsupported analogues.[a]
Entry
Ligand
Time [h]
Conversion [%]
1
2
3
4
5
6
A
L1
B
L2
C
L3
7
7
3
3
2
2
94
96
>99
>99
>99
>99
[a]
Reaction conditions: 1.0 mmol 4-bromotoluene, 1.5 mmol
phenylboronic acid, 3.0 mmol Na2CO3, 0.01 mmol Pd-
AHCTUNGTRENNUNG
Scheme 4. Synthesis of ꢂclickꢃ dendritic ligands L1–L3.
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Michꢀle Janssen et al.
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bath at 608C and the reaction was allowed to proceed
for 16 h. At the end of the reaction, the complete re-
action mixture was collected by syringe and replaced
by a fresh substrate solution. Between these recycling
runs no additional Pd was added. The results obtained
with the systems Pd/L1–L3 are shown in Table 2.
In case of Pd/L1 and Pd/L2, the recycling runs were
performed with a substrate to Pd ratio of 125:1. In
both cases a clear drop in activity was observed after
the third run. This could be due to either Pd leaching
or catalyst deactivation, although the ttn of the cata-
lysts was not yet reached. ICP-AES analysis of the
product solutions revealed a Pd leaching of 0.8% per
run for Pd/L1 and 0.4% per run for Pd/L2, which
Table 2. Recovery and reuse of Pd/L1–L3 catalysts.[a]
Figure 2. Comparison of activities of Pd/L3 and its unsup-
ported analogue C.
Run
Ligand
Pd added [mol%]
Yield [%]
1
2
3
4
5
1
2
3
4
5
1
2
3
4
5
L1
L1
L1
L1
L1
L2
L2
L2
L2
L2
L3
L3
L3
L3
L3
0.8
0
0
0
0
0.8
0
0
0
0
0.1
0
0
0
0
>99
96
97
90
55
>99
>99
>99
76
66
>99
82
tems in a nanofiltration set-up. This in-house made
set-up consists of a commercially available ceramic
membrane tube,[42] which is capped with Teflon discs
and fixed in a stainless steel holder (Figure 3). The
molecular weight cut-off of the applied membrane is
450 Da. Since the molecular weight of our ꢂclickꢃ den-
dritic ligands is higher than 1600 Da, the membrane
should in principle be able to retain the correspond-
ing catalysts.
Prior to use, the membrane tube was thoroughly
evacuated, filled with N2 and soaked in THF. Subse-
quently, the ꢂclickꢃ dendritic Pd catalyst solution was
injected into the membrane tube. The stainless steel
holder was placed in a 50 mL Schlenk tube and a so-
lution of aryl halide, phenylboronic acid and Na2CO3
in 25 mL of THF and 15 mL of water was added. The
Schlenk tube was then placed in a thermostatic shake
78
64
72
[a]
Reaction conditions: 1.0 equiv. 4-bromotoluene, 1.5 equiv.
phenylboronic acid, 3.0 equiv. Na2CO3, Pd:click dendri-
mer=4:1, Pd precursor=PdACHTUNRGTNEUNG(OAc)2, solvent: THF
(30 mL)+H2O (20 mL), T=608C, time=16 h. Yields are
GC yields.
Figure 3. Ceramic nanofiltration membrane set-up.
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ꢂClickꢃ Dendritic Phosphines: Design, Synthesis, Application in Suzuki Coupling
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Experimental Section
General Procedure for the Suzuki–Miyaura Coupling
of Aryl Halides
An oven-dried Schlenk tube was charged with a Teflon
coated stirring bar, aryl halide (1.0 mmol), phenylboronic
acid (183 mg, 1.5 mmol) and Na2CO3 (318 mg, 3.0 mmol)
and evacuated and backfilled with argon for 3 times. Then,
3 mL of THF and 2 mL of water were added. When the sub-
strates and the base had dissolved, the catalyst solution con-
sisting of PdACHTNUTRGNEUNG(OAc)2 (2.2 mg, 0.01 mmol) and the ligand
(0.01 mmol of P) in 1 mL of THF, was added and the mix-
ture was put in a pre-heated oil bath at 608C.
General Procedure for the Recycling Runs
Figure 4. Reaction profile for the formation of 4-methylbi-
phenyl.
The ceramic membrane was oven-dried and evacuated for
16 h in the antechamber of a nitrogen-filled glovebox in
order to remove air. Then, the ceramic membrane was
placed in a stainless steel holder inside the glovebox. The
membrane tube was soaked in THF/water and then filled
with catalyst solution: PdACHTNUTRGNENG(U OAc)2 (2.2 mg, 0.01 mmol) and
seems too small to account for the large drop in activ-
ity.
ligand (0.01 mmol) in 1 mL of THF. The membrane tube
was closed and the holder was placed in a 50 mL Schlenk
tube and a solution of 10 mmol aryl bromide and 15 mmol
phenylboronic acid in 30 mL of THF and 30 mmol Na2CO3
in 20 mL of water was added. This Schlenk tube was placed
in a thermostatic shake bath at 608C. The reaction was al-
lowed to proceed for 16 h.
The recycling runs for Pd/L3 were performed with
a Pd loading of only 0.1 mol%. The first run revealed
a higher activity of the catalyst systems compared to
remaining ones, but the yield of 4-methylbiphenyl was
essentially constant in the last four runs. ICP-AES
analysis of the product solutions showed a Pd leach-
ing of 0.8% per run. To reject the hypothesis that the
leached Pd accounts for the observed activity, we per-
formed an experiment in which the substrate solution
was completely removed from the membrane tube
containing the Pd/L3 catalyst after 40 min. At this
time the conversion had reached 56%. 16 h later, no
significant further increase in conversion (58%) was
observed. The substrate solution was transferred back
into the Schlenk tube containing the membrane tube.
Interestingly, full conversion was reached after 2 h
(Figure 4). From this experiment we can conclude
that the catalytic reaction takes place inside the mem-
brane tube and that the leached Pd accounts only for
a very small amount of conversion (~2% in 16 h).
Moreover, the membrane tube can be stored for 16 h
under argon without significant catalyst deactivation.
In conclusion, a new synthetic route towards stable
dendritic monodentate phosphine ligands via ꢂclickꢃ
chemistry was developed. These ligands were applied
in the Pd-catalyzed Suzuki–Miyaura coupling of aryl
halides and phenylboronic acid. The supported sys-
tems show very similar activities as their original un-
supported analogues. Recycling experiments by
means of nanofiltration using ceramic nanofiltration
membranes demonstrate that these systems can be re-
covered and reused efficiently.
Acknowledgements
We thank A. Elemans-Mehring, W. van Herpen and A. Star-
ing for technical assistance. This research was funded by the
Netherlands Research School Combination on Catalysis
(NRSC-C). C.M. thanks the Netherlands Organization for
Scientific Research (NWO) for financial support.
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