An efficient and recyclable dendritic catalyst able to dramatically decrease palladium leaching in Suzuki couplings

Article abstract of DOI:10.1039/c2gc35832h

A series of novel monomeric and dendritic thiazolyl phosphines (generations 1 and 3) was prepared and the activity these ligands conferred to palladium in Suzuki couplings was evaluated. The heteroaryl ligands were revealed to be very efficient and were able to perform the reactions in mild conditions. Besides, their efficiency was compared to that of the corresponding triphenylphosphines. Moreover, the possibility to reuse both families of dendritic ligands was explored and the thiazolyl phosphine-based catalytic systems could be successfully recycled for five consecutive reactions without loss of activity, contrary to their triphenylphosphine counterparts. Remarkably, the palladium leaching was found to be dramatically reduced by using the dendrimer-supported thiazolylphosphines instead of the monomeric ligand and only trace amounts of metal (<0.55 ppm) could be found in the coupling product before any purification.

Full text of DOI:10.1039/c2gc35832h

View Online / Journal Homepage
Green Chemistry
Accepted Manuscript
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Accepted Manuscripts are published online shortly after acceptance, which is prior
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
Volume 12 | Number 9 | September 2010 | Pages 1481–1676
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
ISSN 1463-9262
COMMUNICATION
CRITICAL REVIEW
Luque, Varma and Baruwati
Dumesic et al.
Magnetically seperable organocatalyst Catalytic conversion of biomass
for homocoupling of arylboronic acids to biofuels
1463-9262(2010)12:9;1-U
www.rsc.org/greenchem
Registered Charity Number 207890

Green Chemistry
Page 1 of 9Journal Name
Dynamic Article Links ►
View Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
An efficient and recyclable dendritic catalyst able to dramatically
decrease palladium leaching in Suzuki couplings
Michel Keller,a,b Aurélien Hameau, a,b Grégory Spataro, a,b Sonia Ladeira, a,b Anne-Marie Caminade, a,b*
Jean-Pierre Majoral, a,b* Armelle Ouali. a,b*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A series of novel monomeric and dendritic thiazolyl phosphines (generations 1 and 3) was prepared and
the activity these ligands conferred to palladium in Suzuki couplings was evaluated. The heteroaryl
ligands revealed very efficient and allowed to perform the reactions in mild conditions. Besides, their
10 efficiency was compared to that of the corresponding triphenylphosphines. Moreover, the possibility to
reuse both families of dendritic ligands was explored and thiazolyl phosphines-based catalytic systems
could successfully be recycled in five consecutive reactions without loss of activity contrary to their
triphenylphosphine counterparts. Remarkably, the palladium leaching was found to be dramatically
reduced by using the dendrimer-supported thiazolylphosphines instead of the monomeric ligand and only
15 traces of metal (< 0.55 ppm) could be found in the coupling product before.
catalyzed arylations of nucleophiles when using nitrogen ligands
Introduction
supported onto the phosphorous dendrimers developed in our
50 group.10 We thus planned to design phosphorous dendrimers
incorporating thiazolyl phosphines as end groups and here we
report the catalytic activity they conferred to palladium in Suzuki
reactions. To evaluate the contribution of the thiazolyl ring with
regard to the specific properties it may confer to the palladium,
55 triphenylphosphine ended dendrimers were also prepared and
tested in the same C-C couplings. Noteworthy, most of the
palladium-based supported catalysts reported for Suzuki reactions
exhibit satisfying activities compared to their non-supported
counterparts and can be recovered and reused several times
60 except in the case of dendritic catalysts whose recycling has only
scarcely been studied.6,7 However, only a few systems are able to
decrease palladium leaching in the coupling products.6,11
Therefore, the recyclability of the dendritic palladium complexes
involving either thiazolyl phosphines or triphenylphosphines was
65 evaluated. Moreover, the metal leaching in the coupling product
was compared when using a dendrimer or a monomer as the
ligand.
Heteroaryl phosphines constitute a class of interesting potential
ligands. Indeed, heterocyclic substituents bound to the
phosphorous atom can confer specific electronic and steric
20 properties to the adjacent phosphorous atom, therefore enabling a
more efficient metal-based catalysis compared to simple
alkyl/aryl phosphines.1 Noteworthy, thiazolines display numerous
applications in various fields such as organic synthesis, medicine,
agrochemistry, and catalysis mainly because of the unique
25 properties of sulphur and therefore, these heterocycles have
attracted the attention of many chemists over the last decade.2 To
the best of our knowledge, only few examples of catalysts
involving thiazolyl phosphines have been reported in the
literature: such ligands have thus for example been associated to
30 copper in N-arylation reactions3 and have also been used in
palladium-catalyzed Suzuki cross-couplings.4 The latter reactions
constitute one of the most versatile and powerful methods for
carbon-carbon bond formation, are generally promoted by
palladium-based catalytic systems involving phosphines or
35 carbenes as ligands and can be performed in conventional organic
or aqueous media.5 Noteworthy, different supports such as
polymers, nanoparticles, inorganic supports (mainly silica), or
dendrimers have been reported to immobilize numerous
palladium-based catalysts able to promote Suzuki couplings.6,7 In
Results and discussion
Preparation of dendritic phosphines
70 The thiazolyl phosphine 5-OH tethered with a phenol moiety for
further grafting on phosphorous dendrimers was obtained in four
steps (Scheme 1). A first condensation of N,N-dimethylthiourea 1
and ethyl-4-chloroacetoacetate in ethanol gave rise to N,N-
dimethylaminothiazole 2 which afforded thiazolyl phosphine 3
75 after phosphorylation with Ph2PCl at 40 °C.4,12 The structure of
this compound in the solid state was determined by X-ray
crystallography (see Supplementary information). The
40
a
general manner, the immobilization of catalysts onto
dendrimers, hyperbranched and perfectly defined
macromolecules, display two main potential advantages: the
recovery and reuse of the catalysts at the end of the reaction
which appears as highly desirable for both economic and
45 ecological reasons in the context of green chemistry and, in some
cases, the enhancement of the catalytic activities.8,9 In this line, a
strong positive dendritic effect could be observed in copper-
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Green Chemistry
Page 2 of 9
View Online
Noteworthy, according to these structures, the presence of the
the ester group was allowed to react with tyramine in the 20 amido-tyramine spacer seems to guarantee the steric accessibility
corresponding carboxylic acid 4 obtained after saponification of
presence of DCC (N,N’-dicyclohexylcarbodiimide) and HoBt (1-
hydroxybenzotriazole) in DMF to provide 5-OH via peptide
coupling. The monomeric model ligand 5-OMe (Scheme 1) was
also synthesized according to a similar procedure than for 5-OH
of the phosphorous atom belonging to the thiazolyl phosphine
ligand within monomers 5-OH and 5-OMe and thus probably
also within the dendrimers.
5
The preparation of the phosphorous dendrimers was indeed
but using 2-(p-methoxyphenyl)ethylamine (Scheme 1, R = Me) 25 achieved using our classical two-step procedure involving first a
instead of tyramine in the last step. Its efficiency has been
compared with that of dendrimers in the catalytic tests.
nucleophilic substitution on chloride atoms of P(S)Cl2 by
hydroxybenzaldehyde in the presence of a base, and then a
condensation reaction of the resulting aldehyde with the
thiophosphorhydrazide H2NNMeP(S)Cl2 (Scheme 3).13 These
30 reactions were applied to the cyclotriphosphazene core to afford
the series of chloride-decorated dendrimers Gn (n = 1 to 3).
Lastly, the thiazolyl phosphine 5-OH functionalized with a
phenol moiety was grafted to dendrimers 1-G1 and 1-G3 via
nucleophilic substitution of the terminal chloride atoms in the
35 presence of cesium carbonate in THF (Scheme 4). Resulting
dendrimers 5-G1 and 5-G3 involving respectively 12 and 48
peripheral thiazolyl phosphine ligands were obtained in good
yields (80 and 75% respectively). As mentioned earlier in
introduction, triphenyl phosphine ended dendrimers 6-G1 and 6-
40 G3 were also prepared in an analogous manner. For this purpose,
4-hydroxyphenyl diphenyl phosphane 614,15 was grafted onto
dendrimers G1 and G3 via nucleophilic substitution to the P-Cl
bonds to afford 6-G1 and 6-G3 in 71 and 65% yields respectively
(Scheme 4).16
10
Scheme 1 Synthesis of the phenol functionalized by the thiazolyl moiety.
Moreover, crystals were grown from the latter and the structure
of 5-OMe could be studied by X-ray crystallography and
compared to that of 5-OH (Scheme 2). As expected, both
15 structures revealed very similar: within the crystal lattice, the
phosphorus atom is pyramidal and the sulfur atom points in the
direction opposite to that of the phosphorous free electron pair.
45
5-OH
5-OMe
Scheme 2 Structures of monomeric thiazolylphosphines 5-OH and 5-OMe. Thermal ellipsoids are drawn at the 50% probability level. All hydrogen
atoms are omitted for clarity.
Scheme 3 Phosphorous dendrimers G0-G3 with P(S)Cl2-end groups; (a) 4-hydroxybenzaldehyde / Cs2CO3, THF, rt; (b) H2NNMeP(S)Cl2, CHCl3, rt.13
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Green Chemistry
Page 3 of 9Journal Name
Dynamic Article Links ►
View Online
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Scheme 4 Grafting of the thiazolyl phosphine and of the triphenylphosphine ligands at the surface of phosphorous dendrimers: (a) Cs2CO3, THF, rt.
reaction was performed in the presence of the monomeric
5
Catalytic activity of monomeric and dendritic phosphines
thiazolyl phosphine 5-OMe for two different phosphine-to-
The former monomeric and dendrimeric phosphines were tested
in palladium-catalyzed Suzuki reactions which consist in the
coupling of an electrophile (aryl or alkyl halide for example) and
a boron compound in the presence of a base.5 Methods involving
palladium (P/Pd) ratios: P/Pd = 2 or 1 (entries 2, 3 respectively).
The yields were found to be similar in both cases (86 and 85%
35 respectively) and therefore, all the following catalytic tests were
performed in the presence of 0.5 mol% of Pd(OAc)2 and 0.5
mol% of ligand. Noteworthy, an excess of monophosphine
compared to palladium is generally required in cross couplings
such as the Suzuki reaction,5d-h but in the case of highly efficient
40 ligands such as the tri-tert-butylphosphine described by Fu and
co-workers,5g,17 a phosphine-to-palladium ratios (P/Pd) of 1 can
be sufficient for high activities to be reached. In these conditions,
the thiazolyl moiety itself (compound 2) gave rise to biphenyl in
only 50% yield (entry 4) which illustrates the requirement of the
10 nanocatalyts (generally heterogeneous) based on different
supports such as polymers, nanoparticles, silica surface or metal
oxides have been more recently developed.6 Among the potential
supports, dendrimers constitute attractive targets since these
perfectly defined hyperbranched polymers are soluble and thus
15 combine the advantages of homogeneous and heterogeneous
catalysis. Dendrimers efficient in Suzuki couplings7,8 mostly
involve Pd/aryl- or alkylphosphine systems and the catalysts can
be placed on their surface 7a,b,c,e,i,l,m or at their core. 7d,f,g,h,j,k Some
45 phosphorous atom to obtain
a good activity. Moreover,
of them have been used in organic media, 7a,b,e,h,j other in aqueous
triphenylphosphine was found much more efficient than 2 and
slightly less efficient than thiazolyl phosphine 5-OMe (73% yield
instead of 85%, entry 5) which may indicate the existence of a
slight synergetic effect between the diphenyl moiety and the
50 thiazolyl ring (entries 3-5).
7c,d,f,g,i,k,l,m
20 media.
In a general manner, the recyclability of
dendritic catalysts for Suzuki reactions has been scarcely studied,
an efficient recycling being reported for only a few examples
7g
either by nanofiltration,7c by dialysis, or by precipitation.7a,l,m
Interestingly, to our knowledge, no dendritic system involving
25 heteroaryl phosphines have been reported so far.
Thiazolyl phosphine 5-OMe thus appeared as a promising ligand
in Suzuki reactions and therefore the corresponding Pd complex
was tested in the couplings of substituted aryl bromides and aryl
boronic acids in the previously described conditions (Table 2).
55
The coupling of bromobenzene and phenyl boronic acid was first
performed in a 2:5 mixture water/THF at 60 °C in the presence of
Pd(OAc)2 (0.5 mol%). In the absence of additional ligand,
biphenyl was obtained in only 40% yield (Table 1, entry 1) but
30 this reaction revealed poorly reproducible. Then the same
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 3

Green Chemistry
Page 4 of 9
View Online
thiazolyl phosphine ligands 5-OMe, 5-G1 and 5-G3 (Scheme 5, i),
a negative dendritic effect could be observed, yields of biphenyl
35 decreasing from 85% with the monomer 5-OMe to 60 and 46%
respectively with 5-G1 and with 5-G3. In the case of
triphenylphosphine derivatives however (Scheme 5, ii), the first
Table 1 Coupling of PhBr and PhB(OH)2 in the presence of Pd(OAc)2 and
phosphine ligands.a
generation dendrimer displayed
a better activity than the
corresponding monomer (87% for 6-G1 against 73% with PPh3)
40 which corresponds to a positive multivalency effect. However,
biphenyl was obtained in only 43% yield in the presence of 6-G3.
Afterwards, the scope of monomeric and dendritic catalysts was
explored (Scheme 5, R = 4-COMe, 4-Me, 4-OMe and 2-Me). As
expected in this type of couplings, electron-poor substrates (R =
45 4-COMe) revealed more reactive than electron-rich (R = 4-Me, 4-
OMe) and bulky substrates (R = 2-Me). Concerning the compared
efficiencies of aryl and heteroaryl ligands, no general tendency
emerged from the results since the performances of the
corresponding palladium complexes were found to depend at the
50 same time from the nature of the substituent, from the nature of
the ligand (monomeric or dendritic) and also from the generation.
However, whatever the nature of the phosphine, either thiazolyl
(i: 5-OMe, 5-G1, 5-G3) or triphenyl (ii: PPh3, 6-G1, 6-G3), a
negative dendritic effect was observed for all substituted aryl
55 bromides. Interestingly, a negative dendritic effect has also been
previously reported in the case of Suzuki couplings involving
diphosphino Pd(II) complexes on DAB dendrimers.7m This
observation was attributed to the steric hindrance at the
dendrimer periphery. Noteworthy, such explanation seems less
60 accurate for our phosphorous dendrimers since for the latter
skeletons, the third generation dendrimer does not appear
significantly more hindered than the first generation.19
Ligand
mol %
Phosphine/Pd ratio
Yield b
1
2
3
4
5
no
5-OMe
5-OMe
2
-
-
40
86
85
50
73
1
2
1
1
1
0.5
0.5
0.5
PPh3
a
Pd(OAc)2 (0.005 mmol), phosphine moieties (0.01 mmol for
Pd/Phosphine ratio = 2 or 0.005 mmol for Pd/Phosphine ratio = 1), PhBr
(1 mmol), PhB(OH)2 (1.1 mmol), Na2CO3 (3 mmol), H2O/THF (2:5) (7
mL). b GC yields determined with 1,3-dimethoxybenzene as standard.
5
Table 2 Couplings of substituted aryl bromides and aryl boronic acids in
the presence of Pd(OAc)2 and 5-OMe. a
R1
R2
Product
Yield b
7b
7c
7d
7e
7d
7b
1
2
3
4
5
6
4-COMe
4-Me
4-OMe
2-Me
H
H
H
99
85
H
65 (76 c)
62 (75 c)
70
H
4-OMe
4-COMe
H
60
Besides, the development of supported catalysts operating in pure
water seems particularly suitable for Suzuki couplings insofar as
65 boronic acids are particularly stable in aqueous media.6e
Therefore and given the promising performances of thiazolyl
phosphine ligands reported above in a water/THF mixture, the
efficiency of monomer 5-OMe was evaluated in pure water in the
case of one substrate: 4-bromoacetophenone (Table 3).
70 Interestingly, the latter could be almost quantitatively arylated by
phenyl boronic acid (95% yield) at 25 °C. Noteworthy, the
corresponding biaryl compound was obtained with significantly
lower yield when using PPh3 as the ligand (74%). Dendrimeric
thiazolyl phosphines 5-G1, 5-G3 and triphenylphosphines 6-G1, 6-
75 G3 conferred to palladium almost the same activity (75 to 80 %
yields) in these conditions. The negative dendritic effect observed
previously in the water/THF mixture was thus confirmed in the
case of thiazolyl phosphine ligands 5-G1 and 5-G3 (80% yields
for both instead of 95% for 5-OMe, entries 1, 3 and 4) while no
80 dendritic effect could be highlighted for multivalent
triphenylphosphines 6-G1 and 6-G3 (78 and 75% yields
respectively instead of 74% for PPh3, entries 2, 5 and 6).
Noteworthy, the temperature conditions are very mild (25 °C) and
the loading of palladium very low (0.5 mol%) compared to other
85 examples involving supported palladium-based catalysts able to
promote Suzuki couplings in pure water.6e
a
Pd(OAc)2 (0.005 mmol), 5-OMe (0.005 mmol), ArBr (1 mmol),
b
ArB(OH)2 (1.1 mmol), Na2CO3 (3 mmol), H2O/THF (2:5) (7 mL). GC
c
yields determined with 1,3-dimethoxybenzene as standard. Pd(OAc)2 (1
10 mol%), 5-OMe (1 mol%).
Electron-poor 4-bromoacetophenone could be quantitatively
arylated by phenyl boronic acid (99%, entry 1) whereas electron-
rich substrates such as 4-bromotoluene and 4-bromoanisole gave
rise to the corresponding biaryls in 85% and 65% yield
15 respectively (entries 2,3). The latter could be improved up to
76%, by increasing the palladium and ligand loadings both to 1
mol % (entry 3). Along the same line, arylation of more hindered
2-bromotoluene could be improved from 62% to 75% by
increasing the palladium loading from 0.5 to 1 mol % (entry 4).
20 Aryl boronic acids substituted by electron-donating or
withdrawing groups could also be used as arylating agents
(entries 5 and 6), the corresponding biaryls being obtained in
moderated (R2 = 4-COMe: 60%) to good yields (R2 = 4-OMe:
70%). As a result, ligand 5-OMe revealed more general than
25 glucosamine-based thiazolyl phosphine previously used in Suzuki
coupling whose substrate scope was limited to highly activated 4-
nitroiodobenzene by using 1 mol% Pd(OAc)2 and 3 mol% ligand
in toluene/EtOH/water (3:2:2) mixtures at 60 °C.4
Afterwards, the corresponding dendritic thiazolyl phosphines
30 were also tested in the same reaction conditions while using
substituted aryl bromides and phenyl boronic acid (Scheme 5).18
For arylation of bromobenzene (R1 = H) and in the case of
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 9
Green Chemistry
View Online
Pd(OAc)2 (0.5 mol %)
R1
R1
ligand (0.01 to 0.5 mol %)
Br
R1 = 4-COMe, 4-Me, 4-OMe, 2-Me
(i) Case of thiazolyl phosphines 5-OMe, 5-G1 and 5-G3
+
(HO)2B
Na2CO3
7a-e
H2O/THF, 60 °C, 14 h
(ii) Case of triphenylphosphines PPh3, 6-G1 and 6-G3
PPh3
99
5-OMe
5-G1
95 95
94
91
6-G1
6-G3
87
85
85
81
5-G3
75
73
72
70
65
64
64
63
62
62
60
57
52
49
47
47
45
46
42
43
40
H
4-COMe
4-Me
4-OMe
2-Me
H
4-COMe
4-Me
4-OMe
2-Me
Scheme 5 Yields of biaryls obtained in the presence of thiazolyl phosphines (5-OMe, 5-G1, 5-G3) and triphenylphosphines (PPh3, 6-G1, 6-G3).a,b
Pd(OAc)2 (0.005 mmol), ligand (phosphine-to-palladium ratio: P/Pd = 1; monomeric phosphines: 0.5 mol%; 5-G1 or 6-G1: 0.04 mol%; 5-G3 or 6-G3:
0.01 mol%), PhBr (1 mmol), PhB(OH)2 (1.14 mmol), Na2CO3 (3 mmol), H2O/THF (2:5) (7 mL). GC yields determined with 1,3-dimethoxybenzene as
standard.
a
b
5
Table 3 Coupling of 4-bromoacetophenone and PhB(OH)2 in pure water a
(Scheme 5, i, R = 4-COMe, 94% yield of 7b), to validate the
reusability of the dendritic catalyst (Table 4).20,21 At the end of
the reactions, the crude mixtures were concentrated under
vacuum and further addition of diethylether resulted in the
25 precipitation of the dendritic complexes. The remaining starting
Ligand
5-OMe
PPh3
mol %
0.5
Yield b
95
materials and the expected biaryl compounds could be
successfully extracted in the diethylether phase while aryl
bromide, phenyl boronic acid, base and solvents were added once
more to the precipitate.
1
2
3
4
5
6
0.5
74
5-G1
0.04
0.01
0.04
0.01
80
5-G3
80
30 With 6-G1 and in the case of bromobenzene, a loss of activity of
the catalyst was observed from the first recovery cycle, yield of
biphenyl decreasing from 87% in run 1 to 80% in run 2, and then
to 55% in run 3 (Table 4, entry 1). Unfortunately, an analogous
behavior was observed in the case of 4-bromoacetophenone,
35 yields of 7b decreasing at each cycle: 95% after the first run, 80%
after the second run and only 50% after the third run (Table 4,
entry 2). On the contrary, the dendritic thiazolyl phosphine 5-G1
could be successfully recycled at least 4 times without loss of
activity (Table 4, entry 3) which is among the best performances
40 for systems reported for this reaction.6,7 These results illustrate
the superiority of dendritic thiazolyl phosphines over
triphenylphosphine derivatives in terms of robustness and
opportunities for recycling. Interestingly, it has been previously
reported that the presence of diphosphines was a key condition
45 for the stability and recyclability of dendritic catalyst in Suzuki
couplings and that monophosphine complexes exhibited
decomposition and no recyclability.7m Here we present
monophosphines able to prevent the formation of Pd(0) species
6-G1
78
6-G3
75
a
Pd(OAc)2 (0.005 mmol), phosphine moieties (0.5 mol%), PhBr (1
b
mmol), PhB(OH)2 (1.1 mmol), Na2CO3 (3 mmol), H2O (7 mL). GC
yields determined with 1,3-dimethoxybenzene as standard.
Recyclability of dendritic phosphines
10 One of the obvious advantages to use dendritic catalysts relies on
their possible recycling even if the recyclability of dendritic
systems reported so far for Suzuki couplings has been scarcely
studied.7,8,9 Therefore, the recovery of dendritic catalyst 6-G1 has
been investigated for the coupling of phenyl boronic acid first
15 with bromobenzene since a positive multivalency effect is
observed for this substrate (Scheme 5, ii, R = H, 87% yield of 7a
for 6-G1) and second with 4-bromoacetophenone being arylated
in 95% yield (Scheme 5, ii, R = 4-COMe, product 7b). For
thiazolyl phosphine ligands, we chose 4-bromoacetophenone,
20 substrate that could be almost quantitatively arylated with 5-G1
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Green Chemistry
Page 6 of 9
View Online
monomeric analogues 5-OMe and PPh3 could not be reused after
and allowing the recovery and reuse of the corresponding
complexes. Stabilizing interactions between the thiazole ring and
the metal could account for these observations.22 Noteworthy, the
5
separation from the product.
Table 4 Recovery and reuse of dendritic triphenylphosphine 6-G1 and thiazolyl phosphine 5-G1 for the coupling of bromobenzene (product 7a) or 4-
bromoacetophenone (product 7b) and phenylboronic acid a,b
dendrimer
product
7a
run 1
87
run 2
80
run 3
55
run 4
run 5
1
2
3
6-G1
6-G1
5-G1
-
-
-
-
7b
95
80
50
7b
94
95
96
94
95
a
Pd(OAc)2 (0.025 mmol), ligand (5-G1 or 6-G1: 2.1 µmol; 0.04 mol%), P/Pd ratio = 1, ArBr (5 mmol), PhB(OH)2 (5.5 mmol), Na2CO3 (3 mmol),
H2O/THF (2:5) (35 mL), 60 °C, 24 h. b GC yields determined with 1,3,5-trimethoxybenzene as standard.
50 precipitation as recovery method.8,9 Previously, metal leaching
10 Palladium leaching
studies mainly concerned reactions performed in membrane
reactors (batch or continuous-flow) using nanofiltration
techniques for which the retentions of the dendritic catalysts were
not as efficient as those described in this paper.24 Moreover, to
55 our knowledge, such low palladium leaching (< 0.5 ppm) for
Suzuki reactions is very rare and has been observed in the case of
heterogeneous Pd-based catalysts involving mainly polymer- and
silica-based supports.11
These encouraging results prompted us to compare the leaching
of metal when using a monomeric or a dendritic phosphine as the
ligand. Indeed, contamination of chemical intermediates by
palladium residues is of great concern for the development of
15 large-scale syntheses, in particular in pharmaceutical industry
where metal contaminants are closely monitored. Generally, a
slow and costly purification process is required to meet the
specification limits for residues of metal catalysts.23 Interestingly,
the palladium leaching measured by ICP-MS was found to be
20 greatly reduced by using the dendrimer-supported phosphines 6-
G1 and 5-G1 instead of the corresponding monomeric ligands
PPh3 and 5-OMe respectively (Table 5). Indeed, the dendritic
triphenylphosphine 6-G1 allowed to decrease the Pd leaching to
173 ppm in the coupling product 7b before purification by
25 column chromatography (Table 5, entry 2) instead of about 2200
ppm when using monomeric PPh3 (entry 1). Even more
interestingly, only traces of metal (< 0.55 ppm, entry 4) could be
found when using dendrimer 5-G1 as the ligand instead of about
1400 ppm in the case of monomer 5-OMe (entry 3). Thanks to
30 the thiazolylphosphine-functionalized dendrimer support, the
purification process could be avoided and the crude coupling
products met the requirements of pharmaceutical industry (< 5
ppm for oral route and < 0.5 for parenteral route in the EU).23
Conclusions
60 A series of novel monomeric and dendritic thiazolyl phosphines
was prepared and the activity these ligands conferred to
palladium in Suzuki couplings was evaluated in aqueous media.
The heteroaryl ligands revealed very efficient and allowed to
perform the reactions in mild conditions in water/THF mixtures
65 and even in pure water in the case of one substrate. Besides, the
efficiency of thiazolyl phosphines was compared to the
corresponding triphenylphosphines to evaluate the contribution of
the thiazolyl ring with regard to the electronic and steric
properties it may confer to the metal. The results were found to
70 depend on the nature of the substrates and also on the dendrimer
generation. Moreover, the possibility to reuse both families of
dendritic ligands was evaluated. Interestingly, thiazolyl
phosphines-based catalytic systems revealed more robust and
could successfully be recycled at least 4 times without loss of
75 activity contrary to their triphenylphosphine counterparts.
Noteworthy, the palladium leaching was found to be greatly
decreased by using the dendrimer-supported thiazolylphosphine
instead of the monomeric ligand. The coupling products were
found to be almost free from Pd even before purification by
80 column chromatography (< 0.55 ppm) and met the specification
limits for residues of metal catalysts in pharmaceutical industry.23
Table 5 Palladium leaching in the coupling product a,b
Ligand
PPh3
Pd leaching (ppm) c
2227 ( 63)
173 ( 3)
1
2
3
4
6-G1
5-OMe
5-G1
1432 ( 46)
< 0.55
35 a Pd(OAc)2 (0.005 mmol), ligand (phosphine-to-palladium ratio: P/Pd = 1;
monomeric phosphines: 0.5 mol%; 5-G1 or 6-G1: 0.04 mol%), 4-COMe-
C6H4-Br (1 mmol), PhB(OH)2 (1.14 mmol), Na2CO3 (3 mmol), H2O/THF
b
(2:5) (7 mL). GC yields determined with 1,3-dimethoxybenzene as
c
standard. The amount of Pd was determined by ICP-MS in the crude
Experimental
40 product 7b before any purification (conditions: see Supplementary
Information).
General
NMR spectra were recorded with Bruker DPX 300, AV 300, AV
85 400 spectrometers. All spectra were measured at 25 °C in the
The results obtained in the case of triphenylphosphine-
functionalized dendritic ligands nicely illustrate that dendrimers
indeed combine both advantages of homogeneous (high activity
45 and selectivity) and heterogeneous catalysis (easy separation
from the product and no contamination by metals). To the best of
our knowledge, although this property is often assumed, this is
the first time that such ability of dendritic supports to avoid metal
leaching is demonstrated while using straightforward
1
indicated deuterated solvents. H, 13C and 31P chemical shifts (δ)
are reported in ppm and coupling constants (J) are reported in
Hertz (Hz). The signals in the spectra are described as s (singlet),
d (doublet), t (triplet), m (multiplet) and br (broad resonances).
90 Attribution was carried out thanks to two-dimensional
experiments when necessary (COSY, HMBC, HMQC). Mass
spectrometry was carried out with a Thermo Fisher DS QII
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 9
Green Chemistry
View Online
= 19.6 Hz), 138.04 (d, JC-P = 6.8 Hz), 155.19, 156.09 (d, JC-P =
31.7 Hz), 169, 56, 174.47. DCI-MS (NH3) m/z: 490.2 [M+H]+.
1
2
(DCI/NH3 or DCI/CH4). Gas chromatography (GC) were
recorded on a Shimadzu instrument with a Shimadzu GC-2010
Plus AF and a HP5-MS 30 m x 0.25 mm capillary apolar column.
ICP-MS was performed on a Serie X 2 from Thermo Electron
with a Meinhard nebulizer (see Supporting information for more
details). Chemicals were purchased from Aldrich, Acros, Fluka,
Alfa Aesar and Strem, and were used without further purification,
except for P3N3Cl6 which was recrystallized from hexane and for
bromobenzene which was distilled. Organic solvents were dried,
60
Thiazolyl phosphine 5-OMe
To a solution of 44 (200 mg, 5.39.10-1 mmol) in DMF (5 mL) was
added at 0°C 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride [EDC] (0.127 g, 6.28.10-1 mmol) and HoBt (0.088
g, 6.28.10-1 mmol). After two hours at 0°C, 2-(p-
5
65 methoxy)ethylamine (160 µL, 1.07 mmol) was added dropwise
and after 1.5 hours at 0°C, the mixture was warmed up to room
temperature and stirred during 3 days (monitoring by 31P NMR).
The mixture was filtered and the filtrate was freeze-dried. The
crude oil was dissolved in dichloromethane (25 mL) and washed
70 twice with 15 mL of water. The organic phase was dried over
MgSO4, filtered, and evaporated to dryness. Column
chromatography (CH2Cl2/Acetone (80:20) as eluent, Rf = 0.6) of
the crude product gave 225 mg of the expected compound as a
white powder (83% yield). M. p. = 113.6 °C. 31P{1H} NMR
75 (CD2Cl2, 121.50 MHz): δ = -29.65 ppm. 1H NMR (CD2Cl2,
10 distilled according to usual procedures and degassed before
using.25 Purifications by flash column chromatography were
performed with silica gel (50 ꢀm). TLCs were performed on
silica gel 60 F254 plates and detection was carried out under UV
light. Dendrimers Gn were synthesized according to published
15 procedures.13 The preparation and characterization of compounds
16
1, 2, 3, 44 and 5-G1 have been previously described. The latter
were identified in each case by 1H NMR, 13C NMR and 31P NMR
(if applicable) spectroscopies and the data obtained matched
literature values. For compounds 5-OH, 5-OMe, 5-G1, 5-G3, 6-
20 G1, 6-G3, attribution of all the NMR signals and related spectra
are available in the Supporting Information. Noteworthy,
whatever the nature of the ligand, either monomeric (5-OMe or
PPh3) or dendritic (5-G1, 6-G1, 5-G3 or 6-G3), biaryl compounds
7a-e could be successfully isolated from the crude reaction with
25 very high purities (> 99%). Coupling products were analyzed by
1H NMR spectroscopy and coaddition of authentic samples were
3
300.13 MHz): δ = 2.65 (t, JH-H = 6.9 Hz, 2H), 2.98 (s, 6H), 3.41
(m, 2H), 3.77 (s, 3H), 3.79 (d, JH-P = 1.2 Hz, 2H), 6.75 (m, 2H),
4
6.86 (br s, 1H, NH), 7.00 (m, 2H),7.30-7.50 (m, 10H). 13C{1H}
3
NMR (CD2Cl2, 75.47 MHz): δ = 34.58, 38.52 (d, JC-P = 15.9
80 Hz), 39.86, 40.52, 55.08, 113.17 (d, JC-P = 35.2 Hz), 113.68,
1
128.41 (d, 3JC-P = 6.8 Hz), 128.60, 129.59, 131.24, 132.67 (d, 2JC-
1
= 19.4 Hz), 138.14 (d, JC-P = 6.6 Hz), 156.60 (d, JC-P = 31.0
2
P
1
Hz), 158.06, 168.63, 174.32. DCI-MS (CH4) m/z: 504.2 [M+H]+.
performed. Some H NMR spectra of isolated products are given
in Supporting Information.
Thiazolyl phosphine 5-G1
CCDC 883180, 883178 and 883179 contain the supplementary
30 crystallographic data for compounds 3, 5-OH and 5-OMe. These
data can be obtained free of charge from The Cambridge
85 Cesium carbonate (349 mg, 1.07.10-3 mol) was added at 0°C to a
solution of G1 (89 mg, 4.87.10-2 mmol) and 5-OH (310 mg,
6.33.10-1 mmol) in THF (10 mL). The mixture was stirred two
hours at 0°C and warmed up to room temperature. The progress
of the reaction was monitored by 31P NMR. After complete
90 conversion (36 hrs) the crude mixture was centrifuged and the
supernatant collected. The solvent was removed in vacuum and
the crude product purified by column chromatography (first with
dichloromethane/acetone (70:30) as eluent to eliminate the excess
of free phenol, Rf = 0.6 and then with dichloromethane/ethanol
95 (93:7) as eluent, Rf = 0.2) to give 278 mg of the desired
compound as a white powder (80% yield).
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif and are contained in the
Supporting Information.
35 Preparation of ligands
Thiazolyl phosphine 5-OH
To
a
solution of 4 (315 mg, 8.05.10-1 mmol) in N,N-
dimethylformamide [DMF] (6.5 mL) were added at 0°C
hydroxybenzotriazole [HoBt] (0.156 g, 1.02 mmol) and N,N’-
40 dicyclohexylcarbodiimide [DCC] (0.211 g, 1.02 mmol). After
one hour at 0°C, a solution of tyramine (0.233 g, 1.7 mmol) in
DMF (3 mL) was added over 5 minutes. After 2 hours at 0°C, the
mixture was warmed up to room temperature and stirred for 7
days (monitoring by 31P NMR). The mixture was filtered and the
31P{1H} NMR (CD2Cl2, 121.50 MHz): δ = -29.68, 8.12, 62.78. 1H
NMR (CD2Cl2, 300.13 MHz): δ = 2.62 (t, JH-H = 6.6 Hz, 24H),
3
2.92 (s, 72H), 3.23 (d, 2JH-P = 10.2 Hz, 18H), 3.34 (m, 24H), 3.77
100 (br s, 24H), 6.82 (br t, 12NH), 6.90-7.12 (m, 60H) , 7.19-7.49 (m,
120H), 7.58-7.70 (m, 18H, 6 C5-H). 13C{1H} NMR (CD2Cl2,
75.47 MHz): δ = 33.07 (d, 2JC-P = 11.9 Hz), 34.98, 38.48 (d, 3JC-P
45 filtrate was freeze-dried.
A first column chromatography
(CH2Cl2/EtOH = 93/7 as eluent) of the crude product permitted to
eliminate the excess of tyramine, DCU and a large part of the
1
= 15.8 Hz), 40.12, 40.49, 114.00 (d, JC-P = 33.2 Hz), 121.12 (d,
3
3JC-P = 4.5 Hz), 121.33, 128.28, 128.48 (d, JC-P = 6.8 Hz),
oxidized compound.
A
second column chromatography
2
105 128.84, 129.80, 132.26, 132.72 (d, JC-P = 18.9 Hz), 136.45,
(CH2Cl2/AcOEt (80:20) as eluent) gave 196 mg of the expected
50 product as a white powder (47% yield). 31P{1H} NMR (CD2Cl2,
137.96 (d, 1JC-P = 6.6 Hz), 138.69 (d, 3JC-P = 14.3 Hz), 148.99 (d,
2JC-P = 7.5 Hz), 151.23, 156.08 (d, JC-P = 31.7 Hz), 169.22,
2
1
121.50 MHz): δ = -29.79 ppm. H NMR (CD2Cl2, 300.13 MHz):
174.32.
3
δ = 2.62 (t, JH-H = 6.8 Hz, 2H), 2.98 (s, 6H), 3.42 (m, 2H), 3.84
(d, JH-P = 1.2 Hz, 2H), 6.47 (s, 1H, OH), 6.70 (m, 2H), 6.90 (m,
4
Thiazolyl phosphine 5-G3
2H), 7.06 (br t, 3JH-H = 5.7 Hz, 1H), 7.25-7.50 (m, 10H). 13C{1H}
55 NMR (CD2Cl2, 75.47 MHz): δ = 34.56 (C5), 38.27 (d, JC-P
16.2 Hz), 39.93, 40.79, 113.64 (d, JC-P = 33.2 Hz), 115.36,
128.45 (d, 3JC-P= 6.8 Hz), 128.64, 129.63, 130.06, 132.68 (d, 2JC-P
110 Cesium carbonate (348 mg, 1.07 mmol) was added at 0°C to a
solution of G3 (130 mg, 1.21.10-2 mmol) and 5-OH (310 mg,
6.33.10-1 mmol) in THF (10 mL). The mixture was stirred two
3
=
1
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Green Chemistry
Page 8 of 9
View Online
hours at 0°C and warmed up to room temperature. The progress
of the reaction was monitored by 31P NMR. After complete
conversion (72 hrs), the mixture was centrifuged and the
supernatant collected. The solvent was removed in vacuum and
solvent was removed under vacuum and 1,3-dimethoxybenzene
(standard, 1 mmol, 130 ꢀL) was added. Water (3 mL) and
dichloromethane (5 mL) were added and the aqueous phase
extracted twice with dichloromethane (5 mL). The organic layers
5
the crude product purified by size exclusion chromatography 60 were combined and filtered through a plug of Celite® and
(THF as eluent) to eliminate the excess of phenol and to give 420
mg of the desired compound as white powder (75% yield).
31P{1H} NMR (CD2Cl2, 121.50 MHz): δ = -29.67, 7.65, 62.77,
analyzed by GC.
General procedure for recycling experiments
1
62.90. H NMR (CD2Cl2, 300.13 MHz): δ = 2.61 (m, 96H), 2.88
After standard cycles of evacuation and back-filling with argon, a
round bottom Schlenk flask equipped with a magnetic stirring bar
65 was charged with Pd(OAc)2 (0.025 mmol) and dendritic ligand
(0.00208 mmol for 5-G1 or 6-G1). After another standard cycle of
evacuation and back-filling with argon, THF (25 mL) and water
(10 mL) were added. After one hour stirring at room temperature,
aryl bromide (5 mmol), aryl boronic acid (5.5 mmol) and Na2CO3
70 (15 mmol) were introduced. The flask was sealed under a positive
pressure of argon, stirred, and heated to 60 °C for 24 h. After
cooling to room temperature, solvent was removed under vacuum
and 1,3,5-trimethoxybenzene (standard, 3 mmol, 500 mg) and
degassed Et2O (25 mL) were added. The precipitate was filtered
10 (s, 288H), 3.10-3.50 (m, 222H), 3.62-4.02 (br s, 96H), 6.75-7.12
(m, 252H), 7.13-7.52 (m, 552H), 7.53-7.90 (m, 126H). 13C{1H}
NMR (CD2Cl2, 75.47 MHz): δ = 32.53 (m), 32.99 (d, 2JC-P = 12.5
3
Hz), 34.90, 38.57 (d, JC-P = 15.8 Hz), 39.91, 40.40, 113.35 (d,
3
1JC-P = 32.5 Hz), 121.18 (d, JC-P = 4.4 Hz), 121.83, 128.33,
15 128.47 (d, 3JC-P = 6.8 Hz), 128.65, 129.81, 132.44, 132.65 (d, 2JC-
1
= 19.3 Hz), 136.63, 138.07 (d, JC-P = 6.5 Hz), 138.95 (d, JC-P
3
P
= 14.4 Hz), 139.54, 149.02 (d, 2JC-P = 7.1 Hz), 151.38, 156.60 (d,
2JC-P = 31.5 Hz), 168.73, 174.28.
Triphenylphosphine 6-G3
20 Cesium carbonate (365 mg, 1.12 mmol) was added to a solution 75 and washed twice with degassed Et2O (15 mL). The filtrate was
of 4-(diphenylphosphino)phenol 610 (203 mg, 0.73 mmol) and G3
(150 mg, 0.014 mmol) in THF (10 mL). The mixture was stirred
overnight at room temperature, then filtered under argon and the
filtrate was evaporated to dryness. The resulting oil was dissolved
filtered through a plug of Celite® and analyzed by GC or isolated
by silica flash chromatography purification. After standard cycles
of evacuation and back-filling with argon, the precipitate was
directly used for a new catalytic run. THF (25 mL), water (10
25 in CH2Cl2 (2 mL) and this solution was added to a mixture of 50 80 mL), aryl bromide (5 mmol), aryl boronic acid (5.7 mmol) and
mL n-pentane/Et2O (10:1 then 5:5 then 5:15) to allow dendrimer
6-G3 to precipitate. 6-G3 was obtained as a white powder in 65 %
yield (184 mg, 0.005 mmol). 31P-{1H} NMR (121.5 MHz,
CD2Cl2, 25°C) δ (ppm): -6.73, 7.92, 61.59, 62.36, 62.65. 1H
30 NMR (300 MHz, CD2Cl2, 25°C) δ (ppm): 3.23-3.26 (m, 126H),
7.02-7.05 (m, 12H), 7.12-7.23 (m, 744H), 7.53-7.62 (m, 126H).
13C-{1H} NMR (75 MHz, CD2Cl2, 25°C) δ (ppm): 32.85 (d, 2JC-P
Na2CO3 (15 mmol) were introduced. The flask was sealed under
a positive pressure of argon, stirred, heated to 60 °C for 24 h.
Acknowledgments
We thank the CNRS and ANR Globucat for funding.
85 Notes and references
3
= 13 Hz), 121.39-121.73, 128.18, 128.28, 128.54 (d, JC-P = 7.1
2
Hz), 128.81, 132.14-132.37, 133.54 (d, JC-P = 19.9 Hz), 134.33
a
Laboratoire de Chimie de Coordination UPR 8241 CNRS, BP 44099,
1
35 (d, JC-P = 12 Hz), 134.98 (d, JC-P = 21.3 Hz), 137.02 (d, JC-P
2
1
205 route de Narbonne, 31077 Toulouse Cedex 04, France
Phone : (+33) 561-333-134 ; Fax: (+33) 561-553-003 ; E-mail: anne-
marie.caminade@lcc-toulouse.fr, jean-pierre.majoral@lcc-toulouse.fr,
90 armelle.ouali@lcc-toulouse.fr
b Université de Toulouse ; UPS, INPT ; LCC ; F-31077 Toulouse, France
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
=
11.6 Hz), 139.02, 151.18-151.29.
Catalysis
Catalytic reactions were carried out under argon atmosphere
using Radley Carousel “reaction stations RR98030”. For
40 arylation reactions, the yields are calculated by GC using 1,3-
dimethoxybenzene or 1,3,5-trimethoxybenzene as the standard.
GC method: Initial temperature: 50 °C; Initial time: 2 min; Ramp:
10 °C/min; Final temperature: 230 °C; Final time: 10 min.
95
1
a) Y. Canac, C. Maaliki, I. Abdellah, R. Chauvin, New. J. Chem.
2012, 36, 17-27; b) R. J. Seacome, M. P. Coles, J. E. Glover, P. B.
Hitchcock, G. J. Rowlands, Dalton Trans. 2010, 39, 3687-3694; c) R.
Ghosh, A. Sarkar, J. Org. Chem. 2010, 75, 8283-8286; d) J. Wu, A.
S. C. Chan, Acc. Chem. Res. 2006, 39, 711-720; e) S. Bell, B.
Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A. Pfaltz, Science
2006, 311, 642-644; f) A. Fihri, J. C.Hierso, A. Vion, D. H. Nguyen,
M. Urrutigoity, P. Kalck, R. Amardeil, P. Meunier, Adv. Synth.
Catal. 2005, 347, 1198-1202; g) A. Zapf, R. Jackstell, F. Rataboul, T.
Riermeier, A. Monsees, C. Fuhrmann, N. Shaikh, U. Dingerdissen,
M. Beller, Chem. Commun. 2004, 38-39; h) N. G. Andersen, B. A.
Keay, Chem. Rev. 2001, 101, 997-1030; i) P. Espinet, K. Soulantica,
Coord. Chem. Rev. 1999, 195, 499; j) Z.-Z. Zhang, H. Cheng, Coord.
Chem. Rev. 1996, 147, 1-39; k) G. R. Newkome, Chem. Rev. 1993,
93, 2067-2089.
100
105
110
115
General procedure for standard catalytic tests
45 After standard cycles of evacuation and back-filling with argon, a
Radley tube Carousel equipped with a magnetic stirring bar was
charged with Pd(OAc)2 (0.005 mmol) and ligand (0.005 mmol for
monomeric ligands, 0.00042 mmol for 5-G1 or 6-G1, 0.000104
mmol for 5-G3 or 6-G3). After another standard cycle of
50 evacuation and back-filling with argon, THF (5 mL) and water (2
mL) were added. After one hour stirring at room temperature,
aryl bromide (1 mmol), aryl boronic acid (1.1 mmol) and Na2CO3
(3 mmol) were introduced. The tube was sealed under a positive
pressure of argon, stirred, and heated to the required temperature
55 for the required time period. After cooling to room temperature,
2
3
A.-C. Gaumont, M. Gulea, , J. Levillain Chem. Rev. 2009, 109, 1371-
1401.
G. Oshovsky, A.Ouali, N. Xia, M. Zablocka,R. T. Boere, C.
Duhayon, M. Taillefer, J.-P. Majoral Organometallics 2008, 27,
5733-5736.
8
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 9
Green Chemistry
View Online
4
5
R. Kolodziuk, A. Penciu, M. Tollabi, E. Framery, C. Goux-Henry, A.
Iourtchenko, D. Sinou J. Organomet. Chem. 2003, 687, 384-391.
For some reviews dealing with Suzuki reactions, see: a) C. Ming, F.
Y. Kwong, Chem. Soc. Res. 2011, 40, 4963-4972; b) G. C. Fortman,
S. P. Nolan, Chem. Soc. Res. 2011, 40, 5151-5169; c) X.-F. Wu, P.
Anbarasan, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2010, 49,
9047-9050; d) G. A. Molander, B. Canturk, Angew. Chem. Int. Ed.
2009, 48, 9240-9261; e) G. Fu, Acc. Chem. Res. 2008, 41, 1555-
1564; f) R. Martin, S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461-
1473; g) S. Würtz, F. Glorius, Acc. Chem. Res. 2008, 41, 1523-1533;
h) N. Marion, S. P. Nolan, Acc. Chem. Res. 2008, 41, 1440-1449.
For some reviews dealing with supported catalysts for Suzuki
couplings, see: a) A. Fihri, M. Bouhrara, B. Nekoueishahraki, J.-M.
Basset, V. Polshettiwar, Chem. Soc. Rev. 2011, 40, 5181-5203; b) A.
Balanta, C. Godard, C. Claver, Chem. Soc. Rev. 2011, 40, 4973-4985;
c) A. Molnar, Chem. Rev. 2011, 111, 2251-2320; d) V. Polshettiwar,
R. Luque, A. Fihri, H. Zhu, P. Bouhrara, J.-M. Basset, Chem. Rev.
2011, 111, 3036-3075; e) M. Lamblin, L. Nassar-Hardy, J.-C. Hierso,
E. Fouquet, F.-X. Felpin, Adv. Synth. Catal. 2010, 352, 33-79.
70 12 The preparation and characterization of compounds 1, 2, 3, 4 have
been previously described (see reference 4). Compounds 5-OH and
5-OMe are new.
13 a) N. Launay, A.-M. Caminade, R. Lahana, J.-P. Majoral, Angew.
Chem. Int. Ed. 1994, 33, 1589-1592; b) N. Launay, A.-M. Caminade,
5
10
15
20
25
30
35
40
45
50
75
J.-P. Majoral, J. Am. Chem. Soc. 1995, 117, 3282-3283.
14 O. Herd, A. Hessler, M. Hingst, M. Tepper, O. Stelzer, J. Organomet.
Chem. 1996, 522, 69-76.
15 This phenol has been previously grafted onto phosphorous dendrons
with various focal points: a) I. Angurell, C.-O. Turrin, R. Laurent, V.
Maraval, P. Servin, O. Rossell, M. Seco, A.-M. Caminade, J.-P.
Majoral, J. Organomet. Chem. 2007, 692, 1928-1939; b) L. Brauge,
G. Magro, A.-M. Caminade, J.-P. Majoral, J. Am. Chem. Soc. 2001,
123, 6698-6699; c) S. Merino, L. Brauge, A.-M. Caminade, J.-P.
Majoral, D. Taton, Y. Gnanou, Chem. Eur. J. 2001, 7, 3095-3105.
80
6
85 16 V. Maraval, A.-M. Caminade, J.-P. Majoral, J.-C. Blais, Angew.
Chem. Int. Ed. 2003, 42, 1822-1826.
17 S. Lou, G. Fu, Adv. Synth. Catal. 2010, 352, 2082-2084.
18 Noteworthy, whatever the nature of the ligand, either monomeric (5-
OMe or PPh3) or dendritic (5-G1 , 6-G1, 5-G3 or 6-G3 ), biaryl
7
For examples of Suzuki couplings involving dendritic ligands, see:
a) J. Liu, Y. Feng, Y. He, N. Yang, Q.-H. Fan, New J. Chem. 2012,
36, 380-385; b) G. Jayamurugan, N. Jayaraman, Adv. Synth. Catal.
2009, 351, 2379-2390; c) M. Janssen, C. Müller, D. Vogt, Adv. Synth.
Catal. 2009, 351, 313-318; d) D. J. M. Snelders, G. van Koten, R.S J.
M. Klein Gebbink J. Am. Chem. Soc. 2009, 131, 11407-11416; e) J.
Kühnert, M. Lamaĉ, J. Demel, A. Nicolai ,H. Lang, P. Stěpniĉka J.
Mol. Catal. A 2008, 285, 41-47 ; f) D. J. M. Snelders, R. Kreiter, J. J.
Firet, G. van Koten, R. J. M. Klein Gebbink Adv. Synth. Catal. 2008,
350, 262-266; g) M.Meise, R. Haag, ChemSusChem 2008, 1, 637-
642; h) H. Ohta, T. Fujihara, Y. Tsuji, Dalton Trans. 2008, 379-385;
90
compounds could be successfully isolated from the crude reaction
with very high purities (> 99%, see supporting information).
19 M. Slany, M. Bardaji, M.-J. Casanove, A.-M.-Caminade, J.-P.
Majoral, B. Chaudret, J. Am. Chem. Soc. 1995, 117, 9764-9765.
20 The reusability of the dendritic catalyst involving 5-G1 was not
evaluated in the case of bromobenzene since the yield of 7a was
moderate in this case (Scheme 5, i, R = H, 60% yield).
95
21 In all the cases, scale-up of the reaction by a factor 5 and subsequent
increase of the reaction time from 14 to 24 h were necessary.
22 a) A. Betz, L. Yu, M. Reiher, A.-C. Gaumont, P.-A. Jaffrès, M.
Gulea, J. Organomet. Chem. 2008, 693, 2499-2508; b) I. Abrunhosa,
L. Delain-Bioton, A.-C. Gaumont, M. Gulea, S. Masson, Tetrahedron
2004, 60, 9263-9272.
i) P. Servin, R. Laurent, A. Romerosa, M. Peruzzini, J.-P. Majoral, 100
A.-M.-Caminade, Organometallics 2008, 27, 2066-2073; j) T.
Fujihara, S. Yoshida, H. Ohta, Y. Tsuji, Angew. Chem. Int. Ed. 2008,
47, 8310-8314; k) H. Hattori, K.-I. Fujita, T. Muraki, A. Sakaba,
Tetrahedron Lett. 2007, 48, 6817-6820; l) J. Lemo, K. Heuzé, D.
23 M. Pagliaro, V. Pandarus, R. Ciriminna, F. Béland, P. D. Cara,
ChemCatChem 2012, 4, 432-445.
Astruc, Chem. Commun. 2007, 4351-4353; m) J. Lemo, K. Heuzé, D. 105 24 a) L. H. Gade, Topics in Organometallic Chemistry, Springer, 2006
Astruc, Org. Lett. 2005, 7, 2253-2256.
and references cited herein ; b) M. Janssen, C. Müller, D. Vogt,
Green Chem. 2011, 13, 2247-2257.
8
9
A.-M. Caminade, C.-O. Turrin, R. Laurent, A. Ouali, B. Delavaux-
Nicot, Dendrimers: Towards Catalytic, Material and Biomedical
Uses, Wiley-VCH, 2011.
25 D. D. Perrin et W. L. F. Almerego Purification of Laboratory
chemicals, 3rd ed., Pergamon Press. Oxford, 1998.
110
115
120
125
130
135
a) D. A. Tomalia, P. R. Dvornik, Nature 1994, 372, 617-618; b) D.
Astruc, F. Chardec, Chem. Rev. 2001, 101, 2991-3023; c) L. J.
Twyman, A. S. H. King, I. K. Martin, Chem. Soc. Rev. 2002, 31, 69-
82; d) R. van Heerbeek, P. C. J. Kamer, P. W. N. M. van Leeuwen, J.
N. H. Reek, Chem. Rev. 2002, 102, 3717-3756; e) A.-M. Caminade,
J.-P. Majoral, Coord. Chem. Rev. 2005, 249, 1917-1926; f) D. Méry,
D. Astruc, Coord. Chem. Rev. 2006, 250, 1965-1979; g) B. Helms, J.
M. J. Fréchet, Adv. Synth. Catal. 2006, 348, 1125-1148; h) R.
Andrés, J. de Jesús, J. C. Flores, New J. Chem. 2007, 31, 1171-1191.
i) A.-M. Caminade, P. Servin, R. Laurent, J.-P. Majoral, Chem. Soc.
Rev. 2008, 37, 56-67; j) A.-M. Caminade, A. Ouali, M. Keller, J.-P.
Majoral, Chem. Soc. Rev. 2012, 41, 4113-4125.
10 A. Ouali, R. Laurent, A.-M. Caminade, J.-P. Majoral, M.Taillefer, J.
Am. Chem. Soc. 2006, 128, 15990-15991.
55 11 Supported catalytic systems allowing to decrease the palladium
leaching in Suzuki couplings (< 0.5 ppm): a) M. C. Hong, M. C.
Choi, Y. W. Chang, Y. Lee, J. Kim, H. Rhee, Adv. Synth. Catal.
2012, 354, 1257-1263; b) M. Pagliaro, V. Pandarus, F. Béland, R.
Ciriminna, G. Palmisano, P. D. Cara, Catal. Sci. Technol. 2011, 1,
60
736-739; c) S. Schweizer, J.-M. Becht, C. Le Drian, Tetrahedron
2010, 66, 765-772; d) N. Hoshiya, N. Isomura, M. Shimoda, H.
Yoshikawa, Y. Yamashita, K. Iizuka, S. Tsukamoto, S. Shuto, M.
Arisawa, ChemCatChem 2009, 1, 279-285; e) T. J. Colacot, W. A.
Carole, B. A. Neide, A. Harad, Organometallics 2008, 27, 5605-
5611; f) S. Schweizer, J.-M. Becht, C. Le Drian, Org. Lett. 2007, 9,
3777-3780; g) J. M. Richardson, C. W. Jones, J. Cat. 2007, 251, 80-
93; h) J. D. Webb, S. MacQuarrie, K. McEleney, C. M. Crudden, J.
Cat. 2007, 252, 97-109; i) C. M. Crudden, M. Sateesh, R. Lewis, J.
Am. Chem. Soc. 2005, 127, 10045-10050.
65
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9