Highly efficient reusable polymer-supported Pd catalysts of general use for the Suzuki reaction

Article abstract of DOI:10.1016/j.tet.2009.11.050

Short and efficient syntheses of various polymer-supported Pd catalysts are reported. The reactivity of these catalysts has been determined for the Suzuki reaction. It turned out that the (tert-butylphenylphosphinomethyl)polystyrene-supported Pd catalyst 2′a is highly efficient for versatile Suzuki reactions from aryl chlorides. These couplings are performed in the presence of low amounts (4 mequiv) of supported Pd, the catalyst can be reused more than seven times without loss of efficiency and the Pd leaching is extremely low (<0.1% of the initial amount).

Full text of DOI:10.1016/j.tet.2009.11.050

Tetrahedron 66 (2010) 765–772
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient reusable polymer-supported Pd catalysts of general use
for the Suzuki reaction
*
´
Stephane Schweizer, Jean-Michel Becht , Claude Le Drian
Institut de Science des Mate´riaux de Mulhouse, LRC-CNRS 7228, ENSCMu, 3 rue Alfred Werner, F-68093 Mulhouse Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Short and efficient syntheses of various polymer-supported Pd catalysts are reported. The reactivity of
these catalysts has been determined for the Suzuki reaction. It turned out that the (tert-butylphenyl-
phosphinomethyl)polystyrene-supported Pd catalyst 20a is highly efficient for versatile Suzuki reactions
from aryl chlorides. These couplings are performed in the presence of low amounts (4 mequiv) of sup-
ported Pd, the catalyst can be reused more than seven times without loss of efficiency and the Pd
leaching is extremely low (<0.1% of the initial amount).
Received 3 September 2009
Received in revised form
3 November 2009
Accepted 10 November 2009
Available online 14 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reactivity, which moreover could decrease,13c or even disappear,
after use.13d
Transition metal catalyzed cross-couplings are fundamental
transformations in modern organic synthesis.1 Among them, the Pd
catalyzed Suzuki reaction is very efficient for the formation of aryl–
aryl bonds,2,3 and therefore finds widespread applications for the
synthesis of molecules possessing interesting pharmacological or
physical properties.4 These couplings proceed generally in high
yields under very mild and non-anhydrous reaction conditions and
tolerate the presence of many functional groups. Usually, they are
performed in the presence of a homogeneous (soluble) Pd catalyst,1
the major drawbacks being the impossibility to recover for direct
reuse these expensive catalysts and the difficulties frequently en-
countered to avoid the presence of Pd in waste and, even more
importantly, in the reaction products. During the last decade, ex-
tensive work has been devoted to the development of reusable Pd
catalysts for C–C bond forming reactions: the precious metal is
generally grafted on inorganic5 or polymeric supports.6 For exam-
ple, Pd can be encapsulated7 or incarcerated8 in a polymeric matrix
or bound to polymer-supported carbene9 or phosphine ligands.10,11
Concerning the Suzuki reaction, an additional challenge is the
development of Pd catalysts allowing the use of aryl chlorides in-
stead of the more reactive but much more expensive aryl bromides
or iodides. Several homogeneous Pd catalysts have been developed
for the Suzuki coupling of aryl chlorides,12 but only few efficient
heterogeneous Pd catalysts, which are of general use for this re-
action have been reported.13 Compared to their homogeneous an-
alogues, heterogeneous Pd catalysts often suffer from a lower
In a previous report, we have described reusable (diaryl-
phosphinomethyl)polystyrene-supported Pd catalysts for Suzuki
reactions of aryl bromides.11b Besides this first family of catalysts,
we developed a second family by replacing, on the polymer, the
(diarylphosphinomethyl) substituents by (aryl-tert-butylphosphi-
nomethyl) substituents.11c,14 This modification brought a consider-
able improvement: the catalysts are either highly efficient and of
general use for Suzuki reactions from aryl chlorides. We present
here the detailed results of the Suzuki coupling.
2. Results and discussion
2.1. Preparation of the heterogeneous polymer-supported
Pd catalysts
The Pd catalysts were prepared from two types of commercially
available halogenated polymers: Merrifield resin for catalysts 2a–g
and 20a and Tentagel-Br resin for catalyst 2h.
Inspired by our previous work,11 the heterogeneous Pd catalysts
were prepared in two steps: lithiation of the (aryl-tert-butyl)- or
di(tert-butyl)-chlorophosphines 1a–f followed by substitution of
the halogen atoms of the polymer and then introduction of the
precious metal (Scheme 1).
Chlorophosphine 1a was obtained from tert-butyllithium and
dichlorophenylphosphine, whereas chlorophosphines 1b–e were
generated from the reactions of aryllithiums with tert-butyldi-
chlorophosphine.15 Since the air- and moisture-sensitive chloro-
phosphines 1a–e were obtained with a purity (determined by 31P
and 1H NMR) already above 90%, they were directly reacted with
lithium without further purification.16 By reaction of the
* Corresponding author. Tel.: þ33 3 89 33 67 20; fax: þ33 3 89 33 68 60.
E-mail address: jean-michel.becht@uha.fr (J.-M. Becht).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.050

766
S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
Scheme 1. Syntheses of polymer-supported Pd catalysts.
phosphinolithiums with halogenated polymers, the desired aryl-
tert-butyl- or di-tert-butylphosphino-polymers were obtained:
when a halomethyl group was present on the starting polymer, 99%
of the halogen atoms were removed, however only ca. 80% of the
theoretical amount of phosphino groups were introduced in 2a–f,
2h, and 20a. In the case of catalyst 2g, 98% of the bromine atoms
disappeared but only 25% of them were replaced by phosphino
groups. The polymer-supported Pd catalysts 2a–h and 20a were
then obtained via an exchange reaction with Pd(PPh3)4 as a soluble
Pd source.11b During the synthesis of catalyst 20a, we have shown
that 4 equiv of PPh3 were recovered. Elemental analysis of the re-
action medium (performed according to Section 4.4. of the Exper-
imental section) proved that more than 99% of the amount of Pd
used was grafted on the resins. The Pd content of the catalyst was
confirmed according to Section 4.5. of the Experimental section and
by conventional elemental analysis (see General remarks of the
Experimental section). Comparable P/Pd ratios were obtained for
all catalysts 2a–f (for further details see Experimental section). It is
important to note that these catalysts could easily be prepared on
a 20 g scale. Besides, they are air- and moisture-stable and can
therefore be easily stored and handled.
only 0.2 mequiv of Pd (entries 8 and 9). We studied also the in-
fluence of the polymeric support: replacing the Merrifield resin by
a Tentagel resin brought a considerable improvement since in the
presence of only 0.05 mequiv of supported Pd a 87% yield of 3a was
still obtained (entry 13).
The possibility to reuse catalysts 20a and 2h was then examined.
For this purpose, the catalyst was recovered by filtration on
a membrane and directly reused in a second run (for further details
see Experimental section). Unfortunately, the first reuse of catalyst
20a resulted in a significantly lower 35% yield of 3a. For 2h, the first
reuse was satisfactory, however the subsequent reuses led to de-
creasing yields (Table 2).
Table 1
Suzuki reactions of 4-chloroacetophenone and phenylboronic acid
O
O
2a-h or 2'a,
B(OH)2
Na2CO3
+
Cl
Toluene/EtOH/H2O
reflux, 20 h
3a
2.2. Suzuki reactions of aryl chlorides
Entrya
Catalyst
Pd (mequiv.)
Yieldb (%)
The reactivity of catalysts 2a–h and 20a was then determined for
the Suzuki reaction using 4-chloroacetophenone and phenyl-
boronic acid as model substrates (Table 1). This coupling was ini-
tially performed in the presence of Na2CO3 in a 5:1:1 mixture of
toluene/EtOH/H2O (Table 1).
In the presence of the polystyrene-supported Pd catalyst 2a
containing 0.3% of Pd, the desired biaryl 3a was obtained in an
excellent 99% yield with 2 mequiv of supported Pd (entry 1). A
lower 73% yield was observed by using only 1 mequiv of supported
Pd (entry 2). Except catalysts 2c and 2d, which gave excellent yields
of 3a with 2 mequiv of Pd (entries 4–5), the other polystyrene-
supported Pd catalysts 2b, 2e–g afforded 3a in lower yields (entries
3, 6–7, 11). The Pd/P ratio seems to have a notable influence since
considerable improvement was achieved by using catalyst 20a
(%Pd¼0.1), which afforded an almost quantitative yield of 3a with
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2d
2e
2f
20a
20a
20a
2g
2h
2h
2
1
2
2
2
2
2
0.5
0.2
0.1
2
0.1
0.05
99
73
14
95
90
33
74
99
98
47
58
99
87
9
10
11
12
13
a
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.1 equiv of phenylboronic acid, 1.2 equiv of Na2CO3.
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
stituents of crude reaction mixtures.

S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
767
Table 2
Table 4
Recycling tests
Screening of bases
2'a or 2h
O
B(OH)2
(0.5 mequiv Pd),
Na2CO3
O
2'a, Base
+
3a
B(OH)2
Toluene/H2O (0.3%)
reflux, 20 h
Cl
+
3a
Cl
Toluene/EtOH/H2O
reflux, 20 h
Entrya
Base
Pd (mequiv.)
Yieldb (%)
1
2
3
4
5
6
Na2CO3
Ag2CO3
Cs2CO3
Cs2CO3
CsF
0.5
0.5
0.5
2
0.5
4
3
Runa
Yieldb (%) 20a
Yieldb (%) 2h
Traces
66
1
2
3
4
98
35
d
d
99
94
83
53
93 (99)c
45
CsF
88 (99)c
a
a
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.1 equiv of phenylboronic acid, 1.2 equiv of Na2CO3.
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.1 equiv of phenylboronic acid, 1.2 equiv of base.
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
stituents of crude reaction mixtures.
stituents of crude reaction mixtures.
c
Reactions performed with 1.4 equiv of phenylboronic acid and 1.5 equiv of base.
It should be noted that the loss of Pd during the first use of catalyst
20a was only 1% of the initial amount, proving that the deactivation of
20a is not caused by a loss of the metal. Moreover, TEM images of the
catalyst before and after use showed no significant difference. We
have therefore no explanation for this deactivation of the catalyst.
Then, we examined if catalyst 20a was stable in a 5:1:1 mixture of
toluene/EtOH/H2O. For this purpose, three independant experiments
were performed (Table 3): 20a was respectively refluxed for 20 h in
toluene, in a 5:1 mixture of toluene/EtOH and in a 5:1:1 mixture of
toluene/EtOH/H2O. Then, 20a was recovered by filtration and directly
reacted in a Suzuki reaction using the previous reaction conditions. It
turned out that no deactivation of 20a was observed in toluene since
the desired coupling product was obtained in 98% yield (entry 1), but
that heating 20a in a mixture of toluene and an protic solvent was
detrimental to its reactivity (entries 2 and 3).
Table 5
Recycling test of catalyst 20a
O
B(OH)2
2'a, CsF
Toluene/H2O (0.3%)
reflux, 20 h
+
3a
Cl
Runa
Yieldb (%)
1
2
3
4
5
6
7
99
95
99
98
99
98
98
a
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.4 equiv of phenylboronic acid, 1.5 equiv of CsF.
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
stituents of crude reaction mixtures.
Table 3
Stability tests of catalyst 20a
We then thought necessary to examine the reactivity of cata-
lysts 2a–f and 20a under these notably different conditions and to
compare them with commercially available heterogeneous Pd
EnCat TPP30 and Pd EnCat NP30 (Table 6). It turned out that the
catalysts 2a and 20a were still the most reactive and that 20a was
more efficient than 2a (entries 1–7). Decreasing the amount of
supported Pd (entry 8), the excess of phenylboronic acid, or the
temperature, afforded only lower yields of 3a. The Pd Encat TPP30
Solvent
Suzuki
Coupling
3a
2'a
reflux, 20 h
Entrya
Solvent
Toluene
Toluene/EtOH 5:1
Toluene/EtOH/H2O 5:1:1
Yieldb (%)
1
2
3
98
46
38
a
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.1 equiv of phenylboronic acid, 1.2 equiv of Na2CO3.
Table 6
Suzuki reactions under the reoptimized conditions
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
O
stituents of crude reaction mixtures.
B(OH)2
2'a, CsF
+
3a
We had therefore to reoptimize the reaction conditions in order to
recover a reusable catalyst. The Suzuki reaction was run in conditions
avoiding protic solvents. We tried several bases in anhydrous toluene
(Table 4): Cs2CO3 gave good results (entries 3 and 4). However er-
ratical yields were sometimes obtained. We found that traces of H2O
insured reproducibility and we always introduced 0.3% of H2O, an
arbitrary amount, which turned out to have no detrimental side-ef-
fect. It turned out that 2 mequiv of supported Pd and a slight excess of
boronic acid and base were necessary to get a 99% yield. Un-
fortunately, duringthe firstreuse ofcatalyst20a only a lower 75% yield
of 3a was obtained. We could therefore conclude that the presence of
important amounts of protic solvent was not the only factor pre-
venting reusability of the catalyst. Replacement of Cs2CO3 by CsF,
which is known to be a very efficient base in anhydrous media also
gave very good results during the first use (entries 5 and 6) and
moreover allowed an excellent reusability of the catalyst, which still
afforded a 98% yield in the seventh use (Table 5).
Cl
Toluene/H2O (0.3%)
reflux, 20 h
Entrya
Catalyst
Pd (mequiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
20a
20a
4
4
4
4
4
4
4
3
4
4
84
29
74
83
31
36
99
87
Pd EnCat TPP30
Pd EnCat NP30
No reactionc
No reactionc
10
a
Reactions performed with 1.0 equiv (0.65 mmol) of 4-chloroacetophenone,
1.4 equiv of phenylboronic acid, 1.5 equiv of CsF.
b
Yields were calculated by comparison of the 1H NMR integrations of the con-
stituents of crude reaction mixtures.
c
The starting materials were recovered unchanged.

768
S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
and Pd Encat NP30 catalysts were found to be totally inactive, 4-
chloroacetophenone being recovered unchanged (entries 9–10).
The catalysts of the first family developed in our laboratory, where
the polymer bears diarylphosphino groups, are only slightly ac-
tive: even in the presence of 20 mequiv of supported Pd, only
a low yield (19%) of 3a could be obtained.11b
acids. The reaction between 3-thiopheneboronic acid and 4-chloro-
acetophenone gave the expected biaryl 3r in 64% isolated yield,
whereas the cross-coupling of 2-chloropyridine and phenylboronic
acid afforded 2-phenylpyridine (3s) in 88% isolated yield.
3. Conclusions
A hot filtration test was then performed using catalyst 20a in
order to figure out if soluble Pd species are present in the reaction
medium: after 20 min of reaction (Table 6, entry 7), 20a was re-
moved by filtration (yield of 3a at that point:73%), and the filtrate
was refluxed for another 20 h after which the yield reached only
74%. This result proves the absence of any soluble catalytic entity.
Moreover, the amount of Pd present in the filtrate was less than 0.1%
of the initial amount. Finally, catalyst 20a was studied by trans-
mission electron microscopy (TEM), which showed only very scarce
Pd aggregates. Interestingly, many aggregates appeared in 20a very
quickly after the beginning of the reaction: they were already found
after only 20 min. Neither their size (up to ca. 15 nm) nor their
abundance changed significantly thereafter, even after seven uses.
The exact nature of the catalytic sites remains to be studied. The Pd
contents of the fresh catalyst and of the catalyst recovered after
seven uses were found to be identical within experimental error.
The cross-couplingof variousarylchloridesand arylboronic acids
were performed in the presence of catalyst 20a (Table 7) and very
good yields were obtained in the presence of either electron-rich or
electron-deficient substituents on each reactant. Noteworthily,
sterically crowded 2-substituted, 2,6-disubstituted and even 2,6,20-
trisubstituted biaryls could be prepared in good yields (entries 3,10–
12,16).1,4-Dichlorobenzene reacted with 1.1 equivof phenylboronic
acid to give the monosubstituted biaryl 3h in 66% yield (entry 8).
However, in the presence of 2.8 equiv of phenylboronic acid and
3.1 equiv of CsF, p-terphenyl was obtained in 86% yield.
Short and efficient syntheses of air- and moisture-stable, easy to
recover and reuse, polymer-supported Pd catalysts have been de-
veloped. In particular, the (tert-butylphenylphosphinomethyl)po-
lystyrene-supported Pd catalyst 20a was highly reactive for Suzuki
couplings of aryl chlorides. It can easily be reused more than seven
times without any loss of efficiency. Remarkably, less than 4 mequiv
of Pd are lost during this reaction. Therefore, the crude biaryls
obtained contain only a negligible amount of Pd contaminants,
which considerably simplifies their purification procedures.
Moreover, the environment-related preoccupation to preserve
scarce natural resources is fullfilled.
4. Experimental section
4.1. General remarks
The reagents were obtained from commercial sources and were
used without further purifications. Dichlorophenylphosphine, tert-
butyldichlorophosphine and di-tert-butylchlorophosphine were
purchased from Sigma–Aldrich. The Merrifield resin was purchased
fromPolymerLaboratories(PL-CMSResin, 0.86 mmol/g, 75–150 mm).
The Tentagel-Br and the bromopolystyrene resins were purchased
from Fluka. THF and cyclohexane were distilled from sodium/ben-
zophenone. The syntheses of chlorophosphines 1a–e, catalysts 2a–h
and 20a were performed in dry glassware under an atmosphere of
argon. Since aryl-tert-butylchlorophosphines 1a–e were air-, water-
and heat-sensitive (they are only stable for some hours at 0 ꢀC), they
were used directly and attempts to get analytical samples were, as
expected, unfruitful. Catalysts 2a–h and 20a were air- and moisture-
stable. The reaction mixtures were filtered on a polytetrafluor-
Finally, 20a can be successfully used for cross-couplings
involving heterocyclic aryl chlorides or heterocyclic arylboronic
Table 7
Syntheses of biaryls
ethylene Whatman membrane (0.2
were recorded using a 400 MHz instrument in CDCl3. Chemical shifts
are reported in parts per million ( ) downfield from TMS. Spin mul-
m
m). 1H- and 31P NMR spectra
R1
R2
d
B(OH)2
2'a (4 mequiv), CsF
R1
tiplicities are indicated by the following symbols: s (singlet), d (dou-
blet), t (triplet), and m (multiplet). The 1H NMR spectra of biaryls 3a–s
and the melting points of solid biaryls were in accordance with lit-
erature reports (see below). Elemental analyses were performed by
the Service Central d0Analyses du CNRS, Solaize (France).
+
Toluene/H2O (0.3%)
reflux, 20 h
Cl
R3
R2
R3
Entrya
R1
R2
R3
Product
Yieldb (%)
1
2
3
4
5
6
H
H
H
H
H
H
H
H
4-Ac
3-Ac
2-Ac
4-NO2
H
4-Me
4-OMe
4-Cl
3-Me
2-Me
2-Me
2-Me
4-Ac
4-Ac
4-Ac
4-Ac
4-Ac
H
H
H
H
H
H
H
H
H
H
6-Me
6-Me
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
90
78
90
86
98
86
72
66
79
82
88
61
93
69
90
86
78
4.2. Syntheses of the polymer-supported Pd catalysts
4.2.1. Synthesis of tert-butylchlorophenylphosphine (1a). Dichloro-
phenylphosphine (27.1 mL, 0.2 mol, 1.0 equiv) was added in small
portions to a mixture of a 1.5 M solution of tert-butyllithium in pen-
tane (160 mL, 0.24 mol, 1.2 equiv) and anhydrous cyclohexane
(700 mL) at ꢁ40 ꢀC under an atmosphere of argon. The reaction
mixture was successively stirred at ꢁ40 ꢀC for 1 h, warmed to rt for
20 h and centrifuged (3000 t/min for 3 min) under an atmosphere of
argon to remove the inorganic salts. The organic solvents were dis-
tilled off under an atmosphere of argon. The residue was dried under
vacuum (0.1 mbar) for 20 h. The resulting yellowish oil (34.9 g, 87%)
contained 1a(purity>90%)and nodichlorophenylphosphinewasleft.
7
8c
9
H
H
H
10
11
12
13
14d
15
16
17d
2-Me
4-OMe
3-NH2
4-Me
2-Me
3-NO2
1H NMR (400 MHz, CDCl3):
d
0.91 (d, 3J(H,P)¼13.6 Hz, 9H), 7.28 (m,
3H), 7.49 (m, 2H). 31P NMR (162 MHz, CDCl3):
d 109.5.
a
Reactions performed with 1.0 equiv (0.65 mmol) of aryl chloride, 1.4 equiv of
arylboronic acid, 1.5 equiv of CsF.
b
Isolated yields after flash chromatography of the crude reaction mixture on
4.2.2. General procedure for the syntheses of aryl-tert-butyl-
chlorophosphines 1b–e. A 1.5 M solution of tert-butyllithium in
pentane (12.6 mL, 18.9 mmol, 2.2 equiv) was added dropwise at
0 ꢀC to solutions of aryl bromides (9.46 mmol, 1.1 equiv) in
silica gel.
c
Reaction performed with 1.0 equiv (0.65 mmol) of 1,4-dichlorobenzene,
1.1 equiv of phenylboronic acid and 1.2 equiv of CsF in toluene/H2O.
d
Reactions performed in the presence of EtOH.

S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
769
anhydrous cyclohexane (20 mL) underan atmosphere of argon. The
resulting suspensions were then warmed to rt for 20 h. A solution
of tert-butyldichlorophosphine (1.37 g, 8.6 mmol, 1.0 equiv) in
anhydrous cyclohexane (20 mL) was then added dropwise at 0 ꢀC.
The resulting suspensions were stirred at 0 ꢀC for 15 min then
warmed to rt for 1 h. The reaction mixtures were centrifuged
(3000 t/min for 3 min) under an atmosphere of argon to remove
the inorganic salts. The organic solvents were distilled off under an
atmosphere of argon. The residues were dried under vacuum
(0.1 mbar) for 20 h. The resulting yellowish oils contained 1b–e
(purities>90%) and no tert-butyldichlorophosphine was left.
4.2.3.3. (tert-Butyl-[3-methylphenyl]phosphinomethyl)-poly-
styrene-supported Pd catalyst (2c). Yellow resin. Elemental analysis
(%): P, 1.90; Pd, 0.29.
4.2.3.4. (tert-Butyl-[4-methylphenyl]phosphinomethyl)-poly-
styrene-supported Pd catalyst (2d). Yellow resin. Elemental analysis
(%): P, 1.99; Pd, 0.31.
4.2.3.5. (tert-Butyl-[1-naphthyl]phosphinomethyl)polystyrene-
supported Pd catalyst (2e). Yellow resin. Elemental analysis (%): P,
0.93; Pd, 0.30.
4.2.2.1. tert-Butylchloro-(2-methylphenyl)phosphine (1b). 86% yield
4.2.4. Synthesis of (tert-butylphenylphosphinomethyl)-polystyrene-
supported Pd catalyst (20a). Lithium wires (3.6 g, 0.52 mol,
30 equiv) were added to a solution of 1a (0.17 mol, 10 equiv) in
anhydrous THF (400 mL) under an atmosphere of argon. The re-
action mixture was stirred at rt for 15 h. The resulting dark red
solution was added in small portions to a suspension of a Merrifield
resin (20 g, 17.2 mmol of Cl) in anhydrous THF (600 mL) under an
atmosphere of argon. The reaction mixture was stirred at rt for 72 h
then quenched by addition of a 2:1 mixture of acetone/H2O
(600 mL). This reaction mixture was stirred for 30 min, the white
resin was filtered under vacuum and washed with H2O (3ꢂ600 mL),
acetone (3ꢂ600 mL), CHCl3 (3ꢂ600 mL), toluene (3ꢂ600 mL), and
Et2O (3ꢂ600 mL). The resin was then refluxed in a 3:1 mixture of
EtOH/toluene (400 mL) for 20 h, then cooled to rt, filtered under
vacuum, washed successively with toluene (600 mL), Et2O
(600 mL) and finally dried under vacuum (0.1 mbar) for 20 h.
Pd(PPh3)4 (0.22 g, 0.19 mmol) was then added at rt to a suspension
of this resin (20 g) in anhydrous toluene (1 L) under an atmosphere
of argon. The reaction mixture was degassed with argon and stirred
at rt for 20 h. The resin 20a was filtered under vacuum and washed
successively with toluene (3ꢂ400 mL) and Et2O (3ꢂ400 mL). These
filtrates were combined and evaporated to dryness. The amount of
Pd was then determined after complete mineralization (see below)
(1.59 g). Yellowish oil. 1H NMR (400 MHz, CDCl3):
d 1.02 (d,
3J(H,P)¼13.6 Hz, 9H), 2.48 (s, 3H), 7.10 (m, 1H), 7.21 (m, 2H), 7.69 (m,
1H). 31P NMR (162 MHz, CDCl3):
d 102.1.
4.2.2.2. tert-Butylchloro-(3-methylphenyl)phosphine (1c). 87% yield
(1.61 g). Yellowish oil. 1H NMR (400 MHz, CDCl3):
d 0.95 (d,
3J(H,P)¼13.8 Hz, 9H), 2.30 (s, 3H), 7.14 (m, 1H), 7.21 (m, 1H), 7.33 (m,
2H). 31P NMR (162 MHz, CDCl3):
d 109.5.
4.2.2.3. tert-Butylchloro-(4-methylphenyl)phosphine (1d). 86% yield
(1.59 g). Yellowish oil. 1H NMR (400 MHz, CDCl3):
d 1.04 (d,
3J(H,P)¼13.6 Hz, 9H), 2.39 (s, 3H), 7.23 (d, 3J(H,H)¼8.0 Hz, 2H), 7.53 (d,
3J(H,H)¼3J(H,P)¼8.0 Hz, 2H). 31P NMR (162 MHz, CDCl3):
d 109.4.
4.2.2.4. tert-Butylchloro-(1-naphthyl)phosphine (1e). The same
procedure as above was followed on a small scale (2.37 mmol of 1-
bromonaphthalene). The residue was dried under vacuum (0.1 mbar)
for 20 h to give 480 mg (89%) of 1e as a yellowish oil (purity>90%, no
tert-butyldichlorophosphine was left). 1H NMR (400 MHz, CDCl3):
d
1.11 (d, 3J(H,P)¼13.8 Hz, 9H), 7.54 (m, 3H), 7.89 (m, 2H), 8.01 (m,1H),
8.59 (m, 1H). 31P NMR (162 MHz, CDCl3):
d 103.7.
4.2.3. General procedure for the syntheses of (aryl-tert-butylphos-
phinomethyl)polystyrene-supported Pd catalysts 2a–f. Lithium wires
(180 mg, 25.9 mmol, 30 equiv) were added to solutions of 1a–f
(8.60 mmol, 10 equiv) in anhydrous THF (20 mL) under an atmo-
sphere of argon. The reaction mixtures were stirred at rt for 15 h.
The resulting dark red solutions were added in small portions to
suspensions of a Merrifield resin (1.0 g, 0.86 mmol of Cl) in anhy-
drous THF (30 mL) under an atmosphere of argon. The reaction
mixtures were stirred at rt for 72 h then quenched by addition of
a 2:1 mixture of acetone/H2O (30 mL). These reaction mixtures
were stirred for 30 min, the white resins were filtered under vac-
uum and washed successively with H2O (3ꢂ30 mL), acetone
(3ꢂ30 mL), CHCl3 (3ꢂ30 mL), toluene (3ꢂ30 mL), and Et2O
(3ꢂ30 mL). The resins were then refluxed in a 3:1 mixture of EtOH/
toluene (20 mL) for 20 h, then cooled to rt, filtered under vacuum,
washed successively with toluene (30 mL), Et2O (30 mL) and finally
dried under vacuum (0.1 mbar) for 20 h. Pd(PPh3)4 (32.6 mg,
and found to be 13 mg (0.3%). The white resin was finally dried
under vacuum (0.1 mbar) for 20 h to give 20.9 g of 20a. Elemental
analysis (%): P, 1.57; Pd, 0.10.
4.2.5. Synthesis of (tert-butylphenylphosphino)polystyrene-sup-
ported Pd Catalyst 2g. Lithium wires (260 mg, 37.5 mmol, 30 equiv)
were added to a solution of 1a (2.51 g, 12.5 mmol, 10 equiv) in an-
hydrous THF (20 mL) under an atmosphere of argon. The reaction
mixture was stirred at rt for 15 h. The resulting dark red solution
was added in small portions to a suspension of a bromopolystyrene
resin (1.0 g, 1.25 mmol of Br) in anhydrous THF (20 mL) under an
atmosphere of argon. The reaction mixture was stirred at rt for 72 h
then quenched by addition of a 2:1 mixture of acetone/H2O
(30 mL). This reaction mixture was stirred for 30 min, the white
resin was filtered under vacuum and washed successively with H2O
(3ꢂ30 mL), acetone (3ꢂ30 mL), toluene (3ꢂ30 mL), and Et2O
(3ꢂ30 mL). The resin was then refluxed in a 3:1 mixture of EtOH/
toluene (20 mL) for 20 h, then cooled to rt, filtered under vacuum,
washed successively with toluene (30 mL), Et2O (30 mL) and finally
dried under vacuum (0.1 mbar) for 20 h. Pd(PPh3)4 (10.9 mg,
28.2 mmol) was then added in portions at rt to suspensions of these
resins (1.0 g) in anhydrous toluene (50 mL) under an atmosphere of
argon. The reaction mixtures were degassed with argon and stirred
at rt for 20 h. The resins 2a–f were filtered under vacuum and
washed with toluene (3ꢂ20 mL) and Et2O (3ꢂ20 mL). These resins
were finally dried under vacuum (0.1 mbar) for 20 h.
9.4 mmol) was then added in portions at rt to a suspension of this
resin (1.0 g) in anhydrous toluene (50 mL) under an atmosphere of
argon. The reaction mixture was degassed with argon and stirred at
rt for 20 h. The resin 2g was filtered under vacuum and washed
successively with toluene (3ꢂ20 mL) and Et2O (3ꢂ20 mL). The
resin was finally dried under vacuum (0.1 mbar) for 20 h to give
0.99 g of 2g. Elemental analysis (%): P, 0.93; Pd, 0.10.
4.2.3.1. (tert-Butylphenylphosphinomethyl)-polystyrene-sup-
ported Pd catalyst (2a). Yellow resin. Elemental analysis (%): P, 1.84;
Pd, 0.26.
4.2.3.2. (tert-Butyl-[2-methylphenyl]phosphinomethyl)-poly-
styrene-supported Pd catalyst (2b). Yellow resin. Elemental analysis
(%): P, 1.70; Pd, 0.30.
4.2.6. Synthesis of (tert-butylphenylphosphino)polystyrene-poly-
ethyleneoxide-supported Pd catalyst 2h. Lithium wires (100 mg,
14.4 mmol, 30 equiv) were added to a solution of 1a (960 mg,

770
S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
4.8 mmol, 10 equiv) in anhydrous THF (12 mL) under an atmo-
sphere of argon. The reaction mixture was stirred at rt for 15 h.
The resulting dark red solution was added in small portions to
a suspension of a Tentagel-Br resin (1.0 g, 0.48 mmol of Br) in
anhydrous THF (12 mL) under an atmosphere of argon. The re-
action mixture was stirred at rt for 72 h then quenched by addi-
tion of a 2:1 mixture of acetone/H2O (30 mL). This reaction
mixture was stirred for 30 min, the white resin was filtered under
vacuum and washed successively with H2O (3ꢂ30 mL), acetone
(3ꢂ30 mL), toluene (3ꢂ30 mL), and Et2O (3ꢂ30 mL). The resin was
then refluxed in a 3:1 mixture of EtOH/toluene (20 mL) for 20 h,
then cooled to rt, filtered under vacuum, washed successively with
toluene (30 mL), Et2O (30 mL) and finally dried under vacuum
4.3.1.6. 4-Methylbiphenyl (3f). Elution with Et2O/Cyclohexane
1:99 afforded 94 mg (86% yield) of a yellowish solid. Mp 47–48 ꢀC
(lit. mp 47.7 ꢀC).20 1H NMR (400 MHz, CDCl3)
d (ppm): 2.41 (s, 3H),
7.40 (m, 3H), 7.44 (t, 3J(H,H)¼7.6 Hz, 2H), 7.50 (d, 3J(H,H)¼8.4 Hz,
2H), 7.59 (d, 3J(H,H)¼8.4 Hz, 2H).
4.3.1.7. 4-Methoxybiphenyl (3g). Elution with AcOEt/Cyclohex-
ane 2:98 afforded 86 mg (72% yield) of a white solid. Mp 92–94 ꢀC
(lit. mp 91.1–92.3 ꢀC).21 1H NMR (400 MHz, CDCl3)
d (ppm): 3.87 (s,
3H), 6.99 (d, 3J(H,H)¼8.8 Hz, 2H), 7.31 (t, 3J(H,H)¼7.3 Hz, 1H), 7.42
(m, 2H), 7.55 (m, 4H).
4.3.1.8. 4-Chlorobiphenyl (3h). Elution with cyclohexane affor-
(0.1 mbar) for 20 h. Pd(PPh3)4 (10.9 mg, 9.4
mmol) was then added
ded 81 mg (66% yield) of a white solid. Mp 78–79 ꢀC (lit. mp 79–
in portions at rt to a suspension of this resin (1.0 g) in anhydrous
toluene (50 mL) under an atmosphere of argon. The reaction
mixture was degassed with argon and stirred at rt for 20 h. The
resin 2h was filtered under vacuum and washed successively with
toluene (3ꢂ20 mL) and Et2O (3ꢂ20 mL). The resin was finally
dried under vacuum (0.1 mbar) for 20 h to give 1.01 g of 2h. Ele-
mental analysis (%): P, 1.69; Pd, 0.10.
79.5 ꢀC).22 1H NMR (400 MHz, CDCl3)
4H).
d (ppm): 7.41 (m, 5H), 7.54 (m,
4.3.1.9. 3-Methylbiphenyl (3i). Elution with Et2O/Cyclohexane
1:99 afforded 86 mg (79% yield) of an orange oil. 1H NMR (400 MHz,
CDCl3)
d
(ppm):11b 2.46 (s, 3H), 7.20 (m, 1H), 7.39 (m, 6H), 7.62 (d,
3J(H,H)¼7.3 Hz, 2H).
4.3.1.10. 2-Methylbiphenyl (3j). Elution with Et2O/Cyclohexane
4.3. Syntheses of biaryls 3a–s
1:99 afforded 90 mg (82% yield) of a yellowish oil. 1H NMR
(400 MHz, CDCl3)
3H), 7.41 (m, 2H).
d
(ppm):11b 2.29 (s, 3H), 7.26 (m, 4H), 7.35 (m,
4.3.1. General procedure for the syntheses of biaryls 3a–g, 3i–m, 3o–
p and 3r–s. Catalyst 20a (277 mg, 4 mequiv of Pd) was added to
a solution of aryl chloride (0.65 mmol, 1.0 equiv), arylboronic acid
(0.91 mmol, 1.4 equiv), CsF (149 mg, 0.98 mmol, 1.5 equiv) in
a mixture of toluene (3.5 mL) and H2O (10
was degassed with argon and heated at reflux for 20 h. After cooling
to rt, 20a was filtered under vacuum on a 0.2
m membrane. The
catalyst was washed with AcOEt (3ꢂ10 mL). The combined organic
phase was washed with H2O (20 mL), dried over MgSO4, filtered
and concentrated under vacuum. The residue was purified by flash
chromatography on silica gel to afford pure biaryls after drying
under vacuum.
4.3.1.11. 2,6-Dimethylbiphenyl (3k). Elution with cyclohexane
afforded 104 mg (88% yield) of a yellowish oil. 1H NMR (400 MHz,
m
L). The reaction mixture
CDCl3) d
(ppm):23 2.05 (s, 6H), 7.14 (m, 5H), 7.35 (m,1H), 7.42 (m, 2H).
m
4.3.1.12. 2,6,20-Trimethylbiphenyl (3l). Elution with cyclohexane
afforded 78 mg (61% yield) of a colorless oil. 1H NMR (400 MHz,
CDCl3)
d
(ppm):23 1.96 (s, 6H), 1.98 (s, 3H), 7.17 (m, 7H).
4.3.1.13. 1-(4-(40-Methoxy)biphenylyl)ethanone
(3m). Elution
with AcOEt/Cyclohexane 10:90 afforded 137 mg (93% yield) of
a yellowish solid. Mp 152–153 ꢀC (lit. mp 153.5–155 ꢀC).24 1H NMR
4.3.1.1. 1-(4-Biphenylyl)ethanone (3a). Elution with AcOEt/Cy-
clohexane 10:90 afforded 115 mg (90% yield) of a white solid. Mp
123–124 ꢀC (lit. mp 122–123 ꢀC).17 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) d (ppm): 2.64 (s, 3H), 3.88 (s, 3H), 7.01 (d,
3J(H,H)¼8.8 Hz, 2H), 7.59 (d, 3J(H,H)¼8.8 Hz, 2H), 7.65 (d,
3J(H,H)¼8.3 Hz, 2H), 8.02 (d, 3J(H,H)¼8.3 Hz, 2H).
d
(ppm): 2.66 (s, 3H), 7.45 (m, 3H), 7.64 (d, 3J(H,H)¼7.0 Hz, 2H), 7.69
(d, 3J(H,H)¼6.7 Hz, 2H), 8.05 (d, 3J(H,H)¼6.7 Hz, 2H).
4.3.1.14. 1-(4-(40-Methyl)biphenylyl)ethanone (3o). Elution with
AcOEt/Cyclohexane 10:90 afforded 123 mg (90% yield) of a white
solid. Mp 122–123 ꢀC (lit. mp 121–121.4 ꢀC).25 1H NMR (400 MHz,
4.3.1.2. 1-(3-Biphenylyl)ethanone (3b). Elution with AcOEt/Cy-
clohexane 5:95 afforded 100 mg (78% yield) of a colorless oil. 1H
CDCl3)
d
(ppm): 2.42 (s, 3H), 2.65 (s, 3H), 7.29 (d, 3J(H,H)¼8.1 Hz,
NMR (400 MHz, CDCl3)
d
(ppm):11b 2.67 (s, 3H), 7.31 (t,
2H), 7.54 (d, 3J(H,H)¼8.1 Hz, 2H), 7.68 (d, 3J(H,H)¼8.3 Hz, 2H), 8.03
(d, 3J(H,H)¼8.3 Hz, 2H).
3J(H,H)¼7.6 Hz, 1H), 7.39 (t, 3J(H,H)¼7.6 Hz, 2H), 7.46 (t,
3J(H,H)¼7.4 Hz, 1H), 7.54 (d, 3J(H,H)¼7.6 Hz, 2H), 7.70 (d,
3J(H,H)¼7.4 Hz, 2H, 1H), 7.85 (d, 3J(H,H)¼7.4 Hz, 1H), 8.1 (s, 1H).
4.3.1.15. 1-(4-(20-Methyl)biphenylyl)ethanone (3p). Elution with
AcOEt/Cyclohexane 10:90 afforded 118 mg (86% yield) of a yellow-
4.3.1.3. 1-(2-Biphenylyl)ethanone (3c). Elution with AcOEt/Cy-
ish oil. 1H NMR (400 MHz, CDCl3) (ppm):11b 2.28 (s, 3H), 2.66 (s,
d
clohexane 5:95 afforded 115 mg (90% yield) of a colorless oil. 1H
3H), 7.28 (m, 4H), 7.44 (d, 3J(H,H)¼8.5 Hz, 2H), 8.02 (d,
NMR (400 MHz, CDCl3)
(m, 2H).
d
(ppm):11b 2.01 (s, 3H), 7.41 (m, 7H), 7.54
3J(H,H)¼8.5 Hz, 2H).
4.3.1.16. 4-(3-Thienyl)-acetophenone (3r). Elution with AcOEt/
4.3.1.4. 4-Nitrobiphenyl (3d). Elution with AcOEt/Cyclohexane
Cyclohexane 10:90 afforded 84 mg (64% yield) of a white solid. Mp
1:99 afforded 111 mg (86% yield) of a yellowish solid. Mp 114–
150–151 ꢀC (lit. mp 149–150).26 1H NMR (400 MHz, CDCl3)
d (ppm):
115 ꢀC (lit. mp 113–115 ꢀC).18 1H NMR (400 MHz, CDCl3)
d
(ppm):
2.64 (s, 3H), 7.45 (m, 2H), 7.59 (m, 1H), 7.70 (d, 3J(H,H)¼8.5 Hz, 2H),
7.49 (m, 3H), 7.64 (d, 3J(H,H)¼7.1 Hz, 2H), 7.75 (d, 3J(H,H)¼7.1 Hz,
8.00 (d, 3J(H,H)¼8.5 Hz, 2H).
2H), 8.31 (d, 3J(H,H)¼7.1 Hz, 2H).
4.3.1.17. 2-Phenylpyridine (3s). Elution with AcOEt/Cyclohex-
4.3.1.5. Biphenyl (3e). Elution with AcOEt/Cyclohexane 1:99
ane 2:98 afforded 89 mg (88% yield) of a colorless oil. 1H NMR
afforded 98 mg (98% yield) of a white solid. Mp 71–72 ꢀC (lit. mp
(400 MHz, CDCl3) d
(ppm):27 7.25 (m, 1H), 7.43 (m, 3H), 7.75
71 ꢀC).19 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.41 (m, 6H), 7.61 (d,
(m, 2H), 8.00 (d, 3J(H,H)¼8.6 Hz, 2H), 8.71 (d, 3J(H,H)¼4.8 Hz,
3J(H,H)¼7.3 Hz, 4H).
1H).

S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
771
4.3.2. General procedure for the syntheses of biaryls (3n) and
References and notes
(3q). Catalyst 20a (277 mg, 4 mequiv of Pd) was added to a solution
of aryl chloride (0.65 mmol,1.0 equiv), arylboronic acid (0.91 mmol,
1.4 equiv), CsF (149 mg, 0.98 mmol, 1.5 equiv) in a mixture of tol-
1. (a) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 1998; (b) Tsuji, J. Palladium Reagents and Catalysts: New Per-
spectives for the 21st Century; John Wiley: New York, NY, 2004.
uene (3.5 mL), EtOH (0.25 mL), and H2O (10
mixture was degassed with argon and heated at reflux for 20 h.
After cooling to rt, 20a was filtered under vacuum on a 0.2
m
L). The reaction
2. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36, 3437;
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (c) Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633; (d) Hassan, J.; Se´vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
m
m
membrane. The catalyst was washed with AcOEt (3ꢂ10 mL). The
organic phase was washed with H2O (20 mL), dried over MgSO4,
filtered and then concentrated under vacuum. The residue was
purified by flash chromatography on silica gel to afford pure biaryls
after drying under vacuum.
3. Other powerful transition metal-catalyzed synthetic methods for the prepa-
ration of biaryls are available. (a) For Cu-catalyzed cross-coupling reactions see:
Fanta, P. E. Synthesis 1974, 9; (b) For Ni-catalyzed cross-coupling reactions see:
Lee, C.-C.; Ke, W.-C.; Chan, K. T.; Lai, C.-L.; Hu, C.-H.; Lee, H. M. Chem.dEur. J.
2007, 13, 582 and references therein; (c) For C–H activation reactions see: Al-
berico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (d) For de-
carboxylative Pd-catalyzed reactions see: Becht, J.-M.; Catala, C.; Le Drian, C.;
Wagner, A. Org. Lett. 2007, 9, 1781 and references therein; (e) Becht, J.-M.; Le
Drian, C. Org. Lett. 2008, 10, 3161.
4. (a) Lloyd-Williams, P.; Giralt, E. Chem. Soc. Rev. 2001, 30, 145 and references
therein; (b) Pu, L. Chem. Rev. 1998, 98, 2405 and references therein.
5. (a) De Vos, D. E.; Dams, M.; Sels, B. F.; Jacobs, P. A. Chem. Rev. 2002, 102, 3615;
(b) Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2002, 124, 14127; (c) Mori, K.; Yamaguchi, T.; Hara, T.; Mizukagi, T.;
Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2002, 124, 11572; (d) Bulut, H.; Artok, L.;
Yilmaz, S. Tetrahedron Lett. 2003, 44, 289; (e) Shimizu, K. I.; Kan-no, T.; Kodama,
T.; Hagiwara, H.; Kitayama, Y. Tetrahedron Lett. 2002, 43, 5653; (f) Baleizao, C.;
Corma, A.; Garcia, H.; Leyva, A. Chem. Commun. 2003, 606; (g) Sayah, R.; Gle-
gola, K.; Framery, E.; Dufaud, V. Adv. Synth. Catal. 2007, 349, 373; (h) Trilla, M.;
Pleixats, R.; Wong Chi Man, M.; Bied, C.; Moreau, J. J. E. Adv. Synth. Catal. 2008,
350, 577.
4.3.2.1. (1-(30-Amino)biphenylyl)ethanone (3n). Elution with
AcOEt/Cyclohexane 10:90 afforded 95 mg (69% yield) of an orange
solid. Mp 162–163 ꢀC (lit. mp 160–161 ꢀC).27 1H NMR (400 MHz,
CDCl3)
d
(ppm): 2.97 (s, 3H), 4.13 (br s, 2H), 7.06 (d, 3J(H,H)¼8.1 Hz,
1H), 7.35 (d, 3J(H,H)¼7.6 Hz, 1H), 7.60 (m, 2H), 7.99 (d,
3J(H,H)¼7.9 Hz, 2H), 8.34 (d, 3J(H,H)¼7.9 Hz, 2H).11b
4.3.2.2. (1-(30-Nitro)biphenylyl)ethanone (3q). Elution with
AcOEt/Cyclohexane 10:90 afforded 122 mg (78% yield) of a yellow-
ish solid. Mp 110–111 ꢀC (lit. mp 110.5–111 ꢀC).28 1H NMR
(400 MHz, CDCl3)
d
(ppm): 2.68 (s, 3H), 7.67 (t, 3J(H,H)¼8.0 Hz, 1H),
6. (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217; (b) McNamara, C. A.;
Dixon, M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275; (c) Dickerson, T. J.; Reed, N.
N.; Janda, K. D. Chem. Rev. 2002, 102, 3325; (d) Bergbreiter, D. E. Chem. Rev.
2002, 102, 3345; Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815.
7. (a) Ramarao, C.; Ley, S. V.; Smith, S. C.; Shirley, I. M.; DeAlmeida, N. Chem.
Commun. 2002, 1132; (b) Ley, S. V.; Ramarao, C.; Gordon, R. S.; Holmes, A. B.;
Morrison, A. J.; McConvey, I. F.; Shirley, I. M.; Smith, S. C.; Smith, M. D. Chem.
7.74 (d, 3J(H,H)¼8.2 Hz, 2H), 7.96 (d, 3J(H,H)¼8.0 Hz, 1H), 8.09 (d,
3J(H,H)¼8.2 Hz, 2H), 8.27 (d, 3J(H,H)¼8.0 Hz, 1H), 8.50 (s, 1H).
4.4. General procedure for hot filtration and determination of
the Pd leached in the reaction medium during the Suzuki
reaction
´
´
Commun. 2002, 1134; (c) Trzeciak, A. M.; Mieczynska, E.; Ziolkowski, W.;
Bukowska, A.; Noworo´l, J.; Okal, J. New J. Chem. 2008, 32, 1124.
8. (a) Akiyama, R.; Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3412; (b) Okamoto, K.;
Akiyama, R.; Kobayashi, S. Org. Lett. 2004, 6, 1987; (c) Nishio, R.; Sugiura, M.;
Kobayashi, S. Org. Lett. 2005, 7, 4831; (d) Hagio, H.; Sugiura, M.; Kobayashi, S.
Org. Lett. 2006, 8, 375; (e) Akiyama, R.; Kobayashi, S. Chem. Rev. 2009, 109, 594.
9. (a) Kim, J.-H.; Kim, J.-W.; Shokouhimehr, M.; Lee, Y.-S. J. Org. Chem. 2005, 70,
6714; (b) Byun, J.-W.; Lee, Y.-S. Tetrahedron Lett. 2004, 45, 1837; (c) Shokouhi-
mehr, M.; Kim, J.-H.; Lee, Y.-S. Synlett 2006, 4, 618.
The reaction mixture was filtered at reaction temperature on
a
0.2 mm membrane and the catalyst washed with AcOEt
(3ꢂ10 mL). For Pd determinations, the filtrates were combined and
evaporated under reduced pressure. A mixture of concentrated
H2SO4 (3 mL) and fuming HNO3 (2 mL) was added to the residue.
This mixture was heated in a fume hood until disappearance of
nitric fumes, complete evaporation of HNO3 and beginning of the
reflux of the remaining H2SO4. After cooling to 100 ꢀC, fuming
HNO3 (2 mL) was then added, the mixture was heated until evap-
oration of HNO3 and this process was repeated three times, the
heating of the sample in acids during, as a whole, 25 min. Most of
the H2SO4 was then boiled off and after cooling a mixture of con-
centrated HCl (2 mL) and concentrated HNO3 (2 mL) was added and
heated until evaporation of the acids. The residue was then dis-
solved in H2O (25 mL) and the amount of Pd present in this mixture
was then determined by complexation following a procedure de-
scribed in the lit.29 or by ICP-MS.
10. (a) Andersson, C.-M.; Karabelas, K.; Hallberg, A. J. Org. Chem. 1985, 50, 3891; (b)
´
´
Riegel, N.; Darcel, C.; Stephan, O.; Juge, S. J. Organomet. Chem. 1998, 567, 219; (c)
Uozomi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384; (d) Dahan, A.;
Portnoy, M. Org. Lett. 2003, 5, 1197; (e) Uozomi, Y.; Kimura, T. Synlett 2002,
2045; (f) Yamada, Y. M.; Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem. 2003,
68, 7733; (g) Kang, T.; Feng, Q.; Luo, M. Synlett 2005, 15, 2305; (h) Guino´, M.;
Hii, K. K. Chem. Soc. Rev. 2007, 36, 608; (i) Lombardo, M.; Chiarucci, M.;
Trombini, C. Green Chem. 2009, 11, 574.
11. (a) Fenger, I.; Le Drian, C. Tetrahedron Lett. 1998, 39, 4287; (b) Schweizer, S.;
Becht, J.-M.; Le Drian, C. Adv. Synth. Catal. 2007, 349, 1150; (c) Schweizer, S.;
Becht, J.-M.; Le Drian, C. Org. Lett. 2007, 9, 3777.
12. (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1871; (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685; (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1998, 37, 3387; (d) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed.
2000, 39, 4153; (e) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804; (f) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc. 2003,
125, 16194; (g) Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444; (h)
Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731; (i) Botella, L.; Na´jera, C. Angew.
Chem., Int. Ed. 2002, 41, 179; (j) Dai, Q.; Gao, W.; Liu, D.; Kapes, L. M.; Zhang, X.
J. Org. Chem. 2006, 71, 3928; (k) Wu¨rtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41,
1523.
4.5. General procedure for the determination of the Pd
content of the catalyst
13. (a) Inada, K.; Miyaura, N. Tetrahedron 2000, 56, 8661; (b) Parrish, C. A.; Buch-
wald, S. L. J. Org. Chem. 2001, 66, 3820; (c) Glegola, K.; Framery, E.; Pie-
trusiewicz, K. M.; Sinou, D. Adv. Synth. Catal. 2006, 348, 1728; (d) Bedford, R. B.;
Coles, S. J.; Hursthouse, M. B.; Scordia, V. J. M. Dalton Trans. 2005, 991; (e)
Sommer, W. J.; Weck, M. Adv. Synth. Catal. 2006, 348, 2101; (f) Leyva, A.; Garcı´a,
H.; Corma, A. Tetrahedron 2007, 63, 7097; (g) Colacot, T. J.; Carole, W. A.; Neide,
B. A.; Harad, A. Organometallics 2008, 27, 5605.
The same procedure as above was used using a 20 mg sample of
catalyst instead of the reaction residue. Three independent exper-
iments were performed and the average value retained.
14. Schweizer, S.; Becht, J.-M.; Le Drian, C. Fr. Patent FR2,914,867, Application Nr.
2007-54500, April/16/2007; PCT Extension FR2008/050639, April/11/2008
(University of Haute Alsace/CNRS).
Acknowledgements
15. Noteworthily when sec- or n-butyllithium was reacted with dichloro-
phenylphosphine by using the same reaction conditions than for the prepa-
ration of 1a, only complex mixtures were obtained. Several attempts were then
carried out in order to prepare sec- or n-butylchlorophenylphosphine by
changing the nature of the solvent (Et2O, THF), the temperature of the reaction
(ꢁ78 ꢀC in Et2O or THF), replacing the alkyllithium reagents with the corre-
sponding Grignard reagents, but all were unsuccessful.
`
´
We thank the Ministere de l’Enseignement Superieur et de la
Recherche for financial support of this work through a grant to S.
Schweizer. We are also grateful to the Centre National de la
Recherche Scientifique for financial support, to Dr. D. Le Noue¨n
(FRE-CNRS 3253) for NMR spectra and to Dr. L. Vidal (LRC-CNRS
7228) for TEM images.

772
S. Schweizer et al. / Tetrahedron 66 (2010) 765–772
16. Attempts to store the chlorophosphines several days under an atmosphere of
argon at low temperature were unsuccessful.
17. Fieser, L. F.; Berliner, E.; Bondhus, F. J.; Chang, F. C.; Dauben, W. G.; Ettlinger, M.
G.; Fawaz, G.; Fields, M.; Heidelberger, C.; Heymann, H.; Vaughan, W. R.; Wilson,
A. G.; Wilson, E.; Wu, M.-i.; Leffler, M. T.; Hamlin, K. E.; Moore, E. E.; Moore, M.
B.; Zaugg, H. E. J. Am. Chem. Soc. 1948, 70, 3177.
22. Eliel, E. L.; Daignault, R. A. J. Org. Chem. 1965, 30, 2450.
23. Terao, Y.; Wakui, H.; Nomoto, N.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem.
2003, 68, 5236.
24. Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729.
25. Berliner, E.; Liu, L. H. J. Org. Chem. 1953, 75, 2417.
26. Dawood, K. M.; Kirschning, A. Tetrahedron 2005, 61, 12121.
27. Mowery, M. E.; De-Shong, P. J. Org. Chem. 1999, 64, 3266.
28. Bradsher, C. K.; Brown, F. C.; Porter, H. K. J. Am. Chem. Soc. 1954, 76, 2357.
29. Kasahara, I.; Tachi, I.; Tsuda, E.; Hata, N.; Taguchi, S.; Goto, K. Analyst 1989, 114,
1479.
18. Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
19. Berlman, I. B.; Wirth, H. O.; Steingraber, O. J. J. Am. Chem. Soc. 1968, 90, 566.
20. Gomberg, M.; Pernet, J. C. J. Am. Chem. Soc. 1926, 48, 1372.
21. Shi, M.; Qian, H.-x. Tetrahedron 2005, 21, 4949.