Suzuki cross-coupling reactions of aryl halides in phosphonium salt ionic liquidunder mild conditions

Article abstract of DOI:10.1039/b204699g

The Suzuki cross-coupling of aryl boronic acids with aryl halides, including aryl chlorides, proceeds in the phosphonium salt ionic liquid tetradecyltrihexylphosphonium chloride under mild conditions.

Full text of DOI:10.1039/b204699g

Suzuki cross-coupling reactions of aryl halides in phosphonium salt ionic
liquid under mild conditions
a
a
a
a
a
b
James McNulty,* Alfredo Capretta, Jeff Wilson, Jeff Dyck, George Adjabeng and Al Robertson
a
Institute of Molecular Catalysis, Department of Chemistry, Brock University, St. Catharines, Ontario L2S
A1, Canada. E-mail: jmcnulty@chemiris.labs.brocku.ca; Fax: +1 905 682 9020; Tel: +1 905 688 5550
3
ext. 3405
b
Cytec Canada Inc, PO Box 240, Niagara Falls, Ontario L2E 6T4, Canada.
E-mail: Al_Robertson@WE.cytec.com; Fax: +1 905 374 5879; Tel: +1 905 356 9000
Received (in Cambridge, UK) 15th May 2002, Accepted 18th July 2002
First published as an Advance Article on the web 7th August 2002
The Suzuki cross-coupling of aryl boronic acids with aryl
halides, including aryl chlorides, proceeds in the phosphon-
ium salt ionic liquid tetradecyltrihexylphosphonium chlo-
ride under mild conditions.
As can be seen from Table 1 (entries 1–9), the cross-coupling
reaction of variously substituted iodobenzenes including elec-
tron rich derivatives (Table 1, entry 7) with a variety of
arylboronic acids proceeded efficiently in THPC and were all
complete within 1 h at 50 °C. The reaction was chemoselective
in the case of the mixed halide 4-chloroiodobenzene (Table 1,
entry 9). The corresponding aryl bromides (Table 1, entries
11–13) also reacted under these conditions but proved to be
somewhat more sluggish. We found that the addition of a
catalytic amount of triphenylphosphine allowed for complete
conversion and high isolated yields even for the electron rich
substrates such as 4-methoxybromobenzene (Table 1, entries 12
and 13). As expected, reactions involving aryl chlorides were
considerably slower, however addition of triphenylphosphine
and heating at 70 °C allowed high conversion of 4-chlor-
oacetophenone (Table 1, entries 14 and 15). The electron rich
4-methoxychlorobenzene was still slow to react under these
conditions (Table 1, entry 16).
1
The Suzuki cross-coupling reaction has become a standard
2
method for carbon–carbon bond formation between an sp or
non-b-hydride containing electrophile and a boronic acid
derivative. Recent application of the reaction to aliphatic
electrophiles2 has expanded its scope considerably. Much
recent effort has gone into devising new ligands for this
palladium mediated process and various electron rich alkyl
3
4
phosphines and mixed aryl/alkyl phosphine ligands have been
described. Systems allowing for couplings of aryl chlorides are
especially sought after due, in part, to the lower cost and ready
availability of these substrates and a number of catalysts have
recently been developed which promote their Suzuki coupling
with boronic acid nucleophiles.5
,6
Catalyst expense coupled with the non-recyclability of the
expended catalyst have been shown to be major drawbacks of
these palladium-mediated processes. One solution involves the
application of ionic liquids as solvent. Ionic liquids based on
alkylimidazolium and other quaternary ammonium/pyridinium
salts have emerged as valuable, alternative “green” solvents for
Addition of water and hexane to the reaction products in the
phosphonium salt ionic liquid results in the formation of a
triphasic system that differs from that reported for the
imidazolium salts.11 In the case of imidazolium salts, the ionic
liquid is more dense than water and forms the bottom phase with
an aqueous central phase and organic layer on top. In the case of
THPC, the palladium catalyst remains fully dissolved in the
central phosphonium salt layer while the product biaryls are
extracted into the top hexane phase and inorganic salts
(phosphates/borates) into the lower aqueous phase.
7–10
catalytic processes over the last few years.
Using ionic
liquids, it is often possible to recycle the active palladium
catalyst subsequent to extraction of the organic product and
inorganic salts from the ionic liquid, which form a tri-phasic
system with water and a non-polar organic solvent. This process
has been applied efficiently to the palladium mediated Heck
coupling reaction in quaternary nitrogen ionic liquids11 and can
The reaction of phenylboronic acid with iodobenzene has
been investigated extensively under our conditions in THPC.
The yield obtained from hexane extraction and silica-gel
be conducted at room temperature with the application of
ultrasound.12 The Suzuki reaction has also been carried out
Table 1 Pd mediated Suzuki cross-coupling of aryl halides and boronic
acids in THPC
13
successfully in imidazolium ionic liquids both thermally and
with sonication.14 Quaternary phosphonium salts are another
class of readily available ionic liquid which have received scant
attention in the literature. In one case, hexadecyltributylphos-
phonium bromide was used to effect Heck coupling of aryl
halides with acrylic esters,15 although the reaction was not
efficient with aryl chlorides. We report herein on the use of the
room temperature ionic liquid tetradecyltrihexylphosphonium
chloride (THPC) containing small amounts of water and toluene
Isolated
Temp./
°C
yield
Time/h (%)
Entry
X
R
RA
Ligand
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
I
H
Ac
Ac
Ac
Ac
Ac
OMe
Me
Cl
Ac
Ac
OMe
OMe
Ac
H
H
None
None
None
50
50
50
50
50
50
50
50
50
50
50
50
50
70
70
70
1
1
1
1
1
1
1
1
1
1
1
3
3
30
30
30
95
100
97
97
100
99
86
92
90
99
98
99
95
84
76
17
(
single phase) as an efficient reusable media for the palladium
2-Me
2-Napthyl None
catalyzed Suzuki cross-coupling reaction.
The cross-coupling reactions were found to proceed in THPC
2-OMe
4-OMe
4-OMe
4-OMe
4-OMe
H
4-OMe
H
4-OMe
H
None
None
None
None
None
i
using various bases (Et
3
N, Pr
2
NEt, etc) but most efficiently
when potassium phosphate and water (added for salt solubility)
were employed. In order to maintain complete solubility of both
the boronic acid and aryl halide in the ionic liquid, a small
amount of toluene was added also. All of the reactions reported
in Table 1 were therefore performed in an identical media
I
10
11
Br
Br
Br
Br
Cl
Cl
Cl
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
1
1
1
1
1
2
3
4
5
6
(
H
THPC, aryl halide, aryl boronic acid, Pd
2 3 3 4
(dba) (1%), K PO ,
2
O, toluene) with the addition of triphenylphosphine in certain
cases as noted.† In many instances, the product biaryl
crystallizes from the reaction media as the cross-coupling
proceeds.
Ac
OMe
4-OMe
4-OMe
1
986
CHEM. COMMUN., 2002, 1986–1987
This journal is © The Royal Society of Chemistry 2002

chromatography of the hexane solubles ranged from 82–97%
over several runs. On the other hand, direct filtration of the ionic
liquid through a short silica-gel column gave slightly higher
isolated yields, 95–97%. These results indicate that residual
biaryls are still slightly soluble in THPC. The former procedure
was more applicable towards the development of a catalyst
recycling protocol since chromatography or filtration through
silica would make re-use of the catalyst difficult. Thus,
following Method A,† when further quantities of iodobenzene,
imidazolium salt protocol and Dr Dean Toste for advice on the
preparation of the Pd catalyst precursors.
Notes and references
†
Samples of THPC (trade name Cyphos 3653) can be obtained by
contacting Cytec at the address given. A representative procedure for the
Suzuki cross-coupling is as follows. THPC (1.0 mL) was degassed in a dry
round bottom flask by pumping under reduced pressure (0.5 mm Hg) for 10
min and then filled with argon. Iodobenzene (0.5 mmol, 1.0 equiv.) and
3 4
phenylboronic acid and K PO , but no further catalyst, was
Pd
heated briefly using a heat gun to effect an orange solution. After cooling to
room temperature K PO (1.65 mmol, 3.3 equiv.), phenylboronic acid (0.55
2 3 3
(dba) ·CHCl (0.005 mmol, 0.01 equiv.) were added and the mixture
added to the isolated central ionic liquid, heating again at 50 °C
resulted in complete turnover of iodobenzene. Repetition of the
work-up Method A gave biphenyl in 82–97% yield (repeated
five times) for both the initial and recycled reaction sequences.
Thus it is clear that a competent palladium catalyst remains fully
dissolved in the phosphonium salt allowing its efficient re-
use.
3
4
mmol, 1.1 equiv.) distilled water (0.2 mL) and toluene (0.1 mL) were added.
When triphenylphosphine (0.01 mmol, 0.02 equiv.) was used (see Table 1)
it was added as a solution in the added toluene. The solution so obtained was
heated under argon at the temperature and for the duration indicated in Table
1. The product biaryls can be isolated by using either of two methods.
Method A : Addition of water (5.0 mL) and hexane (15 mL) followed by
vigorous shaking and settling for 0.5–1 h. The top hexanes layer was
removed and concentrated followed by purification of the biaryl on silica
gel. The bottom aqueous phase was removed and discarded leaving the
central ionic liquid-catalyst. Use of this method allowed for most efficient
catalyst recyclability. The ionic liquid was recharged with phenylboronic
The Suzuki cross-coupling reaction recently reported in
imidazolium based ionic liquids requires ultrasonic irradiation
to proceed at 30 °C.14 In addition, inactive Pd black is deposited
during the reaction resulting in lower conversions (82–92%)
with aryl iodides and bromides and particularly so in the case of
electron deficient aryl chlorides (42–65%). Even when pre-
formed Pd–biscarbene catalyst is used in this system, conver-
sion of electron deficient aryl chlorides is low to moderate
3 4
acid, iodobenzene and K PO and reheated as indicated in Table 1. Isolated
yields ranged from 82–97% for both reactions with no difference being
noted in the subsequent reaction. In contrast to the above procedure,
exhaustive or continuous extraction (24 h) of the ionic liquid with hexanes
results in removal of the catalyst and ionic liquid indicating that both active
catalyst and THPC are slightly soluble in hexane.
Method B: In order to determine the isolated yield of the biaryls reported
in Table 1 after one run only, the ionic liquid crude reaction mixture was
filtered through a silica gel plug, washed with hexanes/ethylacetate
followed by silica gel chromatography of the filtrate. Yields reported in
Table 1 are based on isolated mass of the pure biaryls so obtained.
(
39–66%).14 The thermal Suzuki coupling reaction in these
imidazolium based ionic liquids does not proceed with aryl
chlorides, even at 110 °C.13 In contrast to these results,
complete conversion of aryl iodides and bromides and high
conversions with electron deficient chlorides can be achieved in
the THPC ionic liquid without the use of a preformed catalyst at
50–70 °C. The rapid coupling of aryl iodides and bromides and
high conversions obtained with the aryl chlorides indicate that a
very active catalyst is produced in the THPC system. In
addition, the higher conversions and recyclability of this Pd
THPC–catalyst system indicate the relatively high stability of
the active Pd catalyst involved in the Suzuki coupling. Lastly,
no homo-coupled products have been observed using the THPC
catalyst system reported here.
The phosphonium salt ionic liquid THPC is available in litre
quantities and holds a great deal of potential as an economical,
recyclable media for metal promoted reactions and process
chemistry in general and as we have shown here the Suzuki
cross-coupling reaction in particular. Further analysis of the
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active Pd-catalytic species formed by dissolution of Pd
2
(dba)
3
1
1
1
1
in the phosphonium salt ionic liquid and applications of the
process to other coupling partners are currently under investiga-
tion in our laboratories.
We thank Materials and Manufacturing Ontario (Interact
Awards to J. McN. and A. C.) and the Natural Sciences and
Engineering Research Council of Canada (Collaborative Re-
search and Development Award) for financial support. We
thank Dr Tom Welton for valuable discussions on the
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CHEM. COMMUN., 2002, 1986–1987
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