Pd nanoparticle catalysed one-pot sequential Heck and Suzuki couplings of bromo-chloroarenes in ionic liquids and water

Article abstract of DOI:10.1039/c1ob06385e

Pd nanoparticles generated in green reaction media (viz. ionic liquids and water) catalyze the one-pot sequential Heck and Suzuki coupling reactions of bromo-chloroarenes to afford unsymmetrically substituted arenes in good yields.

Full text of DOI:10.1039/c1ob06385e

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PAPER
Pd nanoparticle catalysed one-pot sequential Heck and Suzuki couplings of
bromo-chloroarenes in ionic liquids and water†‡
Pietro Cotugno,a Antonio Monopoli,*a Francesco Ciminale,a Nicola Cioffia and Angelo Nacci*a,b
Received 26th May 2011, Accepted 18th October 2011
DOI: 10.1039/c1ob06385e
Pd nanoparticles generated in green reaction media (viz. ionic liquids and water) catalyze the one-pot
sequential Heck and Suzuki coupling reactions of bromo-chloroarenes to afford unsymmetrically
substituted arenes in good yields.
have to be used.15 Thus, a very attractive and efficient variant
Introduction
would be the one-pot double coupling of commercially available
In the last few decades palladium chemistry has emerged as one
and inexpensive dihaloarenes, with two consecutive couplings
of the most powerful tools for the formation of carbon-carbon
performed in the same reaction flask and in the presence of a
and carbon-heteroatom bonds. The Pd-catalysed cross-coupling
single metal catalyst. So far, only a few successful examples have
strategy has gained considerable attention as a straightforward
been reported.6,7b,9b,10,11
method for C(sp2)–C(sp2) bond formation,1 which opened the
To ensure that such a process occurs successfully, the catalyst
access to highly conjugated systems such as polyenes, aryl
must be highly efficient and chemoselective toward the first
polyenes, and polyaryls, that are a common structural motif in
coupling and still maintain its catalytic activity in the subsequent
many natural products2 and have multiple potential applications
as advanced electronic and photonic materials.3
In pursuing this objective, several authors have been attracted
coupling. Of course, the selective displacement of the halogens
on a dihaloarene becomes crucial to achieve synthetic utility. In
principle, in cases where the halogens are different, the observed
by the sequential multiple couplings strategy involving the well-
selectivity is related to the relative bond dissociation energies of
known Heck, Suzuki, Stille, Negishi, Hiyama etc. reactions,
because these processes are usually high-yielding, stereoselective
and tolerant towards a wide array of functional groups. This
the respective carbon-halogen bonds, the reactivity following the
trend C–I > C–Br > C–Cl. The situation is more complicated in
the case of cross-coupling reactions of substrates bearing multiple
approach has been successful applied for preparing products of
identical halogens.
practical importance such as N,N-diarylaminostilbenes,4 arylated
There are only a handful of reports of such reactions on
heterocycles,5 multisubstituted olefins6 and dienes.7
polyhaloaromatics,8–12 and in most of them the more reactive
Aryl and heteroaryl dihalides have been the privileged substrates
iodo/bromoarenes are usually preferred as substrates, while the
due to their lower cost and wider availability, and a number of
cheaper and challenging bromo-chloroarenes are unexploited,
applications have been reported concerning the synthesis of un-
with few exceptions,8 due to the hard activation of the C–Cl
symmetric terphenyls,8 (tris)-heteroaryls,9 disubstituted arenes,10
bond, and this represents a severe limitation from the synthetic
pyridines,11 and pyrroles.12 To achieve high regioselectivity, di-
standpoint.
haloarene equivalents like for example bromobenzenesulfonates13
Recent reports from these laboratories16 have demonstrated that
and bromoarenediazonium tetrafluoroborate14 have also been
explored.
However, in many cases the sequential coupling approach can
Pd colloids can promote the C–Cl bond activation of Heck-,
Suzuki-, Stille- and Ullmann-type couplings carried out in
tetraalkylammonium ionic liquids (ILs) under aerobic, ligand-
be very tedious and often suffers several disadvantages: two
free, and relatively mild conditions. The high surface-to-volume
different catalysts might be required, the intermediate product
ratio and thus the very active superficial atoms of metal nanopar-
needs to be isolated, or expensive and not easily available substrates
ticles, together with the coordination ability of IL anions, enabled
our catalyst system to promote the Heck coupling between
aDepartment of Chemistry, Universita` degli Studi di Bari Aldo Moro, Via
deactivated electron-rich aryl chlorides and a wide array of
Orabona 4, 70126, Bari, Italy. E-mail: nacci@chimica.uniba.it, antomono@
complex substituted olefins, allowing combinations of substrates
(e.g. chloroanisole and cinnamates) that are commonly unreactive
with most of the traditional catalysts.16c
As a result of our success with simple chloroarenes, we have been
interested in examining the application of similar conditions to
the aryl dihalides to get unsymmetrically substituted arenes, with
libero.it; Fax: +39.080.5442129; Tel: +39.080.5442499
bCNR-ICCOM, Department of Chemistry, Universita` degli Studi di Bari
Aldo Moro, Via Orabona 4, 70126, Bari, Italy
† Dedicated to Professor Vincenzo Calo` on the occasion of his 73rd
birthday.
‡ Electronic supplementary information (ESI) available: spectral data of
unknown reaction products. See DOI: 10.1039/c1ob06385e
808 | Org. Biomol. Chem., 2012, 10, 808–813
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particular attention to those containing unsymmetric 1,2-, 1,3-
and 1,4-diethenylphenyl and terphenyl units, due to their practical
importance for pharmaceutical and material industries.4,8,17,18 Here
we wish to report our results in the sequential one-pot, two-
step process involving Pd colloids-mediated Heck19 and Suzuki20
couplings of bromo-chloroaryls in ionic liquids.
adopting, in the first instance, the same reaction conditions as in
Table 1. After completion of the Heck reaction under the standard
conditions (TBAA as the base, at 100 ◦C), phenyl boronic acid was
added to the mixture and heated to 120 ◦C. At once, TBAA proved
to be a suitable base for the Heck reaction but a poor base for the
Suzuki coupling (Table 2, runs 1–2).
Searching for the best couple of bases we also investigated the
influence of water on the second step, having known16a,20a the
beneficial effect that this solvent exerts on the Suzuki reaction.22
Unsatisfactory results were observed by combining TBAA with
K2CO3, K3PO4 and tetrabutylammonium hydroxide (TBAOH),
with or without the presence of water (Table 2, runs 3–5).
Likewise, disappointing results were obtained with K2CO3 as the
sole base for the overall process (Table 2, runs 7–8). High yields
could be obtained using potassium carbonate in the first step and
cesium carbonate in the second, but in these cases the presence of
water proved to be crucial (Table 2, runs 9–11). However, the latter
couplings were still unsatisfactory in terms of the reaction times,
whereas the couple TBAA/Cs2CO3 came out definitely better as
it successfully afforded a complete conversion in the final product
in only 2.5 h (Table 2, run 6).
With such optimized reaction conditions in hand, we carried
out the sequential cross-coupling reactions using a combination
of typical olefins and phenyl boronic acid with 2-, 3-, or 4-
bromochlorobenzene, to get ethenylsubstituted biphenyl deriva-
tives as reported in Table 3.
Next, in order to highlight the synthetic value of these protocols,
we attempted to extend their application to a more challenging
and intriguing process like the one-pot sequential triple coupling
involving a trihaloarene as substrate.
Results and discussion
Investigations were started by adapting our previous protocol,16c
useful to couple the simple chloroarenes, to the one-pot double
Heck olefination of 1,2-, 1,3- and 1,4-bromochlorobenzene iso-
mers with an array of olefins. Reaction conditions were calibrated
for processing 0.5 mmol of both the dihalide and alkene dissolved
in a molten mixture of tetrabutylammonium bromide (TBAB) as
the solvent and tetrabutylammonium acetate (TBAA) as base, in
the presence of Pd(OAc)2 as the catalyst source (Table 1).
The success of this methodology was obviously dependent
on the chemoselectivity of the first olefination. After many
experiments, we found that the selective displacement of the two
halogens on the benzene ring could be achieved by adjusting the
reaction temperature of the two consecutive steps. In the former, by
virtue of the efficiency of Pd colloids in the activation of the C–Br
bond in these ILs media,21 the substitution of the bromide occurred
◦
at 100 C with both butyl acrylate and styrene as model olefins,
and in all cases quantitative conversions to the corresponding
chlorophenyl intermediates were obtained within 0.5–1 h.
Fortunately, the catalyst system exhibited an excellent regiose-
lectivity, allowing the coupling at the bromine site of the dihalide
to be completed with the formation of only trace amounts of
the symmetric double coupled product. Following the one-pot
modality, the second step was initiated immediately after the end of
theprevious one by thedirectadditionofthe olefin2to the reaction
mixture without either isolation of the chlorophenyl intermediate
or addition of a second catalyst or any other additive, but simply
by raising the reaction temperature to 120 ◦C.
As expected, the second olefination was more difficult as it
involves cleavage of the stronger C–Cl bond. As a consequence,
reaction times were much longer and yields were dependent
on the structure of both the second olefin and the starting
bromochloroarene. For sterical reasons, reactions occurring on
the less hindered 1,4-bromochlorobenzene were generally faster,
giving good to excellent overall yields (Table 1, runs 1–3, 6–8).
However, a moderate yield of 52% was observed when a bulky
olefin such as ethyl cinnamate was the reaction partner in the
second step (Table 1, run 11).
In some cases, unrepeatable results and poor yields during the
progress of the second step were obtained, because the formation
of insoluble disubstituted arene product prevented an efficient
mixing of the reaction mixture.
This problem was surmounted by increasing the reaction
temperature of the second step to 140 ◦C (Table 1, runs 10 and
12). Processes involving 1,2- and 1,3-disubstituted haloarenes were
high-yielding but generally required longer reaction times (Table
1, runs 4–5 and 13).
To this end, we coupled 4-bromo-2-chloro-1-iodobenzene with
three different nucleophilic partners, in order to get an unsym-
metrically trisubstituted arene. In Scheme 1 two representative
examples of consecutive triple Heck and Heck/Heck/Suzuki
couplings are given, respectively.
Processes were accomplished under the same conditions as
for the double coupling of bromochloroarenes, but carrying out
the first step at the temperature of 90 ◦C to allow the selective
activation of the weakest carbon-iodine bond.
Finally, for completing the possible combinations of the cou-
pling processes, we focussed our attempts on the development of a
synthetic procedure that enables sequential chemoselective Suzuki
reactions of bromo-chlorobenzenes with two different arylboronic
acids to get unsymmetrical terphenyls. All the attempts made to
carry the double Suzuki coupling using the protocol of the second
step in Table 3 (TBAB/Cs2CO3/H2O) gave rise to disappointing
results. Most probably, the prolonged reaction times, due to the
additional coupling at the bromine site, along with the high
◦
temperature (120 C) and the aqueous medium, lowered the Pd
colloids stability, so that the completion of the first coupling
reaction stopped during the second step with precipitation of Pd
black.
Based on our recent findings,16a,23 we exploited tetrabutylam-
monium hydroxide (TBAOH), a stronger base with respect to
Cs2CO3, that can act also as surfactant and phase transfer agent
(PTC), creating a favourable environment for the nanocatalysts
and avoiding colloids agglomeration. Indeed, into the emulsioned
mixture generated by this surfactant, reactions presumably occur
into the special layer surrounding the nanoparticles surface, which
Based on these encouraging results, we decided to explore the
one-pot Heck/Suzuki sequential couplings. Optimisation of the
reaction conditions was carried out on 4-bromochlorobenzene
(Table 2), choosing the Heck coupling in the first step and
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Table 1 Double Heck one-pot sequential coupling of bromochlorobenzene isomers in ILsa
Step 1
R1
Step 2
R2
Run
1
t (h)b
R3
H
t (h)c
Product
Yield (%)d
67
CO2Bu
CO2Bu
CO2Bu
0.5
CO2Me
CO2Et
C6H5
4
2
3
0.5
0.5
Me
H
4
2
85
87
4
5
CO2Bu
CO2Me
0.5
0.5
C6H5
C6H5
H
H
14
2
78
80
6
CO2Bu
0.5
4-CF3C6H4
H
2
82
7
8
CO2Bu
CO2Me
0.5
0.5
4-MeOC6H4
4-Py-
H
H
2
4
79
76
9
CO2Bu
0.5
4-Py-
H
4
80
10e
11
CO2Bu
CO2Bu
0.5
0.5
4-ClCH2C6H4
CO2Et
H
5
2
65
52
C6H5
12e
13
C6H5
C6H5
1
1
4-MeOC6H4
4-CF3C6H4
H
H
4
60
73
14
a Ge◦neral reaction conditions: TBAB (1 g), TBAA (1.5 mmol), bromochlorobenzene (0.5 mmol), olefin 1 (0.5 mmol), olefin 2 (0.5 mmol); T (step 1)
100 C, T (step 2) 120 ◦C; stirred under air. b Reaction times needed for the complete conversion of the starting reagents into the intermediate (determined
by GC-MS) c Time of the maximum conversion of the intermediate into the final product. d Overall isolated yields. e Temperature of the second step
140 ◦C.
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Table 2 Optimisation of the reaction conditions in the one-pot Heck/Suzuki sequential coupling on 4-bromochlorobenzenea
Step 1
R
Step 2
Run
Base (1)
t (h)
Conv. (%)
Base (2)
Additived
t (h)
Yield (%)e
1b
2b
3c
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CO2Bu
Ph
TBAA
TBAA
TBAA
TBAA
TBAA
TBAA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
0.5
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
99
99
99
99
99
99
90
90
90
90
80
TBAA
TBAA
K2CO3
K3PO4
TBAOH
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
—
14
14
14
14
14
2
14
14
14
14
14
0
0
0
50
10
95
0
20
0
H2O
H2O
H2O
H2O
H2O
—
H2O
—
H2O
H2O
4c
5c
6c
7b
8b
9c
10c
11c
77
90
a Ge◦neral reaction conditions: TBAB (1 g), 4-bromoclorobenzene (0.5 mmol), olefin (0.5 mmol), boronic acid (0.75 mmol); T (step 1) 100 ◦C, T (step 2)
120 C; under stirring and under air. b Base (1) (1.5 mmol) added only in step 1. c Base (1) (0.75 mmol) and base (2) (1 mmol). d Added before starting the
second step. e GLC overall yields.
Table 3 One-pot Heck/Suzuki sequential couplings in ILsa
be smoothly accomplished by performing the first step (the C–
Br activation) at 60 ◦C; whereas the second step, occurring on
the chlorobiaryl intermediate, required at least 100 ◦C to be
completed (Table 4). It was gratifying to find that these reactions
proceeded equally well for 1,4- (Table 4, runs 1–3), 1,3- (Table
4, runs 4–6) and 1,2- (Table 4, run 7) bromochlorobenzene
Run Reagents
t (h) Product
Yield (%)b
92
isomers, affording o-, m- and p-terphenyl in good to excellent
yields.
1
R = CO2Bu
2
This method can compete with the one recently reported by
Hii,8a in which the first coupling was achieved at room temperature
using a ligandless palladium catalyst, but the second step required
isolation of the chlorobiaryl intermediate, a minimum temperature
of 60 ◦C and the presence of a SPhos ligand.
2
R = C6H5
4
6
90
68
3
4
5
R = CO2Bu
Conclusions
In summary, we have disclosed a series of reactions which
constitute a powerful methodology for the synthesis of extended
p-systems having a multisubstituted unsymmetrical arene as the
basic skeleton.
This protocol, based on an appropriate combination of Heck
and Suzuki cross coupling, complements existing strategies10
broadening their scope with more challenging substrates (bro-
mochloroarenes), and can be particularly intriguing due to the
practical importance of extended conjugated systems in material
science, particularly in the optoelectronic field.6a,17
The practical benefits include readily-available and inexpensive
starting materials, substrate versatility, experimentally straightfor-
ward procedures and good product yields. In addition, the method
is highly sustainable because it employs green solvents (ionic
liquids or water), is ligand-free (no toxic or expensive phospane
ligands) and has relatively mild conditions (T = 60–120 ◦C).
To the best of our knowledge, for the first time in the literature
the one-pot sequential coupling strategy involving the Heck
reaction is applied to bromochloroarenes and simultaneously to a
wide range of alkenes, including some deactivated olefins, such as
cinnamic esters (see Table 1, run 11).
R = CO2Bu 14
67
60
R = C6H5
14
a General reaction conditions: TBAB (1 g), TBAA (0.75 mmol), bro-
mochlorobenzene (0.5 mmol), olefin (0.5 mmol), Cs2CO3 (1 mmol),
boronic acid (0.75 mmol); T (I step) 100 ◦C, T (II step) 120 ◦C; under
stirring and under air. b Overall isolated yields.
contains the organic species, Bu4N+ cations and the anionic
counterpart. In addition, TBAOH would facilitate solvation of
the low polar aryl dihalide in neat water avoiding the use of an
organic co-solvent.
Under these conditions the one-pot double Suzuki coupling
of bromochloroarenes with a number of arylboronic acids could
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Scheme 1 Two examples of triple one-pot sequential couplings.
Table 4 Synthesis of unsymmetrical terphenyls by one-pot double Suzuki coupling of bromochloroarenesa
Run
1
Boronic acids
t (h)b
Product
Yield (%)c
85
Ar1 = C6H5 Ar2 = 4-MeC6H4
1.5
2
Ar1 = C6H5 Ar2 = 4-MeOC6H4
2.5
86
3
4
Ar1 = 4-MeOC6H4 Ar2 = 4-MeC6H4
Ar1 = C6H5 Ar2 = 4-MeC6H4
7
2
70
90
5
6
7
Ar1 = 4-MeC6H4 Ar2 = 4-MeOC6H4
Ar1 = C6H5 Ar2 = 4-MeOC6H4
Ar1 = C6H5 Ar2 = 4-MeC6H4
4
3
8
80
60
62
a Reaction conditions. 1st step: TBAOH 1.5 M (1 ml), bromochloroarene (0.5 mmol), Pd acetate (1 mol%), boronic acid (R1, 0.6 mmol), T = 60 ◦C. 2nd
step: boronic acid (R2, 0.6 mmol), T = 100 ◦C. b Total reaction times. c Isolated yields determined over the two steps.
MS. Olefin 2 (0.5 mmol) was then added and the reaction mixture
Experimental section
was heated to 120 ◦C for the proper reaction time (see Tables 1).
Representative procedure for sequential one-pot double Heck
couplings
Monitoring of the reaction mixture by GLC and GC-MS provided
reagents conversion. After completion of the reaction, the mixture
was added to 20 mL of water and extracted with dichloromethane
(3 ¥ 20 mL). The combined organic layers were washed with water
(2 ¥ 20 mL), dried with anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by chromatography on silica gel
to give the desired product. Unknown compounds were identified
by NMR analysis (see ESI‡).
In a 10 ml vial, equipped with a screw cap and a magnetic bar,
tetrabutylammonium bromide (TBAB, 1 g), tetrabutylammonium
acetate (TBAA, 0.45 g, 1.5 mmol), Pd(OAc)2, (1.7 mg, 0.0075
mmol, 1.5 mol%), olefin 1 (0.5 mmol), and bromochlorobenzene
(0.5 mmol) were placed. The solution was heated to 100 ◦C under
air until the disappearance of the first olefin monitored by GC-
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Representative procedure for sequential one-pot Heck/Suzuki
couplings
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In a 10 ml vial, equipped with a screw cap and a magnetic bar,
TBAB (1 g), 4-bromoclorobenzene (0.5 mmol), olefin (0.5 mmol),
TBAA (0.75 mmol), and Pd(OAc)2, (1.7 mg, 0.0075 mmol, 1.5
mol%) were placed. The mixture was heated to 100 ◦C and
stirred under air. The reaction was monitored by GC-MS until
the completion of the Heck coupling. Then, boronic acid (0.75
mmol) and Cs2CO3 (1 mmol) and 150 ml of H2O were added and
the temperature was raised to 120 ◦C. Monitoring of the reaction
mixture by GLC and GC-MS provided reagents conversion (see
Table 3). After completion of the reaction, both yields and
products identification were carried out after extraction of the
mixture followed by column chromatography as reported in the
previous procedure.
12 S. T. Handy and J. J. Sabatini, Org. Lett., 2006, 8, 1537–1539.
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Representative procedure for sequential one-pot double Suzuki
couplings
In a 10 ml vial, equipped with a screw cap and a magnetic bar, a
solution of TBAOH 1.5 M (1 ml, 1.5 mmol), bromochloroarene
(0.5 mmol), Pd acetate (1 mol%), boronic acid (R1, 0.6 mmol) were
placed. The reaction mixture was heated to 60 ◦C and stirred under
air until the completion of the first step. Then, a boronic acid (R2,
0.6 mmol) was added and the reaction temperature was raised to
100 ◦C for the proper time (see Table 4). Monitoring of the reaction
mixture by GLC and GC-MS provided reagents conversion. After
completion of the reaction, both yields and products identification
were carried out after extraction of the mixture followed by column
chromatography as reported in the previous procedure.
17 For selected examples of photochemical properties and applications
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Acknowledgements
Partial financial support of this work by the Ministry of University
and Scientific Research of Italy (MIUR) and by University of Bari
is gratefully acknowledged.
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