Heck reactions with palladium nanoparticles in ionic liquids: Coupling of aryl chlorides with deactivated olefins

Full text of DOI:10.1002/anie.200902337

Angewandte
Chemie
DOI: 10.1002/anie.200902337
À
C Cl Activation
Heck Reactions with Palladium Nanoparticles in Ionic Liquids:
Coupling of Aryl Chlorides with Deactivated Olefins**
Vincenzo Calꢀ, Angelo Nacci,* Antonio Monopoli, and Pietro Cotugno
The palladium-catalyzed Heck arylation of olefins is one of
the most important carbon–carbon bond-forming processes in
synthetic organic chemistry.[1] There are at present two main
concerns with respect to this reaction: 1) the discovery of
bromide (TBAB) and the efficient base tetrabutylammonium
acetate (TBAA) in an approximately 1:1.5 molar ratio.
However, the coupling of chloroarenes proved to be unsat-
isfactory under these conditions. To extending the scope of
that procedure, we decided to investigate the coupling of
more challenging deactivated chloroarenes and a wider array
of olefins.
With the aim to improve catalyst performance, we
examined the use of TBAB and TBAA in various ratios,
whereby we took into account our recent findings,[7b,10] which
showed a strong dependence of the catalyst activity and
selectivity on the composition of the ionic solvent. After a
preliminary screening,[11] we found that a reversed TBAB/
TBAA ratio of 2:1 increased catalyst efficiency remarkably,
with the activation of a wider range of substrates, including
chloroarenes. The need for greater amounts of TBAB was in
line with our hypothesis that bromide ions, poorly solvated in
these reaction media, can provide adequate electron density
to the Pd0 species in place of the electron-rich phosphane
ligands to facilitate the oxidative-addition step.[7a,9]
By virtue of the improved catalyst performance, we were
able to carry out the reactions under milder conditions, at a
lower reaction temperature than that required previously. For
example, bromobenzene and 4-bromoanisole were coupled
rapidly in high yields at 1008C (Table 1, entries 1 and 2).
The corresponding aryl chlorides were also activated
readily at 1208C (Table 1, entries 3–10). We found that the
catalyst activity was dependent on the olefin/chloroarene
À
catalytic systems that activate the C Cl bond and 2) the
development of phosphane-free palladium catalysts. Chloro-
arenes are the most readily available and cheapest starting
materials; however, they are generally unreactive under the
conditions used to couple the corresponding iodides and
bromides. In particular, the use of neutral and electron-rich
aryl chlorides requires high temperatures (> 1408C) as well as
expensive and air-sensitive phosphane ligands.[2] A further
drawback is that complex substituted olefins (cinnamates or
other 1,2-disubstitued alkenes) are relatively uncommon
substrates as a result of their low reactivity toward typical
catalysts. From a synthetic standpoint, all these factors are
considerable limitations that need to be addressed.
To date, most of the catalysts that show high activity in
Heck reactions of deactivated (electron-rich) chloroarenes
require toxic solvents along with air-sensitive bulky alkyl
phosphane ligands and the presence of a hindered amine.[3]
Other systems are based on either PCP pincer complexes[4] or
N-heterocyclic carbene ligands,[5] whereas very few efficient
methods have been reported in which benign solvents and
ligand-free conditions are used.[6] Moreover, most of these
catalyst systems require harsh conditions (T> 1408C), so that
a reaction may have broad scope with respect to the aryl
chloride substrate but poor generality with respect to the
olefin.
During the past decade, we[7] have demonstrated widely
that tetraalkylammonium ionic liquids (ILs)[8] are superior
reaction media for the Heck coupling catalyzed by Pd
colloids. For instance, we were the first to couple bromoar-
enes with less reactive 1,2-disubstituted alkenes, such as
cinnamates, in a stereospecific manner under ligand-free
conditions.[9] In that study, reactions were carried out at 1308C
in a molten mixture of the solvent tetrabutylammonium
Table 1: Heck arylation of ethyl cinnamate in TBAB/TBAA.[a]
Entry
Aryl halide
Olefin/ArX
T [8C]
t [h]
Yield [%][b,c]
R
X
1
2
3
4
5
6
7
8
9
H
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1:1
1:1
1:1
1:1
2:1
1:1
1:2
1:1
1:2
1:3
100
100
100
100
120
120
120
120
120
120
1
2
14
14
3
3
3
4
4
96
90
–
[*] Prof. V. Calꢀ, Prof. A. Nacci, Dr. A. Monopoli, P. Cotugno
Department of Chemistry
4-OCH3
H
4-OCH3
H
H
H
4-CH3O
4-CH3O
4-CH3O
University of Bari
Via Orabona 4, 70126 Bari (Italy)
Fax: (+39)080-544-2499
–
45
63
95
50
72
90
E-mail: nacci@chimica.uniba.it
Prof. A. Nacci
CNR–ICCOM, Department of Chemistry, University of Bari
Via Orabona 4, 70126 Bari (Italy)
10
4
[**] This research was in part financially supported by the University of
Bari.
[a] Reactions were carried out in a mixture of TBAB (1 g) and TBAA
(0.45 g). [b] The yield was determined by GC by using diethylene glycol
di-n-butyl ether as an internal standard. [c] Unless otherwise indicated,
the E/Z ratio is >98:2, as determined by GC–MS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902337.
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Communications
Table 2: Heck olefination of chloroarenes in TBAB/TBAA.[a]
ratio. In particular, the b,b-diaryl acrylates were formed in
excellent yield when chlorobenzene was used in twofold
excess (Table 1, entries 5–7) or 4-chloroanisole was used in
threefold excess (Table 1, entries 8–10). These findings,
together with our preliminary kinetic observations, which
showed that in these cases the reaction rate is zero-order in
the olefin, are consistent with the oxidative addition as the
turnover-limiting step.
Entry Olefin
Ar
t [h] Product
Yield [%][b,c]
1[d]
2[d]
3[d]
C6H5
4-CH3C6H4
4-CH3OC6H4
2
1
6
90[e]
98[e]
88[e]
Nevertheless, another explanation for the influence of the
aryl chloride on the reaction yield is possible, if one assumes,
as also reported by Schmidt and Smirnov[12] for the Heck
coupling of bromoarenes under similar conditions, that an
increased concentration of the aryl halide would favor partial
recovery of the aggregated palladium species into the
catalytic cycle through oxidative addition of the aryl chloride.
A corresponding increase in the catalyst concentration would
be expected to lead to higher yields.
To expand the scope of our procedure, we applied these
optimized conditions to a wide array of substrates. The
catalytic reactions appeared quite general with respect to the
nature of the olefin (Table 2). Alkyl monosubstituted alkenes,
such as 1-octene, proved to be extremely reactive; they
underwent coupling at 1008C even with deactivated chloro-
arenes (Table 2, entries 1–3).[13] Styrene was also coupled
smoothly with a wide range of activated and deactivated
chloroarenes at 1208C (Table 2, entries 4–8). Unfortunately,
the reaction of less reactive (electron-rich) butyl vinyl ether
with unactivated chlorobenzene was unsatisfactory (Table 2,
entry 10).
4
5
6
7
8
4-CF3C6H4
4-CH3COC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
3
3
3
3
2
95
98
88
90
95
9
10
4-CH3COC6H4
C6H5
5
8
76[f]
25[f]
11[g]
12
C6H5
4-CH3OC6H4
2
3
67[h]
75[h]
13
14
15
16
17[i]
4-NCC6H4
4-CH3COC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
8
5
5
5
5
72
94
95
90
90
18
19
20
21
C6H5
5
2
3
5
80[j]
94[j]
95[j]
92
4-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
The catalyst also proved to be very active with 1,1-
disubstituted alkene substrates. For example, butyl methac-
rylate was transformed into a-methylcinnamic acid deriva-
tives, which are useful intermediates in the synthesis of
pharmaceuticals,[14] in good yields; small amounts of diary-
lated products were also obtained (Table 2, entries 11 and 12).
Remarkable results were obtained with (generally less
reactive) 1,2-disubstituted olefins. b-Substituted a,b-unsatu-
rated esters, which are usually unreactive towards most aryl
chlorides, were coupled smoothly with electron-rich chloro-
arenes at 1208C (Table 2, entries 13–21). For example, under
these conditions, b,b-diaryl acrylates were obtained in excel-
lent yield with excellent stereoselectivity (Table 2, entries 13–
17). These compounds are valuable precursors for the syn-
thesis of a variety of medicinally interesting compounds.[15]
The 1,2-disubstituted alkenes benzylideneacetone and stil-
bene were also compatible with the coupling reaction. The
corresponding synthetically valuable trisubstituted olefins
were obtained in high yield (Table 2, entries 22–27).
To highlight the synthetic value of this method, we
attempted its application to a synthesis of practical impor-
tance for the pharmaceutical and materials industries: the
one-pot sequential coupling of aryl dihalides to produce
unsymmetrically disubstituted arenes.[16] Most of the reported
methods for such transformations suffer from disadvantages,
such as the requirement of two different catalysts, the need to
isolate the intermediate product, or the use of expensive and
not readily available substrates. Moreover, to the best of our
knowledge, no examples of the use of cheaper bromochloro-
arenes as starting materials have been reported until now,
22
23
24
25
4-CH3COC6H4
C6H5
4-CH3C6H4
4-CH3OC6H4
3
3
3
3
98[k]
95
97[k]
90
26
27
C6H5
4-CH3OC6H4
5
5
78
85
[a] TBAB: 1 g, TBAA: 0.45 g, olefin: 0.5 mmol, chloroarene: 1 mmol.
[b] The yield was determined by GC by using diethylene glycol di-n-butyl
ether as an internal standard. [c] Unless otherwise indicated, the E/Z
ratio is >98:2, as determined by GC–MS. [d] The reaction was carried
out at 1008C. [e] The product includes isomers (ca. 40%) of the 1-aryl
1-octene.[13] [f] b/aꢀ80:20; b-arylated products were formed in an E/Z
ratio of 2:1. [g] Olefin/ArCl substrate ratio: 2:1. [h] Value includes the
yield of the diarylated product (15%), which was also formed. [i] Olefin/
ArCl substrate ratio: 1:3. [j] E/Z ratio: 80:20. [k] E/Z ratio: 70:30.
À
because of the difficulty in activating the C Cl bond. With our
catalyst, we were able to couple 1-bromo-4-chlorobenzene
with two different olefins in a one-pot sequential manner by
À
À
activating the C Br and C Cl bonds on the aromatic ring at
the two different temperatures of 100 and 1208C. The
unsymmetrical substituted arenes 1 and 2 were produced in
this way with high reaction rates and in high overall yield
(Scheme 1).
In summary, we have developed a general method for the
Heck coupling of chloroarenes, including deactivated, elec-
tron-rich compounds, with substituted olefins of low reac-
tivity. The reaction conditions are unprecedented: 1) In
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contrast to most reported methods,[3] neither toxic, air-
sensitive phosphane ligands nor an inert atmosphere is
required, 2) an environmentally safer IL medium is
employed, 3) unusual combinations of substrates that are
not compatible with many traditional catalysts are possible
(e.g. chloroanisole and cinnamates), and 4) shorter reaction
times (typically in the range of 1–5 h) and milder temper-
atures are used than in many other procedures.[3c–f,5,6]
Furthermore, these findings open the way to the use of
bromochloroarenes as starting materials for sequential cou-
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operationally simple method can compete with the most
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(0.5 mmol) and ethyl cinnamate (1 mmol) in the presence of the
catalyst (1.5 mol%) in the solvent TBAB (1 g) at 1208C (n.r. =
no reaction):
Experimental Section
General procedure: TBAB (1 g), TBAA (0.45 g, 1.5 mmol), Pd-
(OAc)2 (1.7 mg, 0.0075 mmol, 1.5 mol%), the olefin (0.5 mmol), the
aryl halide (1 mmol), and diethylene glycol di-n-butyl ether (internal
standard, 50 mL) were placed in a 10 mL vial equipped with a screw
cap and a magnetic stirrer bar. The reaction mixture was stirred and
heated in air at the temperature and for the time indicated (see
Table 1 and Table 2). Product yields were determined by GLC and
GC–MS of the reaction mixture. Products were identified by the same
techniques and comparison with spectral data reported in the
literature.
Received: May 1, 2009
Published online: July 14, 2009
TBAA clearly plays a key role. Indeed, a generic source of
acetate did not have the same effect on catalyst activity. Two
plausible explanations can be given for this difference in
reactivity: 1) NaOAc (and other inorganic bases) show low
solubility in TBAB, and 2) the presence of inorganic cations can
lower the basicity of the acetate anion in the IL by forming tight
ion pairs.
Keywords: aryl chlorides · colloids · Heck reaction · ionic liquids ·
.
palladium
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[13] Products included isomers (ca. 40%) of the 1-aryl 1-octene.
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À
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Angew. Chem. Int. Ed. 2009, 48, 6101 –6103
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