Toward waste-free production of heck products with a catalytic palladium system under oxygen

Article abstract of DOI:10.1002/anie.200351524

A 100% carbon-efficient, halide- and solvent-free alternative for the synthesis of Heck-type products is the direct oxidative coupling of arenes with olefins, catalyzed by Pd(OAc)₂ under oxygen (see scheme). The reactions can be performed under mild conditions, and water is the only by-product. (TON = turnover number, TOF = turnover frequency.).

Full text of DOI:10.1002/anie.200351524

Communications
Green C-C Coupling Reactions
olefins (Scheme 1). Pd0 intermediates can be reoxidized to
active PdII species under an appropriate pressure of O2. As no
reactive substituents are required on the arene, water is the
only by-product. The reactions can be performed under mild
conditions, for example at 908C and under O2 (0.8 MPa), have
a high turnover frequency, and do not require a solvent or a
halide promoter.
Toward Waste-Free Production of Heck Products
with a Catalytic Palladium System under
Oxygen**
Mieke Dams, Dirk E. De Vos, Sofie Celen, and
Pierre A. Jacobs*
Only a few methods exist for the transition-metal-
catalyzed reaction of an arene with an olefin through direct
[4]
À
C H bond activation. These include the chelation-assisted
The sp2–sp2 coupling of an aromatic ring with an alkene is one
of the key transformations catalyzed by Pd. This reaction was
pioneered by Heck and Mizoroki and has undergone a lot of
progress since that time, but it still suffers from one major
drawback, namely the production of salt waste.[1] Indeed, the
use of halogenated aromatic compounds requires the use of
stoichiometric amounts of base for Pd0 regeneration, which
leads to the formation of large quantities of halide salt by-
products, especially in large-scale processes. To circumvent
these problems, aromatic carboxylic acid anhydrides and
esters have been used by de Vries and co-workers[2] and
Gooßen et al.,[3] respectively, as sources of the aryl compo-
nent in the PdCl2-catalyzed sp2–sp2 coupling. When benzoic
anhydride is used as the arylating reagent, the benzoic acid
produced as a side product can be recycled to the anhydride
by dehydration;[2] when an activated p-nitrophenyl ester is
used, the nitrophenol produced can be esterified to give the
starting ester by reaction with the appropriate carboxylic
acid.[3] Although CO and H2O are the only by-products, these
reactions still have the disadvantages that they require high
temperatures (1608C), two separate steps, and a minimum
concentration of alkali-metal halides for moderate catalyst
activity (maximum TON (total turnover number= moles of
coupling product per mole of Pd) of 400–150).
alkylation of aromatic ketones mediated by Ru or Rh,[5–6] the
hydroarylation of alkenes or alkynes with Ir or Pd,[7–8] and the
arylation of an olefin with Rh,[9] Ru,[10] or Pd.[8c,11] This last
type of catalytic coupling reaction requires an oxidant.[10,11]
As dioxygen is the cheapest available oxidant, we attempted
in an initial experiment to couple toluene (1b) with ethyl
trans-cinnamate (2b) in the presence of Pd(OAc)2 (1 mol%)
and Mn(OAc)3 (4 mol%) under O2 at 908C in neat toluene.
Surprisingly, the arylation product 3e was obtained in 91%
yield, together with the diarylated product ethyl 3-phenyl-2,3-
ditolyl-propenoate (1.7%).[12] By contrast, when the reaction
was carried out under the classical conditions for such Pd-
catalyzed coupling reactions, namely in a mixture of acetic
acid and acetic anhydride, 3e was obtained in only 2.5%
yield, along with an equimolar amount of the by-product
benzyl acetate, formed by the acetoxylation of toluene.[13,14]
Thus, in acetic acid only low reactivity and a selectivity of
50% were observed, whereas under solvent-free conditions
the reaction proceeded to high conversion with high selectiv-
ity.
This first experiment showed convincingly that O2 can be
used for Pd0 reoxidation instead of, for example, tBuOOH,
which has been recognized until now as the most effective
oxidant for a Fujiwara coupling reaction.[15] Just as observed
for oxidative phenol carbonylation[16] or the Wacker olefin
oxidation,[17] the electron transfer from Pd0 to O2 may be
accelerated by cocatalysts. Over 15 transition-metal salts were
Herein we propose a 100% carbon-efficient and halide-
free alternative for the synthesis of Heck-coupling products,
which involves the direct Pd-catalyzed coupling of arenes with
Scheme 1. Pd-catalyzed oxidative coupling of an arene with an olefin under O2.
screened in the reaction of anisole (1c) with ethyl trans-
cinnamate (2b). Acetate complexes appear to be more
effective than acetylacetonate complexes. Nearly full con-
version of the cinnamate occurred in the presence of CoII,
FeII, MnII, and MnIII acetates, of which the MnII and MnIII
acetates gave the best results (see Table 1, entries 1–3).
Remarkably, the reaction reached completion even in the
absence of a cocatalyst (Table 1, entry 4), and the same was
[*] Prof. P. A. Jacobs, M. Dams, Prof. D. E. De Vos, S. Celen
Centre for Surface Chemistry and Catalysis, K. U. Leuven
Kasteelpark Arenberg 23, 3001 Leuven (Belgium)
Fax: (+32)16-321-998
E-mail: pierre.jacobs@agr.kuleuven.ac.be
[**] Thiswork wassupported by the Belgian Federal Government within
the framework of an IAP program for supramolecular catalysis. M.D.
is a research assistant of FWO (Belgium).
3512
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DOI: 10.1002/anie.200351524
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Angewandte
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Table 1: Optimization of the coupling of anisole (1c) with ethyl trans-cinnamate (2b).[a]
Entry Additive (mmol)
t1 [h] Conv. [%][b] t2 [h] Conv. [%][c] TON
solubility. Excellent results were
Max. TOF [hÀ1
]
obtained with benzoic acid
(Table 1, entry 8), and to a lesser
extent with p- and o-toluic acid.
These acids eliminate the induction
period and the conversion of the
cinnamate proceeds about four
times faster than in the absence of
an additive (Figure 1). 1H NMR
1
2
3
4
Mn(acac)2 (0.06)
Co(OAc)2·4H2O (0.06)
Mn(OAc)3·2H2O (0.06) [e]
-
Mn(OAc)3·2H2O (0.12)
Mn(OAc)3·2H2O (0.12)
Mn(OAc)3·2H2O (0.12)
PhCOOH (0.6)
4-iPr-C6H4COOH (0.6)
3-Cl-C6H4COOH (0.6)
PhCOOH (0.18)
22
22
22
22
25
26
20
25
25
24
23
24
0.9
83
0.9
87
100
96
99
93
73
97
50
51
0.2
3.7
7.6
4.3
4.4
3.5
3.6
13.4
3.3
8.9
7.5
73
[d]
99
94
97
92
71
98
49
50
96
90
[d]
5
4
3.5
6.2 83
8.5 27
5
17
11
6
6[f]
7[g]
8
spectroscopic
experiments
in
9
[D6]benzene indicated that under
these conditions the acetate ligands
are displaced and a Pd–benzoate
species is formed.[18] Neither elec-
tron-donating nor electron-with-
drawing groups on the benzoic
acid improve the catalyst efficiency
(Table 1, entries 9 and 10). With
some aliphatic acids, such as
acetic, trifluoroacetic, and hexa-
10
11[h]
12[i]
6
40
6.6 27
8 66
174
762
PhCOOH (0.18)
[a] Reaction conditions, unless otherwise indicated: 1c (4 mL, 37 mmol), 2b (3 mmol), 908C, O2
(0.8 MPa), and Pd(OAc)2 (1 mol% with respect to 2b). [b] Conversion of 2b after t1. [c] Conversion of 2b
after t2. [d] Induction period: 2.5 h. [e] Induction period: <1 h. [f] O2: 0.4 MPa. [g] O2: 1.6 MPa.
[h] Pd(OAc)2: 0.55 mol%. [i] Pd(OAc)2: 0.12 mol%, 1108C.
observed for arylations of butyl acrylate and ethyl cinnamate
with benzene or toluene. In the absence of a cocatalyst there
is an induction period, but not when hydrated Mn(OAc)3 is
present (Figure 1). This induction period can also be elimi-
nated by the addition of water (0.6 mmol; Figure 1). All these
elements indicate that the metal salts do not necessarily
intervene in a rate-determining Pd0 reoxidation; rather, both
water and the hydrated acetate salts appear to facilitate the
formation of a suitable catalytically active PdII species in the
initial phase of the reaction.
noic acids, the reaction does not reach completion, in contrast
with the acid-free reaction (Figure 1). The unique accelerat-
ing effect of benzoic acid on the Pd catalysis appears to be
generally true for these coupling reactions, for example, for
those of anisole (1c) and toluene (1b) with butyl acrylate
(2a), ethyl trans-cinnamate (2b), and trans-4-phenyl-3-buten-
2-one (2c) (Table 2). In all these reactions, high rates were
observed without an induction period.
Several reaction parameters, such as O2 pressure, reaction
volume, and concentration of benzoic acid were optimized for
the Pd-catalyzed coupling of anisole with ethyl trans-cinna-
mate. For 4 mL of anisole, 0.8 MPa of O2 appears to be
optimal. When the pressure is too high, lower catalytic
activity is observed (Table 1, entries 5–7). A sixfold excess of
PhCOOH with respect to Pd2+ is sufficient to promote high
reaction rates. Under these conditions, the Pd concentration
could be reduced to 0.12 mol% at 1108C (Table 1, entries 11
and 12) with complete conversion to ethyl 3-anisyl-3-phenyl-
propenoate (3h) maintained, which corresponds to a total
turnover number (TON) of 762. The maximum turnover
frequency (TOF = moles of coupling product per mole of
Pd(OAc)2 per hour) was 73 hÀ1. To our knowledge, these are
the highest TON and TOF values described for such oxidative
coupling reactions.[19]
Although the Pd/PhCOOH catalyst gives rise to selectiv-
ities of over 95% in these coupling reactions, several
regioisomers are formed under the solvent-free conditions
with anisole and toluene (Table 2).[20] The Pd catalyst attacks
Figure 1. The conversion y of 2b asa function of time: a) no additive
*
( ); b) Mn(OAc)3·2H2O (2 mol%; ”); c) water (0.6 mmol; +); d) ben-
~
&
zoic acid (0.6 mmol; ), e) trifluoroacetic acid (0.6 mmol; ); f) hexa-
noic acid (0.6 mmol; &). Other reaction conditions: 1c (4 mL,
37 mmol), 2b (3 mmol), Pd(OAc)2 (1 mol% with respect to 2b), O2
(0.8 MPa), 908C.
À
all aromatic C H bonds, with attack at the para position of
anisole favored over the ortho and, to a greater extent, meta
positions. On the other hand, when toluene is used as the
arylating agent, more of the meta isomer is formed than the
ortho isomer. Such data suggest that the first step in the
catalytic cycle may not correspond to a classical electrophilic
aromatic substitution, as such reactions heavily favor ortho
and para substitution.[21]
À
Earlier work on aromatic C H activation suggests that Pd
À
can break the C H bond by electrophilic aromatic substitu-
tion to form an arene–PdII complex. As high reactivity has
been ascribed to highly electrophilic PdII species such as
Pd(OOCCF3)+,[8c] over 20 different acids were tested as
additives in the Pd(OAc)2-catalyzed coupling of ethyl trans-
cinnamate (2b) with neat anisole (1c). The effect of the acids
largely depends on their structure, substitution pattern, and
As the reaction mixture contains a 12–15-fold excess of
the arene, the olefin can be arylated once, twice, or possibly
even three times. The selectivity for these multiply arylated
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Table 2: Influence of the cocatalyst Mn(OAc)3·2H2O and the additive benzoic acid on the induction
period and the catalyst activity in the oxidative coupling of arenes and olefins.[a]
accelerating effect of benzoic acid,
together with the relative reactivity
of several arenes as described ear-
lier, suggest the reaction may occur
through an electrophilic attack on
the aromatic compound, which was
also the first step in the mechanism
originally proposed by Fuji-
wara.[11f] The rather high fraction
of meta products formed in some
cases indicates that the Pd species
might not be of a purely electro-
philic nature. Besides the catalyti-
cally active PdII species, the cata-
lytic cycle probably also involves a
Pd0 intermediate. Indeed, under
standard conditions (see Table 2),
in the presence of PhCOOH
(0.18 mmol), bromobenzene does
not only undergo oxidative cou-
pling with ethyl cinnamate, but a
Entry
1
2
Additive
t1 [h] Conv. [%][b] t2 [h] Conv. [%][c] Sel. [%][d]
o/m/p[e]
1
2
3
4
5
6
7
8
c
c
c
c
c
c
c
c
c
b
b
b
a
a
a
a
a
a
b
b
b
a
a
a
c
c
c
b
a
c
b
a
a
a
a
c
–
6
10
22.5 94
21.5 99
100:0
86:14
100:0
100:0:0
25:75:0
91:9:0
100:0
100:0
100:0
85:15
38:14:48
37:16:47
32:15:53
45:55[f]
Mn(OAc)3 (2 mol%)
PhCOOH (0.6 mmol)
–
Mn(OAc)3 (2 mol%)
PhCOOH (0.6 mmol)
–
Mn(OAc)3 (2 mol%)
PhCOOH (0.6 mmol)
PhCOOH (0.6 mmol)
PhCOOH (0.6 mmol)
PhCOOH (0.6 mmol)
Mn(OAc)3 (4 mol%)
–
–
3.5 18
6.2 83
6.5 12
5.5 26
8.2 74
8
25
8.2 25
4.5 12
7.5 76
7.5 14
90
24
47
76
165
77
25
98
25.2 75
22.7 93
44:56[f]
30
96
168
120
96
14
87
99
43:57[f]
6
31
34:13:53
35:12:53
33:17:50
30:40:30
9
10
11
12
13
14
15
16
17
18
21.5 89
24.5 96
15:85:0[g] 24:36:40
118
97
n.d.[h]
95:5
99:1:0
89:11:0
37:63:0
7:18:75
100:0
n.d.[h]
97
56
98
97
98
99
–
–
–
–
–
–
–
–
Mn(OAc)3 (4 mol%)
[a] Reaction conditions: arene (4 mL, 37–45 mmol), olefin (3 mmol), Pd(OAc)2 (1 mol%), O2 (0.8 Mpa),
908C. All organic productswere isolated and characterized by GC–MS, aswell as
1H and 13C NMR
spectroscopy. [b] Conversion of the olefin after t1. [c] Conversion of the olefin after t2. [d] Selectivity for
the 1:1 arene–olefin, 2:1 arene–olefin, and possibly 3:1 arene–olefin adducts after t2. [e] Selectivity for
the ortho, meta, and para adduct after t2. [f] The ortho and meta isomers could not be separated by GC.
[g] After 7.5 h the selectivity for the monoarylated product was 90%. [h] Not determined.
stoichiometric
amount
(with
respect to the catalyst: 0.03 mmol)
of the Heck product is also formed,
probably through oxidative addi-
0
À
tion of the C Br bond to Pd .
In conclusion, we have pre-
olefins can be tuned. By stopping the reaction at appropriate
times, one may obtain a high yield of the mono-, di-, or even
triarylated product. The clean consecutive coupling process is
illustrated in Table 2 (entries 14–17) for the reaction of
benzene with butyl acrylate. Similar double or triple couplings
are feasible with, for example, anisole and toluene.
In the catalytic Pd/O2 system described above, the
reactivity of the aromatic compounds decreases in the
following order: anisole > toluene > benzene > acetophe-
none and chlorobenzene. Thus, the activation of an aromatic
sented a 100% carbon-efficient, halide- and solvent-free
system for the oxidative arylation of olefins, with water as the
only by-product. No organic oxidants or electron-transfer
mediators are required, the Pd/benzoic acid catalyst appears
to be infinitely stable, and both the TON and the TOF are far
higher than those observed previously in similar reactions.
This work therefore presents a significant step toward waste-
free Heck reactions.
Received: March 31, 2003 [Z51524]
À
C H bond by Pd is facilitated by electron-donating groups.
Keywords: C–C coupling · green chemistry ·
homogeneouscatalysis· oxygen · palladium
The trends are less clear for the olefinic component.
Unsaturated esters such as acrylates and cinnamates react
smoothly. Steric hindrance may explain the sometimes lower
reactivity of ethyl trans-cinnamate in comparison with butyl
acrylate. The unsaturated ketone trans-4-phenyl-3-buten-2-
one also undergoes complete conversion, but only when a
metal cocatalyst or benzoic acid is used (Table 2, entries 7–9,
12, and 18). Furthermore, simple olefins such as styrene and 1-
octene can also be oxidatively coupled to arenes. In these
reactions styrene is more reactive than 1-octene.
.
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To gain deeper mechanistic insight, oxidative couplings of
ethyl trans-cinnamate were performed with toluene and
[D8]toluene under the conditions described in Table 2, and
the kinetic isotope effect (KIE) was determined. The rates
considered are derived from the maximal slopes on the
conversion curve, that is, after the induction time. With only
1 mol% of Pd(OAc)2, the vH/vD ratio was 2.6. When benzoic
acid was added, the vH/vD ratio decreased to 2.1. This indicates
[6] Y. G. Lim, J. S. Han, S. S. Yang, J. H. Chun, Tetrahedron Lett.
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[7] T. Matsumoto, D. J. Taube, R. A. Periana, H. Taube, H. Yoshida,
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II
À
that C H activation by Pd is a slow step in the catalytic cycle
rather than Pd0 regeneration, at least in the oxidative coupling
of toluene with ethyl trans-cinnamate under oxygen. The
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[12] Reaction conditions: toluene/ethyl trans-cinnamate = 12.5:1,
neat, 90 h; ratio of isomers of 3e: o/m/p = 29:41:30.
[13] Reaction conditions: toluene/ethyl trans-cinnamate = 5:1,
HOAc (3 mL), Ac2O (1 mL), 70 h; ratio of isomers of 3e:
o/m/p = 25:36:39.
[14] E. Benazzi, C. J. Cameron, H. Mimoun, J. Mol. Catal. 1991, 69,
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[15] For the oxidative coupling of ethyl cinnamate (30 mmol) with
benzene (150 mmol), catalyzed by Pd(OAc)2 (0.06 mmol) and
benzoquinone (0.9 mmol) in the presence of tBuOOH
(60 mmol), in HOAc/Ac2O (30 mL/7 mL) at 908C, Fujiwara
obtained ethyl 3-phenylcinnamate in 56% yield in 15 h with a
TON value of 280.[11f]
[16] A. Vavasori, L. Toniolo, J. Mol. Catal. A 1999, 139, 109; b) A.
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[18] When Pd(OAc)2 (0.01 mmol) and benzoic acid (0.20 mmol) were
heated to 908C in [ D]benzene (1 mL), complete exchange of
6
the acetate and benzoate ligands was observed by 1H NMR
spectroscopy (300 MHz); new peaks were observed at d =
7.95 ppm (d; o-Ar-H, Pd(OBz)2) and at d = 6.71 ppm (m; m-
and p-Ar-H, Pd(OBz)2).
[19] When the oxidative coupling of benzene (30 mmol) with ethyl
acrylate (1.5 mmol) was performed in propionic acid (5 mL) at
908C, catalyzed by
a mixture of Pd(OAc)2 (0.1 mmol),
H7PMo8V4O40 (0.02 mmol), acetylacetone (0.1 mmol), and
NaOAc (0.08 mmol) under O2 (1 atm), Ishii and co-workers
obtained a TON value of 12.6 within 3 h.[11g]
[20] The ortho, meta, and para isomers of 3d–3i were prepared by
Heck reactions of the corresponding iodotoluenes and iodoani-
soles.
[21] See, for example: R. M. Roberts, Friedel–Crafts Alkylation
Chemistry: A Century of Discovery, Marcel Dekker, New
York, 1984.
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