Ligand-free heck reaction: Pd(OAc)2 as an active catalyst revisited

Article abstract of DOI:10.1021/jo034646w

Palladium acetate was shown to be an extremely active catalyst for the Heck reaction of aryl bromides. Both the base and the solvent were found to have a fundamental influence on the efficiency of the reaction, with K ₃PO₄ and N,N-di

Full text of DOI:10.1021/jo034646w

electron-rich phosphines,3 phosphorus,4 nitrogen,5 and
sulfur6-based palladacyles, and very recently, nucleophilic
carbene ligands.7,8 All of these catalyst systems suffer
from drawbacks of one kind or another, such as the high
ligand sensitivity toward air and moisture, the tedious
multistep synthesis, hence the high cost of the ligands,
and the use of various additives. On the other hand, the
operationally and economically more advantageous ligand-
free Heck reaction catalyst systems remain extremely
rare.9,10 Pd(OAc)2 has been traditionally used only as a
Liga n d -F r ee Heck Rea ction : P d (OAc)2 a s
a n Active Ca ta lyst Revisited
Qingwei Yao,* Elizabeth P. Kinney, and Zhi Yang†
Department of Chemistry and Biochemistry,
The Michael Faraday Laboratories, Northern Illinois
University, DeKalb, Illinois 60115-2862
qyao@niu.edu
Received May 14, 2003
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4478. (d) Drisp, G.; Gebauer, M. G. Tetrahedron 1996, 52, 12465-
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A. V.; Wang, L. Tetrahedron 1999, 55, 211-228. (i) Carmichael, A. J .;
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Abstr a ct: Palladium acetate was shown to be an extremely
active catalyst for the Heck reaction of aryl bromides. Both
the base and the solvent were found to have a fundamental
influence on the efficiency of the reaction, with K3PO4 and
N,N-dimethylacetamide being the optimal base and solvent,
respectively.
Palladium-catalyzed coupling of olefins with aryl and
vinyl halides, known as the Heck reaction,1,2 is one of
the prime tools for carbon-carbon bond formation in
organic synthesis. This powerful reaction can lead to the
construction of a C-C bond at an unfunctionalized
olefinic carbon in a single transformation employing a
wide variety of aryl and vinyl halide substrates. Unlike
other C-C bond-forming reactions that involve a polar
addition, the Heck reaction tolerates almost any sensitive
functionality such as unprotected amino, hydroxyl, al-
dehyde, ketone, carboxy, ester, cyano, and nitro groups.1
However, the traditional Heck reaction is typically
performed with 1-5 mol % of a palladium catalyst along
with a phosphine ligand in the presence of a suitable
base. Under these conditions, the maximum turnover
numbers (TON) are only 20-100 and large-scale indus-
trial application is not practical.2i In recent years, numer-
ous efforts have been made to develop more efficient
catalyst systems. A major challenge in this area has been
the development of new Heck reaction catalysts with
higher TON and with enhanced reactivity toward deac-
tivated aryl bromides and, ultimately, toward the more
readily available aryl chlorides. Significant advances
have been made in the past several years in meeting
these goals. These include the use of sterically bulky and
* To whom correspondence should be addressed. Phone: (+1) 815-
753-6841. Fax: (+1) 815-753-4802.
† Permanent address: Shanxi Institute of Chemical Engineering
Design, Taiyuan, Shanxi 030024, China.
(1) Heck, R. F. Acc. Chem. Res. 1979, 12, 146-152.
(2) Selected leading reviews and monographs on the Heck reaction
and related reactions promoted by Pd catalysts: (a) Heck, R. F.
Palladium Reagents in Organic Synthesis; Academic Press: London,
UK, 1985. (b) Heck, R. F. In Comprehensive Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon: New York, 1991; Vol 4, Chapter
4.3. (c) Tsuji, J . Palladium Reagents and Catalysts; J ohn Wiley:
Chichester, UK, 1995. (d) Bra¨se, S.; de Meijere, A. In Metal Catalyzed
Cross Coupling Reactions; Diederich, F., Stang, P. J ., Eds. Wiley: New
York, 1998; Chapter 3. (e) de Meijere, A.; Meyer, F. E. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2379-2411. (f) Crisp, G. T. Chem. Soc. Rev.
1998, 27, 427-436. (g) Casey, M.; Lawless, J .; Shirran, C. Polyhedron
2000, 19, 517-520. (h) Beletskaya, I. P.; Cheprokov, A. Chem. Rev.
2000, 100, 3009-3066. For a recent discussion on the industrial aspects
of the Heck reaction, see: (i) Tucker, C. E.; de Vries, J . G. Top. Catal.
2002, 19, 111-118.
(10) For a ligand-free Heck reaction under phase-transfer conditions
(J effery’s conditions), see: (a) J effery, T. Tetrahedron 1996, 52, 10113-
10130. Some impressive examples: (b) Reiser, O.; Reichow, S.; de
Meijere, A. Angew. Chem., Int. Ed. Engl. 1987, 27, 1277-1278. (c)
Gozzi, C.; Lavenot, L.; Ilg, K.; Penalva, V.; Lemaire, M. Tetrahedron
Lett. 1997, 38, 8867-8879.
10.1021/jo034646w CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/16/2003
7528
J . Org. Chem. 2003, 68, 7528-7531

TABLE 1. Effect of th e Ba se on th e P d (OAc)2-Ca ta lyzed
Rea ction of Br om oben zen e a n d Styr en ea
TABLE 2. Effect of th e Solven t on th e
P d (OAc)2-Ca ta lyzed Rea ction of Br om oben zen e a n d
Styr en ea
mol % of
Pd(OAc)2
entry
base
Et3N
Na2CO3
NaOAc
K3PO4
K3PO4
K3PO4
time (h)
yieldb (%)
TON
entry
solvent
yieldb (%)
1
2
3
4
0.1
0.1
0.1
0.1
0.01
0.00247
21
21
21
19
19
44
56
72
93
82
95
560
720
930
8200
38500
1
2
DMA
DMF
95
74
3
NMP
dioxane
54
<2
5
4c
6c
a
Unless otherwise noted, all reactions were performed with 1.0
a
Unless otherwise noted, all reactions were performed with 1.0
mmol of PhBr in 1.6 mL of the solvent at 140 °C for 19 h. b Isolated
yield after chromatography on silica gel. c This reaction was
performed at 100 °C.
b
mmol of PhBr in DMA (1-2 mL) at 140 °C. Isolated yield after
chromatography on silica gel. c 2.0 mmol of PhBr was used.
convenient and inexpensive source of palladium and its
role as an active catalytic species has not been fully
appreciated, except when the more reactive aryl iodides
are used as the substrates. Herein, we wish to report our
finding that Pd(OAc)2, in combination with K3PO4 as the
base, is an extremely effective catalyst for the coupling
of aryl bromides with terminal olefins.
Heck’s original recommendation for the catalyst cock-
tail involved the combination of Pd(OAc)2, a triaryl
phosphine ligand, and a tertiary amine such as Et3N as
the scavenger base. It is commonly believed that one role
of the phosphine ligand is the reduction of Pd(II) to a
catalytically active Pd(0) species, for which a stabilizing
ligand is required to prevent the formation of palladium
black.1,2a,h,11 The base Et3N has also been implicated as
a reducing agent for the generation of the Pd(0) species.2h
Since many catalytic systems such as these involving
palladacycles have been proposed to be operative by the
[Pd(II)-Pd(IV)] catalytic cycle,4c,g,12 the capability of Pd-
(OAc)2 to participate in productive catalytic turnovers
under appropriate conditions seems plausible.
Our initial attempt was to examine the efficiency of
Pd(OAc)2 in the coupling of bromobenzene with styrene
in the absence of any phosphine ligand. Not surprisingly,
no detectable conversion was observed when Et3N was
used as the base (Table 1, entry 1). However, when
several heterogeneous inorganic bases were substituted
for Et3N, all the reactions examined led to some conver-
sion, albeit with quite different efficiency (Table 1, entries
2-4), with K3PO4 giving the best result. Thus, the
coupling of bromobenzene with styrene in the presence
of only 0.1 mol % of Pd(OAc)2 with N,N-dimethylaceta-
mide (DMA) as the solvent gave trans-stilbene in 93%
isolated yield after 19 h at 140 °C. Decreasing the catalyst
loading to 0.01 mol % still gave a respectable 82% yield
of the product (Table 1, entry 5). When the reaction was
performed for an extended period of time, 0.0025 mol %
of Pd(OAc)2 was found to be sufficient to give a high
conversion with 95% isolated yield of the product, cor-
responding to a TON of 38 000 (Table 1, entry 6). Several
other solvents including DMF, NMP, and 1,4-dioxane
were also tested under similar conditions but all gave
inferior results compared to DMA (Table 2).
Having established that the combination of Pd(OAc)2
and K3PO4 constitutes a highly active catalyst system for
the Heck reaction, we next examined the coupling of
several other representative aryl bromides with different
olefin substrates with the results listed in Table 3. As
expected, the more reactive 4-bromobenzaldehyde un-
derwent clean coupling with styrene, giving essentially
a quantitative yield of the product (entry 1). Reactions
involving deactivated aryl bromides bearing a methyl or
a methoxy group also gave high yields of the coupling
products with either styrene or 4-tert-butylstyrene (en-
tries 2-5), although the sterically hindered 2-bromotolu-
ene gave a diminished yield (entry 6). Furthermore, it
was found that the reaction also proceeded nicely with
the aliphatic olefin vinylcyclohexane. In all cases tested,
high yields of the trans products were obtained by using
0.05-0.1 mol % of Pd(OAc)2 regardless of the electronic
or sterical variation on the aryl bromides (entries 7-10).
Surprisingly, however, with activated terminal olefins
such as n-butyl acrylate the reaction gave low yields
except for the coupling with the more active 4-bromoben-
zaldehyde (entries 11-13). Cyclic olefins such as nor-
bornene and 3,4-dihydropyran did not participate in the
Heck reaction under these conditions. The reactivity of
aryl triflates and chlorides was also examined. The
catalyst system appeared to be completely ineffective for
the Heck coupling of phenyl triflate17 and chlorobenzene
with styrene.
The data presented in Table 4 show that the efficiency
of this new catalyst system toward the Heck coupling of
aryl bromides and terminal olefins compares18 very
favorably with some of the most active catalyst systems
that utilize expensive ligands and/or require the presence
of various additives. The high activity of Pd(OAc)2 toward
(13) Younes, S.; Tchani, G.; Baziard-Mouysset, G.; Stigliani, J . L.;
Payard, M.; Bonnafous, R.; Tisne-Versailles, J . Eur. J . Med. Chem.
1994, 29, 87-93.
(14) Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289-3291.
(15) Ikeda, Y.; Nakamura, T.; Yorimitsu, H.; Oshima, K. J . Am.
Chem. Soc. 2002, 124, 6514-6515.
(16) Liu, J .-T.; J ang, Y.-J .; Shin, Y.-K.; Hu, S.-R.; Chu, C.-M.; Yao,
C.-F. J . Org. Chem. 2001, 66, 6021-6028.
(17) The reaction with phenyl triflate led to complete consumption
and self-coupling of the triflate starting material, and resulted in the
isolation of diphenyl ether in high yield (83%). Although the formation
of diphenyl ether under these conditions points to a process involving
the coupling between the phenyl triflate and a phenoxide nucleophile,
the exact nature of the facile formation of the aryl ether is not clear at
this time.
(11) Amatore, C.; J utand, A. Acc. Chem. Res. 2000, 33, 314-321.
(12) (a) Shaw, B. L. New J . Chem. 1998, 77-79. (b) Sundermann,
A.; Uzan, O.; Martin, J . M. L. Chem. Eur. J . 2001, 7, 1703-1711.
J . Org. Chem, Vol. 68, No. 19, 2003 7529

TABLE 3. P d (OAc)2-Ca ta lyzed Heck Rea ction s of Ar yl Br om id es w ith Ter m in a l Olefin s, Usin g K3P O4 a s th e Ba sea
a
Unless otherwise noted, all reactions were performed with 1.0 mmol of the aryl bromide, 1.2 mmol of the alkene, and 1.4 mmol of
K3PO4 at 140 °C. b Isolated yield after chromatography. Only the trans isomers were isolated in all cases. c When this reaction was repeated
and run for a longer time (42 h), the product was isolated in quantitative yield. 0.5 mmol of the aryl bromide was used. e 2.0 mmol of
d
PhBr was used.
the reaction of aryl bromides, regardless of the nature of
the substituent groups, is unprecedented. In light of the
low reactivity observed with n-butyl acrylate, which is
normally more reactive than styrene for most of the
existing Heck reaction catalysts, the classical Pd(0)-
Pd(II) catalytic cycle seems highly unlikely.19 Although
several Heck reaction mechanisms involving a Pd(II)-
Pd(IV) catalytic cycle have been advanced previously,4c,g,12
the lack of precedent for a direct oxidative addition of
the aryl bromide to Pd(OAc)2 precludes an underligated
Pd(II)-Pd(IV) catalytic cycle. A new mechanism that
reconciles most of our experimental results was proposed
in Scheme 1. This involves first the formation of a
transient palladacycle I20 by the reaction of Pd(OAc)2 with
(18) Gruber, A. S.; Pozebon, D.; Monteriro, A. L.; Dupont, J .
(19) Although we could not rule out the possibility of the involve-
ment of a Pd(0) species in the catalytic cycle, the formation of palladium
black, which could otherwise be expected at the reaction temperature
and in the absence of a stabilizing ligand, was not observed throughout
the reaction except when the acrylate was used as the terminal olefin.
Tetrahedron Lett. 2001, 42, 7345-7348. The literature data compiled
in Table
4 were based on reactions that were performed under
comparable conditions including the reaction temperature and reaction
time.
7530 J . Org. Chem., Vol. 68, No. 19, 2003

TABLE 4. P d (OAc)2/K3P O4 in DMA a s a n Active Ca ta lyst System for th e Heck Rea ction : Com p a r ison w ith Oth er
Ca ta lyst System s18
SCHEME 1. P r op osed Mech a n ism for th e Heck
Rea ction Ca ta lyzed by P d (OAc)2
reaction of both activated and deactivated aryl bromides
in the absence of any stabilizing ligands or special
additives. Although the reactivity of Pd(OAc)2 under
these conditions is limited only to the coupling of aryl
bromides and unactivated terminal olefins, this limita-
tion is more than offset by the benefit of using a ligand-
free, inexpensive catalyst, as well as by the low cost of
the base used.22
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Heck Rea ction of Ar yl
Br om id es w ith P d (OAc)2 a s th e Ca ta lyst (Ta ble 1, en tr y
4). An oven-dried 10-mL Schlenk flask was charged under Ar
with K3PO4 (298 mg, 1.40 mmol) and DMA (1.0 mL). Bromoben-
zene (105 µL, 157 mg, 1.00 mmol) and styrene (140 µL, 127 mg,
1.20 mmol) were added via syringes. A solution of Pd(OAc)2 in
DMA (1.8 × 10-3 M, 560 µL, 0.0010 mmol) was then added via
syringe. The Schlenk tube was sealed under Ar and placed in
an oil bath preheated to 140 °C (controlled by a J -KEM
temperature controller) and the reaction mixture was stirred
for 19 h at this temperature. After being cooled to room
temperature, the reaction mixture was poured into water (25
mL) and extracted with ethyl acetate (3 × 20 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated to dryness under vacuum. The crude product was
purified by flash chromatography on silica (hexane) to give 168
mg (93%) of pure trans-stilbene.
the olefin.21 The palladacycle I is expected to be able to
undergo oxidative addition by the aryl bromide, generat-
ing the Pd(IV) species II. Base-promoted elimination of
the acetate ion gives intermediate III, which subse-
quently collapses to the Pd(II) species IV and releases
the coupling product. Equilibration of IV with the acetate
ion then regenerates Pd(OAc)2. Additionally, IV itself
could participate in the catalytic cycle in a similar way
to that of the first turnover.
Ack n ow led gm en t. This work was supported in part
by the Petroleum Research Fund, administered by the
American Chemical Society (36466-G1).
In summary, we have shown that Pd(OAc)2, in combi-
nation with K3PO4 as the base and DMA as the solvent,
can be used as a highly reactive catalyst for the Heck
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal conditions and characterization of 3e and 3i. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O034646W
(20) By analogy to other palladacycles, I may exist in equilibration
with its dimeric form:
(22) Although the reactions reported in Tables 1-3 were run on
0.5-2 mmol scales, this protocol is readily scalable as exemplified by
the following reactions performed on a 10 mmol scale:
(21) Electrophilic oxypalladation, including the acetoxypalladation
of alkenes with Pd(OAc)2, is a well-documented process and is involved
in many alkene functionalization reactions such as the Pd(OAc)2-
mediated Wacker-type oxidation, see: Tsuji, J . Transition Metal
Reagents and Catalysts; John Wiley: Chichester, UK, 2000; Chapter 11.
J . Org. Chem, Vol. 68, No. 19, 2003 7531