Palladium-catalysed arylation of acetoacetate esters to yield 2-arylacetic acid esters

Article abstract of DOI:10.1016/j.tetlet.2004.04.022

The coupling reaction between ethyl acetoacetate and a number of aryl halides in the presence of palladium acetate, a bulky and electron rich phosphine and K₃PO₄ is described. The arylated acetoacetate ester is de-acylated under the reaction conditions resulting in the generation of 2-arylacetic acid esters, constituting a mild alternative to direct arylation of carboxylate esters.

Full text of DOI:10.1016/j.tetlet.2004.04.022

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4261–4264
Palladium-catalysed arylation of acetoacetate esters to
yield 2-arylacetic acid esters
Jacob G. Zeevaart,a Christopher J. Parkinsona,* and Charles B. de Koningb
aCSIR Bio/Chemtek, Speciality and Fine Chemicals Programme, Modderfontein, 1645, South Africa
bMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, WITS, 2050, South Africa
Received 9 March 2004; revised 31 March 2004; accepted 6 April 2004
Abstract—The coupling reaction between ethyl acetoacetate and a number of aryl halides in the presence of palladium acetate, a
bulky and electron rich phosphine and K3PO4 is described. The arylated acetoacetate ester is de-acylated under the reaction con-
ditions resulting in the generation of 2-arylacetic acid esters, constituting a mild alternative to direct arylation of carboxylate esters.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The preparation of 2-arylalkanoic acid derivatives
especially arylpropionic acids has received significant
attention during the past few decades since they find
application as nonsteroidal anti-inflammatory drugs
(NSAID) (Fig. 1).1 Arylation of b-dicarbonyl carba-
nions has been investigated as a synthetic strategy to
obtain 2-arylacetic or arylpropionic acids. For example,
the preparation of ibuprofen by way of arylation of
methylmalonic acid esters using an aryllead triacetate
was established many years ago.2 More recently the
copper-catalysed arylation of ethyl cyanoacetate and
diethyl malonate has also been demonstrated, using aryl
iodides.3 However, the palladium-catalysed enolate
arylation reaction for the preparation of 2-arylalkanoic
acid derivatives has probably received the most atten-
tion. This chemistry has been mainly developed by the
groups of Hartwig and Buchwald.4;5
CO2H
CO2H
MeO
Ibuprofen
S-Naproxen
Figure 1. Examples of nonsteroidal anti-inflammatory drugs.
CO2Et
CO2Et
O
X
CO2Et
EtO
R
R
Pd source
(Eq 1)
X=I, Br or Cl
CO2tBu
X
t
CO2 Bu
R
R
Pd source
NaHMDS
(Eq 2)
X=Br or Cl
Two strategies in this regard, leading to arylpropionic
acids have recently been published: (a) palladium-
catalysed arylation of diethyl malonate followed by
methylation,4;6 and (b) direct palladium-catalysed aryl-
ation of propionic or acetic acid esters.5 The arylation of
malonate esters requires electron-rich and bulky phos-
phine ligands (Fig. 2, Eq. 1). Aryl iodides and aryl
bromides are the substrates of choice and, with some
speciality ligands, aryl chlorides can be used as well. The
Figure 2. Synthesis of arylpropionic acids using palladium-catalysed
enolate arylation.
arylated malonate ester is methylated, either in situ or in
a separate reaction, hydrolysed under alkaline condi-
tions and decarboxylated under acidic conditions lead-
ing to the arylpropionic acid.6 The ester arylation
protocol, which is an even more direct route to aryl-
propionic acids, was developed simultaneously by Hart-
wig and Buchwald.5 Typically the tert-butyl ester of
propionic acid is treated with an aryl halide (bromide or
chloride) in the presence of a strong base, palladium and
a bulky phosphine ligand or a bulky imidazolinium
Keywords: Palladium catalysis; Enolate arylation; Arylacetic acid
esters.
* Corresponding author. Tel.: +27-11-6052601; fax: +27-11-6083200;
e-mail: cparkinson@csir.co.za
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.022

4262
J. G. Zeevaart et al. / Tetrahedron Letters 45(2004) 4261–4264
Table 1
carbene (Fig. 2, Eq. 2). A disadvantage of this procedure
is that very specific bases have to be used, sodium hexa-
methyldisilazane (NaHMDS) (for propionate esters)
and LiHMDS (for acetate esters). These bases are also
expensive and moisture sensitive.
Acetoacetate Catalyst
ester
Conv. of Yield 3
(%)a
(mol %)
2a (%)
1
2
3
4
5
1a
1b
1b
1b
1b
1% Pd(dba)2/2% PtBu3
1% Pd(dba)2/2% PtBu3
1% Pd(OAc)2/2% PtBu3
5% Pd(OAc)2/20% PPh3
1% Pd(dba)2/2% PCy3
67
100
97
0
55
45
48
0
Although a large number of enolates have been utilised
in palladium-catalysed arylation chemistry,7 acetoace-
tate esters and acetylacetones, have not yet been suc-
cessfully arylated. The explanation presented for the
lack of success with these substrates is linked to the
ability of the enolates of these compounds to form stable
complexes with metals.4a;d
0
0
a Yield determined by GC with naphthalene as internal standard.
3a was determined by GC (internal standard) to be 55%.
The reaction mixture did not contain any residual aceto-
acetate ester although a substantial amount of bromo-
benzene was present. No 2-phenylacetoacetate tert-butyl
ester could be detected by GC–MS and 1H NMR
spectral analysis.
However, with other metals such as copper, the aryl-
ation of ethyl acetoacetate with 2-halobenzoic acid was
demonstrated in 1929 by Hurtley.8 The conditions,
which consisted of sodium ethoxide in ethanol solution
with copper powder or copper(II) acetate, were later
refined by McKillop and co-workers.9 Employing
sodium hydride and 6 mol % copper(I) bromide in ethyl
acetoacetate solution led to high yields of ethyl b-(2-
carboxyphenyl)acetoacetate from ethyl acetoacetate and
2-bromo or chlorobenzoic acid. a-Substituted b-keto
esters also reacted under the same conditions although
yields were lower. Aryl halides without the ortho-carb-
oxylate group were inactive in these reactions. Aceto-
acetate esters have also been arylated with aryllead
triacetates.10
A similar reaction was observed when ethyl acetoacetate
was used under the same conditions (Table 1, entry 2).
Ethyl phenylacetate was formed in 45% yield. Reactions
were also performed with triphenylphosphine and tri-
cyclohexylphosphine (entries 4 and 5) with no product
formation.
Initially, Pd(dba)2 was used as the catalyst precursor but
Pd(OAc)2 was also found to be as effective (48% yield,
Table 1, entry 3).
The use of other aryl halides was investigated. 4-
Bromoanisole 4a resulted in the formation of ethyl (4-
methoxyphenyl)acetate 5a (Scheme 2) albeit in lower
yield than ethyl phenylacetate (Table 2, entry 1). 4-
Chloroacetophenone (an activated aryl chloride) also
gave the desired arylacetic acid ester 5b but again in
lower yield (Table 2, entry 2). The reaction between
ethyl acetoacetate and 1-bromonaphthalene gave
ethyl (1-naphthyl)acetate 5c albeit in only 15% yield.
Hydrodehalogenation of the aryl halide was found to be
In this Letter we wish to disclose novel palladium-
catalysed conditions for the arylation of acetoacetate
esters resulting in the formation of 2-arylacetic acid esters.
When we attempted the arylation of tert-butyl aceto-
acetate 1a with bromobenzene 2a using mild reaction
conditions (K3PO4, ‘Pd(t-Bu3P)2’, toluene, 90 ꢁC) we did
not find any of the desired arylated acetoacetate ester
but we identified a substantial amount of tert-butyl
phenylacetate 3a (Scheme 1). We assumed that during
the reaction tert-butyl acetoacetate was arylated in the
2-position, which was then de-acylated under basic
conditions to give the phenylacetate ester 3a and
potassium acetate. McKillop has described a similar de-
acylation during the copper-catalysed arylation of aceto-
acetate with 2-bromobenzoic acid.9 This reaction was
described as a retro-Claisen condensation as sodium
ethoxide in ethanol was used, but could also be effected
by treating the 2-arylacetoacetate with 2 M NaOH.11
O
"Pd", 2L
+ Ar-X
CO2Et
Ar
CO2Et
5a-d
K3PO4, toluene
1b
4a, 4-bromoanisole
4b, 4-chloroacetophenone
4c, 1-bromonaphthalene
4d, 4-chloroanisole
Scheme 2. Reagents and conditions: 4 mmol aryl halide, 4.4 mmol
acetoacetate ester, 11 mmol K3PO4, 5 mL toluene, 0.04 mmol
Pd(OAc)2, 0.08 mmol PtBu3ÆHBF4, 90 ꢁC, 16 h (see Table 2 for yields).
Apart from the product tert-butyl phenylacetate 3a,
biphenyl was also formed in small amounts. The yield of
X
O
"Pd", 2L
+
Table 2
CO2R
CO2R
K3PO4, toluene
Aryl halide
Product
Yield (%)
1a, R = t-Bu
1b, R = Et
2a, X=Br
2b, X=Cl
3a, R = t-Bu
3b, R = Et
1
2
3
4a
4b
4c
Ethyl (4-methoxyphenyl)acetate 5a 40a
Ethyl (4-acetophenyl)acetate 5b
Ethyl (1-naphthyl)acetate 5c
30b
15c
Scheme 1. Reagents and conditions: 4 mmol bromobenzene, 4.4 mmol
acetoacetate ester, 11 mmol K3PO4, 5 mL toluene, 0.04 Pd(dba)2 or
Pd(OAc)2, 0.08 mmol ligand, 90 ꢁC, 16 h (see Table 1 for catalyst and
ligand, percentage conversion of 2 and yields).
a Isolated yield, 35% anisole.
b Isolated yield, 40% acetophenone.
c Isolated yield, 58% naphthalene.

J. G. Zeevaart et al. / Tetrahedron Letters 45(2004) 4261–4264
4263
loading was lowered to 0.2 mol % palladium and 0.4% of
7 a slower reaction was observed. After 16 h at 90 ꢁC,
42% of the chlorobenzene had been consumed while
34% of 3b had been formed. After a total of 70h the
product yield was 49% with a 63% chlorobenzene con-
version (Table 3, entry 6). Finally, a reaction was per-
formed with a de-activated aryl chloride. The reaction
between 4-chloroanisole 4d and ethyl acetoacetate pro-
ceeded smoothly and gave ethyl 4-methoxyphenylace-
tate 5d (see Scheme 2) in a 75% isolated yield after 40h
at 90 ꢁC, using 0.5% Pd(OAc)2 and 1% of 7 (Table 3,
entry 7).
PtBu2
PtBu2
6
7
Figure 3.
a major side reaction that contributed to aryl halide
consumption.
The choice of base has been demonstrated to be essential
to the outcome of many arylation reactions.4;5;7;12 The
reaction of 1b with 2a to afford ethyl phenylacetate 3b
was chosen to investigate this variable. When K2CO3
was used as the base, 20–25% of the anticipated product,
ethyl phenylacetate 3b, was formed. In addition, a sim-
ilar amount of another product, ethyl 2-phenylaceto-
acetate 8, was identified by spectroscopic techniques.
When sodium tert-butoxide was used as the base, the
starting materials were consumed and only a small
amount of product 3b was formed.
In an effort to improve the yield of the arylacetate the
use of the ligand di-tert-butyl biphenyl phosphine 64b
was evaluated (Fig. 3). The use of 6 led to the selective
reaction of 2a with 1b to afford ethyl phenylacetate 3b in
56% yield with 95% conversion of bromobenzene (Table
3, entry 1). Full consumption of bromobenzene and a
yield of 68% for this reaction was achieved when
2.2 equiv of ethyl acetoacetate (Table 3, entry 2) were
used.
This prompted us to test the biphenyl ligand with an
extra methyl substituent on the second phenyl ring, that
is 7. This ligand has been shown to be especially active in
malonate ester arylation.4b Again, this reaction resulted
in 89% yield of ethyl phenylacetate when 1 equiv of ethyl
acetoacetate was used and 93% with 2 equiv of ethyl
acetoacetate (Table 3, entries 3 and 4).
Subsequently, an investigation of our standard trans-
formation (1b + 2a fi 3b) by varying the concentration
of K3PO4 was conducted. The same by-product 8 was
detected in all reactions but to a much smaller extent
than with the other bases. In a typical reaction, with the
molar ratio of K3PO4 to ethyl acetoacetate being 2.4:1,
the amount of side-product 8 (Fig. 4) was between 1%
and 5%. When the base to substrate ratio was changed
to 2:1, between 10% and 15% of 8 was detected, while
the ethyl phenylacetate yield dropped by a similar
amount. This effect was further demonstrated by low-
ering the base concentration to 0.6 equiv K3PO4 in
relation to ethyl acetoacetate. Only 15% of the desired
product 3b was formed and 55% of 8 was produced.
From this observation it was clear that ethyl acetoace-
tate is arylated in the 2-position during the reaction. The
formation of ethyl phenylacetate then occurs when this
intermediate undergoes base mediated cleavage. This
second step is clearly dependant on base concentration
and strength. To demonstrate this, separate reactions
were run with a lower concentration of K3PO4 to form
8, followed by addition of extra K3PO4 and further
heating. It was noticed that the intermediate 8 was
depleted entirely after heating for 5 h with an increase in
ethyl phenylacetate 3b yield equal to the intermediate 8
consumed.
The use of more than 1 equiv of ethyl acetoacetate is
thought to lead to improved yields in this reaction; ethyl
acetoacetate is the limiting reagent as it is consumed
faster than the aryl halide. An increase in ethyl phenyl-
acetate yield was also observed when tri-tert-butyl-
phosphine was used with 2 equiv of ethyl acetoacetate
(58% vs 48%, Table 1, entry 3).
Since biphenyl ligands 6 and 7 are known to be active
with aryl chlorides in other arylation reactions, chloro-
benzene 2b was examined in a reaction employing the
standard reaction conditions using ligand 7. Ethyl
phenylacetate 3b was produced in 93% yield (by GC,
88% isolated yield, Table 3, entry 5). When the catalyst
Table 3
Aryl
halide
Catalyst
(mol %)
Conv. of
PhBr (%)
Yield
(%)
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2b
4d
1% Pd(OAc)2/2% 6
2% Pd(OAc)2/4% 6
1% Pd(OAc)2/2% 7
2% Pd(OAc)2/4% 7
2% Pd(OAc)2/4% 7
0.2% Pd(OAc)2/0.4% 7
0.5% Pd(OAc)2/1% 7
95
100
100
100
100
63
56a
68b
89a
93b
93b
49b
75b;c
O
O
O
OEt
OEt
100
a Conditions: 4 mmol bromobenzene, 4.4 mmol acetoacetate ester,
11 mmol K3PO4, 5 mL toluene, 90 ꢁC, 16 h.
b Conditions: 2 mmol bromobenzene, 4.4 mmol acetoacetate ester,
11 mmol K3PO4, 5 mL toluene, 90 ꢁC, 16 h.
8
9
c Isolated yield.
Figure 4.

4264
J. G. Zeevaart et al. / Tetrahedron Letters 45(2004) 4261–4264
3. (a) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M.
J. Org. Chem. 1993, 58, 7606; (b) Konopelski, J. P.;
It seems that not only the strength of the base but also
its availability must be tempered to match the rate of
enolate formation with the rate of the arylation reaction.
The same observation has been made by Buchwald in
the amidation of aryl halides.12c Both K3PO4 and
K2CO3 are thought to be thermodynamically strong
bases in aprotic solvents but their low solubility in tol-
uene ensures a slow formation of enolate. From the fact
that no arylation of ethyl phenylacetate was observed
using K3PO4 as the base while the use of sodium tert-
butoxide under identical reaction conditions, did yield
ethyl diphenylacetate 9 (58%), it is concluded that
K3PO4 is not strong enough to deprotonate a phenyl
acetate ester.
ꢀ
Hottenroth, J. M.; Oltra, H. M.; Veliz, E. A.; Yang, Z.-C.
Synlett 1996, 609; (c) Hang, H. C.; Drotleff, E.; Elliott, G.
I.; Ritsema, T. A.; Konopelski, J. P. Synthesis 1999, 398.
4. (a) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 1473; (b) Fox, J. M.; Huang, X.; Chieffi, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360; (c)
Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541;
(d) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4,
269.
5. (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7996; (b) Lee, S.; Beare, N. A.; Hartwig, J. F. J.
Am. Chem. Soc. 2001, 123, 8410; (c) Gooßen, L. J. Chem.
Commun. 2001, 669; (d) Jørgensen, M.; Lee, S.; Liu, X.;
Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 12557; (e) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig,
J. F. J. Am. Chem. Soc. 2003, 125, 11176.
In conclusion, this work constitutes the first example of
a palladium-catalysed intermolecular arylation of an
acetoacetate ester. We have demonstrated the formation
of the arylated acetoacetate ester (e.g., 8) and its in situ
base catalysed de-acylation to an arylacetate ester (e.g.,
3b). A variety of mono-arylated acetate esters can be
prepared in this manner and the reaction is applicable to
both aryl bromides and chlorides.
6. Ugo, R.; Nardi, P.; Psaro, R.; Roberto, D. Gazz. Chim.
Ital. 1992, 122, 511.
7. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36,
234.
8. Hurtley, W. R. H. J. Chem. Soc. 1929, 1870.
9. (a) Bruggink, A.; McKillop, A. Tetrahedron 1975, 31,
2607; (b) McKillop, A.; Rao, D. P. Synthesis 1977, 759.
10. Pinhey, J. T.; Rowe, B. A. Aust. J. Chem. 1980, 33, 113.
11. Acetoacetate esters are known to be de-acylated under
strong alkaline conditions: Adams, R.; Blomstrom, D. C.
J. Am. Chem. Soc. 1953, 75, 3403, and; Kaupp, G.;
Freytler, B.; Behmann, B. Synthesis 1985, 5, 555.
12. (a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1998, 63, 6546; (b) Gaertzen, O.; Buchwald, S.
L. J. Org. Chem. 2002, 67, 465; (c) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421.
References and notes
1. Lednicer, D.; Mitscher, L. A. In The Organic Chemistry of
Drug Synthesis; John Wiley: New York, 1980; Vol. 2, p 62.
2. Pinhey, J. T.; Rowe, B. A. Tetrahedron Lett. 1980, 21, 965.