Practical synthesis of 2-arylacetic acid esters via palladium-catalyzed dealkoxycarbonylative coupling of malonates with aryl halides

Article abstract of DOI:10.1002/adsc.201100102

A new palladium-based system was developed that catalyzes the coupling of aryl halides with diethyl malonates in the presence of mild bases. In the course of the reaction, the intermediately formed diethyl arylmalonate is directly converted into the arylacetic acid ester via liberation of carbon dioxide and an alkanol. This cross-coupling/dealkoxycarbonylation process provides an efficient and high-yielding synthetic entry to diversely functionalized arylacetic acid esters. Two complementary protocols were developed, one of which is optimal for electron-rich, the other for electron-poor aryl halides. Both make use of low loadings of palladium(0) bis(dibenzylideneacetone) (0.5 mol%)/tri-tert-butylphosphonium tetrafluoroborate (1.1 mol%) as the catalyst and diethyl malonate as the reaction solvent. The new procedures are particularly effective for sterically hindered substrates. Copyright

Full text of DOI:10.1002/adsc.201100102

FULL PAPERS
DOI: 10.1002/adsc.201100102
Practical Synthesis of 2-Arylacetic Acid Esters via Palladium-
Catalyzed Dealkoxycarbonylative Coupling of Malonates with
Aryl Halides
Bingrui Song,a Felix Rudolphi,a Thomas Himmler,b and Lukas J. Gooßena,*
a
FB Chemie – Organische Chemie, TU Kaiserslautern, Erwin-Schrçdinger-Straße, Geb. 54, D-67663 Kaiserslautern,
Germany
Fax : (+49)-631-205-3921; e-mail: goossen@chemie.uni-kl.de
Bayer CropScience AG, Alfred-Nobel-Str. 50, D-40789 Monheim, Germany
b
Received: February 10, 2011; Published online: May 23, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100102.
Abstract: A new palladium-based system was devel- tron-rich, the other for electron-poor aryl halides.
oped that catalyzes the coupling of aryl halides with Both make use of low loadings of palladium(0) bis-
diethyl malonates in the presence of mild bases. In
G
(0.5 mol%)/tri-tert-butyl-
the course of the reaction, the intermediately formed phosphonium tetrafluoroborate (1.1 mol%) as the
diethyl arylmalonate is directly converted into the catalyst and diethyl malonate as the reaction solvent.
arylacetic acid ester via liberation of carbon dioxide The new procedures are particularly effective for
and an alkanol. This cross-coupling/dealkoxycarbo- sterically hindered substrates.
nylation process provides an efficient and high-yield-
ing synthetic entry to diversely functionalized aryl-
acetic acid esters. Two complementary protocols Keywords: arylacetic acids; arylation; dealkoxycar-
were developed, one of which is optimal for elec- bonylation; diethyl malonate; palladium
Introduction
formatsky reagents,[8] tin,[9] copper,[10] and other eno-
lates (IV),[11] or ketene acetals (V) have been devel-
Methylenecarboxyl groups are key functionalities in oped.[12] Among these reactions, the palladium-cata-
many biologically active compounds. Examples are lyzed couplings between aryl halides and enolates de-
auxins acting as phytohormonal growth regulators,[1] veloped by Buchwald[13] and Hartwig[14] (VI) are par-
as well as analgesics and non-steroidal anti-inflamma- ticularly straightforward, but the deprotonation of
tory drugs (NSAIDs) (Figure 1).[2,3] The development acetic acid esters requires strong and expensive bases,
of mild and efficient synthetic methods for the intro-
duction of methylenecarboxyl groups into functional-
ized molecules is thus of great interest.
Traditional methods for the preparation of arylace-
tic acids include the hydrolysis of benzyl cyanides
(Scheme 1, I),[4] the carbonylation of benzyl halides
with metal catalysts (II),[5] and the electrocatalytic
carboxylation of benzyl chlorides (III).[6] However,
these processes have inherent disadvantages. For ex-
ample, neither benzyl cyanides nor benzyl halides are
available in great structural variety.[7] Moreover, toxic
carbon monoxide is required in carbonylation reac-
tions, while electrocatalytic carboxylations require an
elaborate reaction set-up.
As modern alternatives, transition metal-catalyzed
cross-coupling reactions between aryl halides and Re- matory drugs.
Figure 1. Examples of auxins and non-steroidal anti-inflam-
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Bingrui Song et al.
FULL PAPERS
Scheme 2. Proposed mechanism for the palladium-catalyzed
dealkoxycarbonylative cross-coupling.
Scheme 1. Traditional and modern syntheses of arylacetic
acids.
such as alkali metal hexamethyldisilazides or tert-but- lized by the newly introduced aryl group, is liberated
oxides. A broader range of functional groups is toler- together with the haloformate 8.[20] On quenching the
ated when using stabilized ketene derivatives or zinc reaction mixture with water, hydrolysis of these inter-
enolates as the coupling partners.[15] The inverse ap- mediates leads to the desired arylacetic acid ester (3)
proach, namely the coupling of a-bromoacetic acid along with an alcohol (4) and carbon dioxide.
derivatives with arylboronic acids (VII) is also com-
Kondo reported that some aryl iodides and activat-
patible with many functional groups, but not effective ed aryl bromides can be coupled this way with diethyl
for sterically demanding substrates, and requires the malonate in the presence of a Pd-catalyst and
use of costly boron reagents.[16]
10 equivalents of Cs2CO3.[21] However, it takes up to
An interesting but less well-known alternative strat- 76 h until the coupling and the subsequent dealkoxy-
egy to obtain 2-arylalkanoic acids consists in an initial carbonylation reach reasonable conversions. C¸ etin-
cross-coupling of malonates or b-keto esters with aryl kaya et al. achieved higher yields within shorter reac-
halides, followed by dealkoxycarbonylation or retro- tion times for a range of aryl halides when employing
Claisen condensation of the thermally labile inter- specially synthesized palladium complexes with cus-
mediates (Scheme 1, VIII).[17] The coupling reaction is tomized N-heterocyclic carbene ligands.[22] However,
mediated by Pd[18] and Cu catalysts.[19] The advantage these ligands are not commercially available and ac-
of this approach is that mild bases suffice to deproto- cessible only via multistep syntheses. De Koning et al.
nate the acidic b-dicarbonyl compounds. This synthet- investigated b-keto esters as alternative substrates
ic pathway is particularly practical if the dealkoxycar- and successively reported a palladium- and a copper-
bonylation takes place in situ under the conditions of catalyzed protocol for the arylation of acetoacetate
the cross-coupling.
esters followed by in situ deacetylation.[23] However,
A plausible mechanism for the dealkoxycarbonyla- these protocols have a rather narrow scope, and the
tive cross-coupling of dialkyl malonates and aryl hal- deacetylation step often does not proceed to comple-
ides is depicted in Scheme 2.[20] Oxidative addition of tion.
the aryl halide (2) to the Pd(0) complex (a) gives rise
We evaluated all known protocols in the context of
to the arylpalladium(II) halide complex (b). The the synthesis of ortho-substituted aryl acetates, which
halide substituent is then replaced by an enolate nu- are important precursors for active substances in crop
cleophile (c) formed via deprotonation of malonate protection.[24] However, only unsatisfactory yields
(1). Reductive elimination of dialkyl a-arylmalonate were achieved in couplings of sterically demanding
(5) from the resulting palladium enolate complex (d) aryl halides, e.g., 2,6-dimethylphenyl bromide. We
regenerates the Pd(0) complex, closing the catalytic thus came to the conclusion that this appealing syn-
circle for the palladium. At elevated temperatures, thetic approach had not yet reached synthetic maturi-
the dialkyl a-arylmalonate (5) directly undergoes ty. More effective catalyst systems involving commer-
dealkoxycarbonylation, presumably via a nucleophilic cially available components and inexpensive bases
addition-elimination sequence. A base or halide nu- were clearly required to advance this reaction into a
cleophile adds to one of the ester carbonyl groups broadly applicable, practical synthetic entry to the im-
with formation of the adduct 6. In the subsequent portant substrate class of arylacetic acids.
elimination step, enolate 7, which is resonance-stabi-
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Practical Synthesis of 2-Arylacetic Acid Esters via Palladium-Catalyzed Dealkoxycarbonylative Coupling
Results and Discussion
(entry 3). In the presence of milder bases such as po-
tassium carbonate (entry 5) or bicarbonate (entry 6),
As a first step towards an effective reaction protocol the dealkoxycarbonylation proceeds much more
for a dealkoxycarbonylative coupling of malonates, slowly. In an attempt to improve the solubility of po-
we investigated the dealkoxycarbonylation reaction of tassium phosphate in the reaction solvent, we added
diethyl 4-tolylmalonate (5a) at 1608C under various catalytic quantities of 18-crown-6. This dramatically
conditions (Table 1). We found that this compound, increased the efficiency of the dealkoxycarbonylation,
which would be the primary product of the desired and almost quantitative yields of the desired arylace-
cross-coupling between an aryl halide and diethyl tate 3a were obtained (entry 8). Control experiments
malonate, is thermally rather unstable. In the pres- confirmed that the crown ether or DEM solvent
ence of cesium carbonate and using polar solvents alone do not promote the reaction (entries 9 and 10),
such as NMP, it rapidly decomposed with formation and that under these conditions, diethyl malonate is a
of multiple products. Only traces of the desired ethyl more effective reaction solvent than even NMP
4-tolyacetate were detected (entry 1). The selectivity (entry 11).
of the dealkoxycarbonylation was substantially higher
when using potassium phosphate as the base. How- koxycarbonylation, we next examined the cross-cou-
ever, the desired product was obtained in only 32% pling step using the reaction of 4-bromotoluene (2a)
yield (entry 2). We next investigated less polar sol- and diethyl malonate as the model. We employed
vents, but did not achieve better results. DEM as both substrate and solvent, and tested vari-
Having thus found optimal conditions for the deal-
ACHTUNGTRENNUNG
We finally tested the substrate for the desired cou- ous palladium catalysts, ligand systems, and bases
pling reaction, diethyl malonate (DEM), as the sol- (Table 2).
vent. This inexpensive, high-boiling compound pos-
sesses a moderate polarity, so that it partially dis- nation of Pd
As the initial palladium catalyst, we used a combi-
(dba)2 and P(t-Bu)3 in the form of its air-
N
ACHTUNGTRENNUNG
solves inorganic bases (entries 3–10). We were pleased stable, easy-to-handle HBF4 adduct. This catalyst is
to see that the selectivity of the dealkoxycarbonyla- known to mediate the cross-coupling of aryl halides
tion improved under these conditions (entry 3). Vari- and malonates. Even at the elevated temperature of
ous bases were tested. Not only the expensive cesium 1608C, the arylmalonate 5a remained the major prod-
carbonate (entry 4) but also the much less costly po- uct for most bases tested (Table 2, entries 1–6). Only
tassium phosphate effectively mediated the reaction cesium carbonate gave the dealkoxycarbonylated
product 3a as the main product, albeit in low yield
(entry 3). The selectivity changed dramatically when
18-crown-6 was added to the reaction mixture
Table 1. Dealkoxycarbonylation of diethyl 4-tolylmalonate.[a]
(entry 7). In combination with potassium bases, this
additive strongly facilitated the dealkoxycarbonyla-
tion, and the arylmalonate was no longer detected.
The highest yields of the arylacetate were achieved
with potassium phosphate (entries 8 and 9). Control
experiments revealed that ammonium salts (en-
tries 11–13) were inferior as phase-transfer catalysts,
and that DMSO (entry 14), which is known to facili-
tate decarboxylation reactions,[25] is not effective in
this context. The presence of stoichiometric quantities
of water has a negative effect on the reaction out-
come (entry 15). We next evaluated various palladium
precursors and phosphine ligands (entries 16–20).
These experiments revealed that several palladium
precursors can be employed, but none of them pos-
Entry Base
Additive Solvent Conv. Yield
[%]
[%]
1
2
3
4
5
6
7
8
Cs2CO3
–
–
–
–
–
–
–
NMP
NMP
100
57
4
K3PO4
K3PO4
Cs2CO3
K2CO3
KHCO3
K2CO3/KHCO3
K3PO4
–
32
40
38
12
11
5
97
2
1
DEM[b] 50
DEM[b] 40
DEM[b] 14
DEM[b] 16
DEM[b] 18
[c]
18-C-6[d] DEM[b] 99
9
10
11
18-C-6[d] DEM[b]
DEM[b]
18-C-6[d] NMP
2
1
42
sesses a higher activity than Pd
the phosphine is much more critical, and besides with
(t-Bu)3, we achieved reasonable yields only with
JohnPhos (38%). Under the optimal conditions using
Pd(dba)2 (0.5 mol%), (t-Bu)3·HBF4 (1.1 mol%),
ACHTUNGRTEN(NNUG dba)2. The choice of
–
–
PACHTUNGTRENNUNG
K3PO4
42
[a]
Reaction conditions: 2a (0.50 mmol), base (1.4 mmol), ad-
ditive (0.25 mmol), solvent (1.0 mL), 1608C, 8 h. Yields
were determined by GC analysis, with n-tetradecane as
internal standard.
Diethyl malonate.
K2CO3 (1.5 mmol), KHCO3 (1.5 mmol).
18-Crown-6.
A
PACHTUNGTRENNUNG
K3PO4 (2.8 equiv.), and 18-crown-6 (0.5 equiv.) in di-
ethyl malonate (6.6 equiv.) at 1608C, ethyl 4-tolylace-
tate 3a was formed in 88% yield within only 8 h
(entry 7). Not even traces of the malonate 5a were de-
tected in the reaction mixture.
[b]
[c]
[d]
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Table 2. Optimization of the dealkoxycarbonylative cross-
Table 3. (Continued)
coupling.[a]
Substrate
Product
Yield [%]
96[b]
95
86
Entry “Pd”
Ligand
Base
Additive Yield
[%]
5a 3a
[c]
1[b]
2[b]
3[b]
4[b]
5[b]
6
Pd
Pd
Pd
Pd
Pd
Pd
N
P
P
P
P
P
P
G
–
–
–
–
–
–
83 10
82 18
88[c]
93
9
90
20
1
47 38
50 46
7
8
9
Pd
G
P
E
0
0
0
0
88
80
75
9
[c]
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
P
P
P
P
P
P
P
P
P
P
P
P
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
R
93
10
11
12
13
14
15
16
17
18
19
20
29 45
20 57
91
ACHTUNGTRENNUNG
A
(t-Bu)3[c] K3PO4 DMSO[f] 70 27
45 19
94
A
E
A
0
0
0
0
2
75
71
60
76
38
[allylPdCl]2
(t-Bu)3[c] K3PO4 18-C-6[d]
83[b]
89[b]
68
Pd
Pd
Pd
N
K3PO4 18-C-6[d]
K3PO4 18-C-6[d]
ACHTUNGTRENNUNG
JohnPhos K3PO4 18-C-6[d]
[a]
Reaction conditions: 1a (1.00 mmol), diethyl malonate
(6.6 mmol), Pd-source (0.5 mol%), ligand (1.1 mol%),
base (2.8 mmol), additive (0.5 mmol); entries 1–6: 1508C,
16 h; entries 6–20: 1608C, 8 h. [allylPdCl]2 =allylpalladi-
ACHTUNGTRENNUNGum(II) chloride dimer; JohnPhos=(2-biphenylyl)di-tert-
88
butylphosphine. Yields were determined by GC analysis,
with n-tetradecane as internal standard.
[b]
89
Pd
ACHTUNGTRENNUNG(dba)2 (1.0 mol%), PACHTUNGTERN(NUGN t-Bu)3·HBF4 (2.2 mol%), bases
(2.3 mmol).
PACHTUNGTRENNUNG
[c]
[d]
[e]
[f]
15[d,e]
Tetrabutylammonium fluoride hydrate.
1.00 mmol.
15[d,f]
Table 3. Reaction scope of substituted aryl halides.[a]
[a]
Reaction conditions A: 1, 9 or 10 (1.00 mmol), Pd
ACHTUNGTRENNUNG(dba)2
(0.5 mol%), P(t-Bu)3·HBF4 (1.1 mol%), diethyl malonate
AHCTUNGTRENNUNG
(6.6 mmol), 18-crown-6 (0.5 mmol), K3PO4 (2.8 mmol),
1608C, 8 h. Yield of isolated product.
12 h.
1708C, 12 h.
GC yields.
[b]
[c]
[d]
[e]
[f]
48% of the m-xylene was detected.
20% of benzonitrile was detected.
Substrate
Product
Yield [%]
87
We also performed mechanistic studies to validate
the proposed reaction pathway (Scheme 2). The de-
tection of CO2 with the help of lime water and of eth-
anol by H NMR supports this mechanism. The obser-
94[b]
1
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Practical Synthesis of 2-Arylacetic Acid Esters via Palladium-Catalyzed Dealkoxycarbonylative Coupling
vation that dimethyl malonate displays a similar reac-
In order to find an alternative set of conditions
tivity to the diethyl derivative excludes an alternative which is optimal for sterically hindered substrates, we
pathway in which ethene is eliminated in the dealk- used the reaction of 2-bromo-m-xylene 2n with dieth-
A
yl malonate as a model to reevaluate various reaction
Having thus found an effective and practical proto- conditions. The results are summarized in Table 4.
col to prepare ethyl arylacetates, we next explored its Under none of the conditions tested was the malonate
scope by coupling a large variety of aryl halides with detected in significant quantities, confirming that in
diethyl malonate under the previously optimized con- contrast to the previous model reaction of 2a, the de-
ditions. As shown in Table 3, the dealkoxycarbonyla- carboxylation step is not critical for this sterically de-
tive cross-coupling reaction proceeded very well for manding substrate. Under the previous reaction con-
electron-rich aryl halides. In all cases, the dealkoxy- ditions, the arylacetate 3n was obtained in low yields,
carbonylated products were exclusively obtained in along with large amounts of m-xylene resulting from
high yields. Various functional groups were tolerated protodehalogenation (entry 1). Without 18-crown-6,
in para (2b–e), ortho (2f), and meta (2g) positions on the yield was similarly unsatisfactory (entry 2).
the aryl ring. 2-Bromonaphthalene (2h) and 9-bromo-
The yields improved substantially when employing
phenanthrene (2i), as well as 3-bromothiophene as an carbonate bases (entries 3 and 4). A systematic study
example of an electron-rich heteroaryl bromide (2j), revealed that the optimal base consists of a 1:1 mix-
were also converted in excellent yields. The new pro- ture of potassium carbonate and bicarbonate. The de-
tocol can be applied also to the coupling of aryl chlor- sired arylacetate 3n was detected in 80% yield with
ides and iodides (9a and 10a). 4-Chlorophenyl bro- the adapted conditions (entry 7). Control experiments
mide (2k) underwent coupling at both halides to give confirmed that a 1:1 ratio between K2CO3 and
the corresponding diester in good yield within a short KHCO3 is crucial for the selectivity of cross-coupling
time. Due to the good ability of the catalyst to acti- vs. protodehalogenation (entries 9 and 10). The origin
vate aryl chlorides, no differential reaction of the Cl of the cooperative effect of these two bases is still un-
and Br groups was observed. Under the reaction con- clear.
ditions, unprotected carboxylic acid groups (2l) are
This second protocol was also effective in the cou-
converted into the corresponding ethyl esters, pre- pling of the electron-deficient substrate 2p (70%
sumably via transesterification with the diethyl malo- yield), which had given only 15% using the protocol
nate present in excess, or condensation with the etha-
nol liberated during the dealkoxycarbonylation step.
In analogy, phenolic OH groups were converted into
Table 4. Optimization for 2-bromo-m-xylene.[a]
the ethyl ethers (2m).
However, the performance limit of this protocol
was reached for sterically hindered substrates such as
2-bromo-m-xylene 2n, and for electron-deficient aryl
halides such as 4-bromobenzonitrile 2p. In both cases,
dehalogenation of the aryl halides was the major side
reaction, and the products were obtained in unsatis-
factory yields. When b-keto esters were subjected to
the same reaction conditions, the phenylacetic acid
derivatives were exclusively formed. This confirms
the findings by de Koning that the retro-Claisen reac-
tion is faster than the dealkoxycarbonylation.[23]
These results indicate that the reaction protocol is
effective mainly for the coupling of electron-rich aryl
halides. For these substrates, the dealkoxycarbonyla-
tion proceeds slowly compared to the cross-coupling,
so that it needs to be facilitated by the most effective
mediator, namely the combination of potassium phos-
phate and 18-crown-6. In contrast, the decarboxyla-
tion proceeds more rapidly than the cross-coupling
for electron-deficient as well as sterically demanding
aryl halides.[26] For these substrates, the bases and con-
ditions must be adjusted such that the cross-coupling
step proceeds with optimal selectivity, so as to avoid
the undesired dehalogenation reactions.[27]
Entry Base [equiv.]
Additive Yield [%]
5n
3n
1
K3PO4 (2.8)
18-C-6[b]
0
1
1
0
0
0
0
0
0
0
15[c]
12
2
K3PO4 (2.8)
–
–
–
–
–
–
–
–
–
3
K2CO3 (2.8)
54[d]
31
4
Cs2CO3 (2.8)
5
6
KHCO3 (2.8)
K3PO4 (1.5)/KHCO3 (1.5)
14[e]
51
80
19
65
7
8
9
10
K2CO3
(1.5)/KHCO
(1.5)
Na2CO3 (1.5)/KHCO3 (1.5)
K2CO3 (2.0)/KHCO3 (1.0)
K2CO2 (1.0)/KHCO3 (2.0)
54
[a]
Reaction
conditions:
2n
(1.00 mmol),
PdACHTUNGTRENNUNG(dba)2
(0.5 mol%),
PACHTNGUTRENNU(G t-Bu)3·HBF4 (1.1 mol%), base (2.8–
3.0 mmol), additive (0.5 mmol), diethyl malonate
(6.6 mmol), 1608C, 8 h. Yields were determined by GC
analysis, with n-tetradecane as internal standard.
18-crown-6.
48% of m-xylene was detected.
32% of m-xylene was detected.
[b]
[c]
[d]
[e]
32% of 2n and 17% of m-xylene were detected.
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Table 5. Reaction scope for sterically hindered and electron-
optimized for electron-rich compounds. Encouraged
by these spot checks, we explored the scope of the
new conditions for various aryl halides (Table 5).
The results confirm that the second set of condi-
tions is superior for the coupling of sterically demand-
ing and electron-deficient aryl bromides. The protode-
halogenation was largely suppressed, and a good
range of arylacetates was obtained in high yields.
Common functionalities such as cyano, ester, benzoyl,
trifluoromethyl, acetyl, and nitro groups were tolerat-
ed (3p–w). We were delighted to find that the condi-
tions were also suitable for the conversion of aryl
chlorides into the corresponding aryl acetates.
deficient substrates.[a]
Substrate
Product
Yield [%]
81
Test reactions confirmed that the protocols used in
Table 3 and Table 5 are complementary to each other.
The first, which involves potassium phosphate in com-
bination with 18-crown-6 as the base, is highly effec-
tive for the coupling of electron-rich aryl halides but
gives low yield for electron-deficient or sterically de-
manding substrates (Table 3, 3n and 3p). In contrast,
the second, which is based on a potassium carbonate/
bicarbonate mixture, allows the coupling of electron-
poor and sterically demanding aryl halides, but is less
effective for the coupling of electron-rich substrates
(Table 5, 3a).
83
70
77
93
93
Conclusions
95
A new palladium catalyst system was developed that
allows the convenient synthesis of diversely function-
alized arylacetates from easily available aryl halides
and diethyl malonate in the presence of mild bases.
The reaction proceeds via the arylation of diethyl
malonate with formation of diethyl 2-arylmalonates.
These intermediates directly undergo a dealkoxycar-
bonylation to give arylacetic acid esters along with
CO2 and ethanol. The dealkoxycarbonylation step
proceeds rapidly for electron-deficient and sterically
demanding derivatives, but is much slower for elec-
tron-rich 2-arylmalonates.
82
73
60
77
88
Two complementary reaction protocols were neces-
sary to provide a general synthetic entry to alkyl 2-ar-
ylacetates. The optimal conditions for the coupling of
73
electron-rich aryl halides involve PdACHTNUGRTNENUG(dba)2 (0.5%)/PACHUTNGTREN(NUGN t-
87
Bu)3·HBF4 (1.1%) as the catalyst and 18-crown-6
(0.5 equiv.)/potassium phosphate (2.8 equiv.) as the
base. This base/crown ether combination is essential
for a quantitative dealkoxycarbonylation.
70
In contrast, electron-deficient and sterically de-
manding aryl halides are best coupled in the absence
of crown ether, using a 1:1 potassium carbonate/bicar-
bonate mixture as the base. This way, the competing
protodehalogenation of the aryl halides, otherwise a
major side reaction, is effectively suppressed.
16[b,c]
[a]
Reaction conditions B: 2 or 9 (1.00 mmol), Pd
ACHTUNGTRENNUNG(dba)2
(0.5 mol%), P(t-Bu)3·HBF4 (1.1 mol%), diethyl malonate
AHCTUNGTRENNUNG
(6.6 mmol), K2CO3 (1.5 mmol), KHCO3 (1.5 mmol),
1608C, 8 h. Yield of isolated product.
GC yield.
[b]
[c]
Overall, the new protocols, characterized by the use
of commercially available, easy-to-handle catalysts
82% of malonate product 5a was detected by GC.
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Adv. Synth. Catal. 2011, 353, 1565 – 1574

Practical Synthesis of 2-Arylacetic Acid Esters via Palladium-Catalyzed Dealkoxycarbonylative Coupling
tassium bicarbonate (1.5 mmol) and diethyl malonate
and mild bases as well as a high functional group tol-
erance, have decisively advanced the dealkoxycarbo-
nylative cross-coupling of aryl halides and dialkyl
malonates towards being a general and practical syn-
thetic entry to the important substrate class of aryl-
acetic acid derivatives.
(6.6 mmol). The reaction vessel was evacuated and filled
with nitrogen three times. The reaction mixture was stirred
at 1608C for 8 h. Upon completion, the reaction solution
was cooled, diluted with ethyl acetate. The solution was
washed successively with water (20 mL), saturated sodium
bicarbonate solution (20 mL) and then with brine (20 mL),
dried over MgSO4, filtered, and the solvents removed under
vacuum. Purification of the residue by column chromatogra-
phy (SiO2, hexane/ethyl acetate gradient) gave the corre-
sponding products 3n–w.
Experimental Section
General Methods
Ethyl 2-p-tolylacetate (3a): Compound 3a was synthesized
according to the general procedure A from diethyl malonate
(1.0 mL, 6.6 mmol) and 4-bromotoluene (171 mg, 123 mL,
1.00 mmol) or 4-chlorotoluene (128 mg, 120 mL, 1.00 mmol)
or 4-iodotoluene (218 mg, 1.00 mmol). After purification by
flash column chromatography (SiO2, ethyl acetate-hexane
5:95), 3a was obtained as a colorless oil; yield: 155 mg
(87%); 148 mg (83%); 159 mg (89%). The spectroscopic
data (NMR) matched those reported in the literature for
ethyl 2-p-tolylacetate [CAS-No. 14062-19-2].
Ethyl 2-(4-methoxyphenyl)acetate (3b): Compound 3b
was synthesized according to the general procedure A from
diethyl malonate (1.0 mL, 6.6 mmol) and 4-bromoanisole
(187 mg, 128 mL, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 10:90),
3b was obtained as a light yellow oil; yield: 183 mg (94%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(4-methoxyphenyl)acetate [CAS-
No. 14062-18-1].
Ethyl 2-(4-(dimethylamino)phenyl)acetate (3c): Com-
pound 3c was synthesized according to the general proce-
dure A from diethyl malonate (1.0 mL, 6.6 mmol) and 4-
bromo-N,N-dimethylaniline (200 mg, 1.00 mmol). After pu-
rification by flash column chromatography (SiO2, ethyl ace-
tate-hexane 10:90), 3c was obtained as a light green oil;
yield: 199 mg (96%). The spectroscopic data (NMR)
matched those reported in the literature for ethyl 2-(4-(di-
methylamino)phenyl)acetate [CAS-No. 17078-29-4].
Ethyl 2-(4-(methylthio)phenyl)acetate (3d): Compound 3d
was synthesized according to the general procedure A from
diethyl malonate (1.0 mL, 6.6 mmol) and 4-bromothioani-
sole (203 mg, 1.00 mmol). After purification by flash column
chromatography (SiO2, ethyl acetate-hexane 5:95), 3d was
obtained as a white solid; yield: 199 mg (95%); mp 57–
588C. The spectroscopic data (NMR) matched those report-
ed in the literature for ethyl 2-(4-(methylthio)phenyl)acetate
[CAS-No. 14062-27-2].
Chemicals and solvents were either purchased (puriss p.A.)
from commercial suppliers or purified by standard tech-
niques. All reactions, if not stated otherwise, were per-
formed in oven-dried glassware containing a teflon-coated
stirrer bar and dry septum under a nitrogen atmosphere. All
reactions were monitored by GC using tetradecane as an in-
ternal standard. Response factors of the products with
regard to tetradecane were obtained experimentally by ana-
lyzing known quantities of the substances. GC analyses were
carried out using an HP-5 capillary column (phenyl methyl
siloxane, 30 mꢁ320ꢁ0.25, 100/2.3–30–300/3, 2 min at 608C,
heating rate 308CminÀ1, 3 min at 3008C). Column chroma-
tography was performed using a Combi Flash Companion-
Chromatography-System (Isco-Systems) and RediSep
packed columns (12 g). NMR spectra were obtained on
Bruker AMX 400 (400 MHz) using CDCl3 as solvent,
400 MHz and 101 MHz, respectively. Mass spectral data
were acquired on a Varian GC-MS Saturn 2100 T. Melting
points were measured on a Mettler FP 61 and infrared spec-
tra on a Perkin–Elmer Spectrum BX, FT-IR System (HeNe
633 nm<0.4 mW).
General Procedure A for the Preparation of Ethyl 2-
Arylacetates 3a–m
In an oven-dried, 20-mL Schlenk tube equipped with a
rubber cap and a stirrer bar were placed aryl halides 2a–m,
9a or 10a (1.00 mmol), bis(dibenzylideneacetone)palladi-
um(0) (0.005 mmol), tri-tert-butylphosphonium tetrafluoro-
borate (0.011 mmol), potassium phosphate (2.8 mmol), 18-
crown-6 (0.5 mmol) and diethyl malonate (6.6 mmol). The
reaction vessel was evacuated and filled with nitrogen three
times. The reaction mixture was stirred at 1608C for 8–12 h.
After the reaction was complete, the mixture was cooled to
room temperature and diluted with ethyl acetate. The result-
ing solution was washed successively with water (20 mL), sa-
turated sodium bicarbonate solution (20 mL) and brine
(20 mL), dried over MgSO4, filtered, and the solvents were
removed under vacuum. Purification of the residue by
column chromatography (SiO2, hexane/ethyl acetate gradi-
ent) gave the corresponding products 3a–m.
Ethyl 2-(4-fluorophenyl)acetate (3e): Compound 3e was
synthesized according to the general procedure A from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 1-bromo-4-fluoro-
benzene (175 mg, 110 mL, 1.00 mmol). After purification by
flash column chromatography (SiO2, ethyl acetate-hexane
5:95), 3e was obtained as a colorless oil; yield: 157 mg
(86%). The spectroscopic data (NMR) matched those re-
ported in the literature for ethyl 2-(4-fluorophenyl)acetate
[CAS-No. 587-88-2].
General Procedure B for the Preparation of Ethyl 2-
Arylacetates 3n–w
Ethyl 2-(2-ethylphenyl)acetate (3f): Compound 3f was
synthesized according to the general procedure A from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 1-bromo-2-ethylben-
zene (185 mg, 139 mL, 1.00 mmol). After purification by
flash column chromatography (SiO2, ethyl acetate-hexane
In an oven-dried, 20-mL Schlenk tube equipped with a
rubber cap and a stirrer bar were placed aryl halides 2n–w,
9p, 9s, or 9u–w (1.00 mmol), bis(dibenzylideneacetone)palla-
dium(0) (0.005 mmol), tri-tert-butylphosphonium tetrafluor-
oborate (0.011 mmol), potassium carbonate (1.5 mmol), po-
Adv. Synth. Catal. 2011, 353, 1565 – 1574
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1571

Bingrui Song et al.
FULL PAPERS
5:95), 3f was obtained as a light yellow oil; yield: 170 mg
(88%). The spectroscopic data (NMR) matched those re-
ported in the literature for ethyl 2-(2-ethylphenyl)acetate
[CAS-No. 105337-78-8].
Ethyl 2-(3-methoxyphenyl)acetate (3g): Compound 3g
was synthesized according to the general procedure A from
diethyl malonate (1.0 mL, 6.6 mmol) and 3-bromoanisole
(187 mg, 128 mL, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 10:90),
3g was obtained as a light yellow oil; yield: 180 mg (93%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(3-methoxyphenyl)acetate [CAS-
No. 35553-92-5].
Ethyl 2-(naphthalene-2-yl)acetate (3h): Compound 3h was
synthesized according to the general procedure A from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 2-bromonaphthaline
(207 mg, 1.00 mmol). After purification by flash column
chromatography (SiO2, ethyl acetate-hexane 10:90), 3h was
obtained as a light yellow oil; yield: 200 mg (93%). The
spectroscopic data (NMR) matched those reported in the
literature for ethyl 2-(naphthalene-2-yl)acetate [CAS-No.
2122-70-5].
Ethyl 2-(phenanthren-9-yl)acetate (3i): Compound 3i was
synthesized according to the general procedure A from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 9-bromophenathrene
(257 mg, 1.00 mmol). After purification by flash column
chromatography (SiO2, ethyl acetate-hexane 5:95), 3i was
obtained as a white solid; yield: 240 mg (91%); mp 83–
848C. The spectroscopic data (NMR) matched those report-
ed in the literature for ethyl 2-(phenanthren-9-yl)acetate
[CAS-No. 101723-22-2].
Ethyl 2-(thiophen-3-yl)acetate (3j): Compound 3j was
synthesized according to the general procedure A from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 3-bromothiophene
(163 mg, 94 mL, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 5:95),
3j was obtained as a light yellow oil; yield: 160 mg (94%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(thiophen-3-yl)acetate [CAS-No.
2122-70-5].
Diethyl 2,2’-(1,4-phenylene)diacetate (3k): Compound 3k
was synthesized according to the general procedure A from
diethyl malonate (1.0 mL, 6.6 mmol) and 1-bromo-4-chloro-
benzene (191 mg, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 5:95),
3k was obtained as a light yellow oil; yield: 171 mg (68%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2,2’-(1,4-phenylene)diacetate [CAS-
No. 36076-26-3].
Ethyl 2-(4-(ethoxycarbonyl)phenyl)acetate (3l): Com-
pound 3l was synthesized through an in situ esterification of
the dealkoxycarbonylative cross-coupling product according
to the general procedure A from diethyl malonate (1.0 mL,
6.6 mmol) and 4-bromobenzoic acid (201 mg, 1.00 mmol).
After purification by flash column chromatography (SiO2,
ethyl acetate-hexane 5:95), 3l was obtained as a light yellow
oil; yield: 208 mg (88%).
Compound 3l was also synthesized according to the gener-
al procedure B from diethyl malonate (1.0 mL, 6.6 mmol)
and ethyl 4-bromobenzoate (229 mg, 160 mL, 1.00 mmol) or
ethyl 4-chlorobenzoate (185 mg, 156 mL, 1.00 mmol). After
purification by flash column chromatography (SiO2, ethyl
acetate-hexane 5:95), 3l was obtained as a light yellow oil;
yield: 219 mg (93%); 208 mg (88%). The spectroscopic data
(NMR) matched those reported in the literature for ethyl 2-
(4-(ethoxycarbonyl)phenyl)acetate [CAS-No. 3516-89-0].
Ethyl 2-(4-ethoxyphenyl)acetate (3m): Compound 3m was
synthesized through an in situ etherification of the dealkoxy-
carbonylative cross-coupling product according to the gener-
al procedure A from diethyl malonate (1.0 mL, 6.6 mmol)
and 4-bromophenol (173 mg, 1.00 mmol). After purification
by flash column chromatography (SiO2, ethyl acetate-
hexane 5:95), 3m was obtained as a light yellow oil; yield:
186 mg (89%). The spectroscopic data (NMR) matched
those reported in the literature for ethyl 2-(4-ethoxypheny-
l)acetate [CAS-No. 40784-88-1].
Ethyl 2-(2,6-dimethylphenyl)acetate (3n): Compound 3n
was synthesized according to the general procedure B from
diethyl malonate (1.0 mL, 6.6 mmol) and 2-bromo-m-xylene
(185 mg, 134 mL, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 5:95),
3n was obtained as a light yellow oil; yield: 156 mg (81%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(2,6-dimethylphenyl)acetate [CAS-
No. 105337-15-3].
Ethyl 2-mesitylacetate (3o): Compound 3o was synthe-
sized according to the general procedure B from diethyl
malonate (1.0 mL, 6.6 mmol) and 2-bromomesitylene
(199 mg, 153 mL, 1.00 mmol). After purification by flash
column chromatography (SiO2, ethyl acetate-hexane 5:95),
3o was obtained as a light yellow oil; yield: 172 mg (83%).
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-mesitylacetate [CAS-No. 5460-08-
2].
Ethyl 2-(4-cyanophenyl)acetate (3p): Compound 3p was
synthesized according to the general procedure B from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 4-bromobenzonitrile
(182 mg, 1.00 mmol) or 4-chlorobenzonitrile (139 mg,
1.00 mmol). After purification by flash column chromatogra-
phy (SiO2, ethyl acetate-hexane 10:90), 3p was obtained as a
white solid; yield: 132 mg (70%); 145 mg (77%); mp 938C.
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(4-cyanophenyl)acetate [CAS-No.
1528-41-2].
Ethyl 2-(3-cyanophenyl)acetate (3q): Compound 3q was
synthesized according to the general procedure B from di-
ethyl malonate (1.0 mL, 6.6 mmol) and 3-bromobenzonitrile
(182 mg, 1.00 mmol). After purification by flash column
chromatography (SiO2, ethyl acetate-hexane 10:90), 3q was
obtained as a white solid; yield: 145 mg (77%); mp 508C.
The spectroscopic data (NMR) matched those reported in
the literature for ethyl 2-(3-cyanophenyl)acetate [CAS-No.
210113-91-0].
Ethyl 2-(4-cyano-2-methylphenyl)acetate (3r): Compound
3r was synthesized according to the general procedure B
from diethyl malonate (1.0 mL, 6.6 mmol) and 4-bromo-3-
methylbenzonitrile (200 mg, 1.00 mmol). After purification
by flash column chromatography (SiO2, ethyl acetate-
hexane 10:90), 3r was obtained as a light yellow oil; yield:
190 mg (93%). 1H NMR (400 MHz, CDCl3): d=7.49–7.41
(m, 2H), 7.28 (d, J=8.0 Hz, 1H), 4.14 (q, J=8.0 Hz, 2H),
3.65 (s, 2H), 2.33 (s, 3H), 1.23 (t, J=8.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=170.1, 138.3, 133.6, 130.9, 129.8,
118.8, 111.1, 61.2, 39.2, 19.4, 14.1; MS (70 eV): m/z (%)=
1572
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1565 – 1574

Practical Synthesis of 2-Arylacetic Acid Esters via Palladium-Catalyzed Dealkoxycarbonylative Coupling
204 (9), 203 (29) [M+], 157 (19), 131 (40), 130 (100), 129 References
˜
(20), 104 (16), 103 (37), 102 (12), 77 (23); IR (NaCl): n=
2981 (vs), 2935 (s), 2229 (vs), 1731 (vs), 1607 (m), 1569 (w),
1499 (m), 1367 (s), 1334 (s), 1256 (s), 1234 (s), 1216 (s), 1174
(s), 1162 (s), 1030 (s), 886 (w), 838 (w), 808 (w), 788 cmÀ1
(w); anal. calcd. for C12H13NO2: H 6.45, C 70.92, N 6.89;
found: H 6.61, C 70.63, N 6.56.
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Acknowledgements
We thank the DFG and Bayer CropScience for financial sup-
port, and the Studienstiftung des Deutschen Volkes, the FCI
for fellowships to Felix Rudolphi, and the DAAD and the
Bayer Science & Education Foundation for fellowships to
Bingrui Song.
Adv. Synth. Catal. 2011, 353, 1565 – 1574
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1573

Bingrui Song et al.
FULL PAPERS
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